alecensa -inn- alectinib · the final consolidated list of questions was sent to the applicant on...
TRANSCRIPT
30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom
An agency of the European Union
Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520
Send a question via our website www.ema.europa.eu/contact
15 December 2016 EMA/197343/2017 Committee for Medicinal Products for Human Use (CHMP)
Assessment report
Alecensa
International non-proprietary name: alectinib
Procedure No. EMEA/H/C/004164/0000
Note
Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.
Assessment report
EMA/197343/2017 Page 2/122
Table of contents
1. Background information on the procedure .............................................. 8
1.1. Submission of the dossier ..................................................................................... 8
1.2. Steps taken for the assessment of the product ........................................................ 9
2. Scientific discussion .............................................................................. 10
2.1. Problem statement ............................................................................................. 10
2.1.1. Disease or condition ........................................................................................ 10
2.1.2. Epidemiology .................................................................................................. 10
2.1.3. Biologic features, Aetiology and pathogenesis ..................................................... 11
2.1.4. Clinical presentation, diagnosis ......................................................................... 11
2.1.5. Management ................................................................................................... 11
2.2. Quality aspects .................................................................................................. 13
2.2.1. Introduction.................................................................................................... 13
2.2.2. Active Substance ............................................................................................. 14
Manufacture, characterisation and process controls ....................................................... 14
Specification ............................................................................................................ 15
Stability................................................................................................................... 16
2.2.3. Finished Medicinal Product ................................................................................ 17
Description of the product and Pharmaceutical development .......................................... 17
Manufacture of the product and process controls .......................................................... 18
Product specification ................................................................................................. 19
Stability of the product .............................................................................................. 19
Adventitious agents .................................................................................................. 20
2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 20
2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 20
2.2.6. Recommendation(s) for future quality development ............................................. 20
2.3. Non-clinical aspects ............................................................................................ 21
2.3.1. Introduction.................................................................................................... 21
2.3.2. Pharmacology ................................................................................................. 21
2.3.3. Pharmacokinetics ............................................................................................ 26
2.3.4. Toxicology ...................................................................................................... 29
2.3.5. Discussion on non-clinical aspects ..................................................................... 36
2.3.6. Conclusion on the non-clinical aspects ............................................................... 40
2.4. Clinical aspects .................................................................................................. 41
2.4.1. Introduction.................................................................................................... 41
2.4.2. Pharmacokinetics ............................................................................................ 41
2.4.3. Pharmacodynamics .......................................................................................... 52
Assessment report
EMA/197343/2017 Page 3/122
2.4.4. Discussion on clinical pharmacology ................................................................... 54
2.4.5. Conclusions on clinical pharmacology ................................................................. 55
2.5. Clinical efficacy .................................................................................................. 56
2.5.1. Dose response study........................................................................................ 56
2.5.2. Main studies ................................................................................................... 58
2.5.3. Discussion on clinical efficacy ............................................................................ 93
2.5.4. Conclusions on the clinical efficacy .................................................................... 96
2.6. Clinical safety .................................................................................................... 96
2.6.1. Discussion on clinical safety ............................................................................ 108
2.6.2. Conclusions on the clinical safety .................................................................... 110
2.7. Risk Management Plan ...................................................................................... 111
2.8. Pharmacovigilance ........................................................................................... 114
2.9. New Active Substance ...................................................................................... 114
2.10. Product information ........................................................................................ 115
2.10.1. User consultation ......................................................................................... 115
2.10.2. Additional monitoring ................................................................................... 115
3. Benefit-Risk Balance ........................................................................... 115
3.1. Therapeutic Context ......................................................................................... 115
3.1.1. Disease or condition ...................................................................................... 116
3.1.2. Available therapies and unmet medical need ..................................................... 116
3.1.3. Main clinical studies ....................................................................................... 116
3.2. Favourable effects ............................................................................................ 116
3.3. Uncertainties and limitations about favourable effects ........................................... 117
3.4. Unfavourable effects ......................................................................................... 117
3.5. Uncertainties and limitations about unfavourable effects ....................................... 118
3.6. Effects Table .................................................................................................... 118
3.7. Benefit-risk assessment and discussion ............................................................... 119
3.7.1. Importance of favourable and unfavourable effects ............................................ 119
3.7.2. Balance of benefits and risks .......................................................................... 120
3.7.3. Additional considerations on the benefit-risk balance ......................................... 120
3.8. Conclusions ..................................................................................................... 121
4. Recommendations ............................................................................... 121
Assessment report
EMA/197343/2017 Page 4/122
List of abbreviations
AJCC American Joint Committee on Cancer
ALK anaplastic lymphoma kinase
ALT alanine aminotransferase
AST aspartate aminotransferase
AUC area under the plasma concentration-time
curve AUC0-last area under the plasma concentration-time
curve from time 0 to the last measurable concentration
AUCinf, AUC0- area under the plasma concentration-time curve from time 0 to infinity
AUCR area under the plasma concentration-time curve ratio
AUCss,12h steady-state area under the plasma concentration-time curve from time 0 to 12 hours
BA Bioavailability
BCRP breast cancer resistance protein
BE Bioequivalence
BID twice daily
BOR best overall response
BSEP bile salt export pump
Caverage average concentration
CDOR central nervous system duration of response
CI confidence interval
CMA Critical material attribute
Cmax maximum observed plasma concentration
CNS central nervous system
CORR central nervous system objective response rate
CPK creatine phosphokinase
CPP Critical process parameter
CR complete response
CrCL creatinine clearance
CSF cerebrospinal fluid
CSR clinical study report
Css, max steady-state Cmax
Css, trough steady-state Ctrough
Ctrough pre-dose plasma concentration at the end of a dosing interval
CV coefficient of variation
DCR disease control rate
DDI drug-drug interaction
DHMA Danish Health And Medicines Authority
Assessment report
EMA/197343/2017 Page 5/122
DLTs dose limiting toxicities
DoE Design of experiments
DOR duration of response
DSC Differential Scanning Calorimetry
DVS Dynamic vapour sorption
ECG Electrocardiogram
ECOG PS Eastern Cooperative Oncology Group performance status
EGFR epidermal growth factor receptor
EMA European Medicines Agency
EML4 echinoderm microtubule associated protein-like
4
EPAR European public assessment report
ER exposure response
EU European Union
FaSSIF fasted state simulated intestinal fluid
FDA Food and Drug Administration
FeSSIF fed state simulated intestinal fluid
FMEA Failure mode effects analysis
GC-MS Gas chromatography mass spectrometry
GCP Good Clinical Practice
GI gastrointestinal
GLP Good Laboratory Practice
GMR geometric mean ratio
hERG human Ether-à-go-go-Related Gene
HGFR hepatocyte growth factor receptor
HPLC High performance liquid chromatography
HR heart rate
HS Head Space
IC Ion chromatography
IC50 50% of maximum inhibitory concentration
ICH International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use
IDR intrinsic dissolution rate
ILD interstitial lung disease
IR Infrared
IRC independent review committee
IV Intravenous
KRAS Kirsten rat sarcoma
LD Laser diffraction
LDPE Low density polyethylene
LFT liver function test
M/P metabolite to parent molar exposure ratio
M4 RO5468924
Assessment report
EMA/197343/2017 Page 6/122
MDZ Midazolam
MET mesenchymal epithelial transition factor
MPA Swedish Medical Products Agency
MRP2 multidrug resistance-associated protein 2
MTD maximum tolerated dose
NDA New Drug Application
NMR Nuclear Magnetic Resonance
NMT Not more than
NSCLC non-small cell lung cancer
OAT organic anion transporter
OATP organic anion transporting polypeptide
OCT organic cation transporter
ORR objective response rate
OS overall survival
PAR Proven Acceptable Range
PBPK physiologically based pharmacokinetic
PD Pharmacodynamic
PFS progression free survival
P-gp p-glycoprotein
PK Pharmacokinetic
PK/PD pharmacokinetic/pharmacodynamic
PO oral administration
popPK population pharmacokinetic
PPI proton pump inhibitor
PR partial response
PSD Particle Size Distribution
QbD Quality by design
QT time between the start of the Q wave and end of the T wave
QTcF QT interval corrected using Fridericia’s formula
RE response evaluable
RECIST response evaluation criteria in solid tumors
RH Relative Humidity
RON recepteur d’origine nantais
ROS1 ros proto oncogene 1
RP2D recommended phase 2 dose
RRT Relative retention time
SAE serious adverse event
SD stable disease
SLS Sodium lauryl sulfate
SmPC Summary of Product Characteristics
T1/2 half-life
TGA Thermo-Gravimetric Analysis
Assessment report
EMA/197343/2017 Page 7/122
TKI tyrosine kinase inhibitor
Tmax time to maximum observed plasma concentration
TQT thorough QT/QTc analysis
TSE Transmissible Spongiform Encephalopathy
ULN upper limit of normal
US United States
USP United States Pharmacopoeia
UV Ultraviolet
V/F apparent volume of distribution
XRPD X-Ray Powder Diffraction
XRSCD X-ray single crystal diffraction
Assessment report
EMA/197343/2017 Page 8/122
1. Background information on the procedure
1.1. Submission of the dossier
The applicant Roche Registration Limited submitted on 8 September 2015 an application for marketing
authorisation to the European Medicines Agency (EMA) for Alecensa, through the centralised procedure falling
within the Article 3(1) and point 3 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised
procedure was agreed upon by the EMA/CHMP on 26 February 2015.
The applicant applied for the following indication:
Alecensa is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive,
locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant
to crizotinib.
The legal basis for this application refers to:
Article 8.3 of Directive 2001/83/EC - complete and independent application
The application submitted is composed of administrative information, complete quality data, non-clinical and
clinical data based on applicants’ own tests and studies and/or bibliographic literature substituting/supporting
certain test(s) or study(ies).
Information on Paediatric requirements
Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA Decision(s)
CW/1/2011 on the granting of a class waiver.
Information relating to orphan market exclusivity
Similarity
Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No
847/2000, the applicant did not submit a critical report addressing the possible similarity with authorised
orphan medicinal products because there is no authorised orphan medicinal product for a condition related to
the proposed indication.
New active Substance status
The applicant requested the active substance Alectinib contained in the above medicinal product to be
considered as a new active substance, as the applicant claims that it is not a constituent of a medicinal
product previously authorised within the European Union.
Scientific Advice
The applicant received Scientific Advice from the CHMP on 20 March 2014, 25 September 2014 and 25 June
2015. The Scientific Advice pertained to insert quality, non-clinical and clinical aspects of the dossier.
Assessment report
EMA/197343/2017 Page 9/122
1.2. Steps taken for the assessment of the product
The Rapporteur and Co-Rapporteur appointed by the CHMP were:
Rapporteur: Filip Josephson Co-Rapporteur: Sinan B. Sarac
• The application was received by the EMA on 8 September 2015.
• The procedure started on 1 October 2015.
• The Rapporteur's first Assessment Report was circulated to all CHMP members on 21 December 2015.
The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 18 December
2015. The PRAC Rapporteur's first Assessment Report was circulated to all PRAC members on 05
January 2016.
• During the meeting on 28 January 2016, the CHMP agreed on the consolidated List of Questions to be
sent to the applicant. The final consolidated List of Questions was sent to the applicant on 29 January
2016.
• The applicant submitted the responses to the CHMP consolidated List of Questions on 15 July 2016.
• The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of
Questions to all CHMP members on 23 August 2016.
• During the CHMP meeting on 15 September 2016, the CHMP agreed on a list of outstanding issues to be
addressed in writing by the applicant on 19 September 2016.
• The applicant submitted the responses to the CHMP List of Outstanding Issues on 15 November 2016.
• The CHMP and PRAC Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to
the List of Questions to all CHMP and PRAC members on 30 November 2016.
• During the meeting on December 2016, the CHMP, in the light of the overall data submitted and the
scientific discussion within the Committee, issued a positive opinion for granting a conditional marketing
authorisation to Alecensa on 15 December 2016.
Assessment report
EMA/197343/2017 Page 10/122
2. Scientific discussion
2.1. Problem statement
2.1.1. Disease or condition
Alecensa as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase
(ALK) positive advanced NSCLC previously treated with crizotinib.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide and represents
a major health problem.
Anaplastic lymphoma kinase, a receptor tyrosine kinase, was first identified as a fusion protein resulting from
chromosomal translocation in the majority of anaplastic large cell lymphomas (ALCL). When fused to other
proteins, ALK becomes constitutively active, leading to increased catalytic kinase function, signal transduction
activity, and oncogenic function. ALK has since been linked with many different fusion partners in different
tumour types (Soda et al 2007).
The frequency of ALK gene rearrangements in patients with NSCLC (referred to as ALK positive NSCLC from
here onwards) is relatively low; it is present in approximately 2 to 7% of tumours tested. However,
considering the high incidence of lung cancer, this small percentage translates into about 60,000 patients
annually worldwide (Kwak et al 2010, Shaw et al 2013, Weickhardt et al 2012).
ALK+ NSCLC exhibit an inversion in chromosome 2 that juxtaposes the 5' end of the echinoderm
microtubule-associated protein-like 4 (EML4) gene with the 3' end of the ALK gene, resulting in the novel
fusion oncogene EML4-ALK. EML4-ALK fusion, and ALK fusions with other genes (Kinesin Family member 5B
[KIF5B]), KLC1 and others define a distinct clinicopathologic subset of NSCLC.
2.1.2. Epidemiology
Lung cancer has been among the most common cancers in the world for several decades. The 2012
worldwide estimates of cancer incidence and mortality by GLOBOCAN, indicate a total of 1.8 million new lung
cancer cases and 1.6 million lung cancer related deaths, accounting for 13.0% of all cancer cases (except
non-melanoma skin cancers) and 19.4% of all cancer deaths (except non-melanoma skin cancers).
Furthermore, lung cancer incidence rates were two-fold higher in males compared to females (1,241,601 and
583,100, respectively). In 2013, the estimated number of lung cancer related deaths is 159,480 in the United
States (Siegel et al 2013) and 269,610 in the European Union (Malvezzi et al 2013).
The two most prevalent sub-types of lung cancer are small cell lung cancer and non-small cell lung cancer
(NSCLC). Approximately 85% of all lung cancers are NSCLC, which is frequently further subdivided into non-
squamous carcinoma (including adenocarcinoma, large-cell carcinoma, and other cell types) and squamous
cell (epidermoid) carcinoma.
Assessment report
EMA/197343/2017 Page 11/122
2.1.3. Biologic features, Aetiology and pathogenesis
ALK gene rearrangements are largely mutually exclusive with EGFR or KRAS mutations (Gainor et al 2013),
consistent with the notion that ALK gene rearrangements defines a unique molecular subset of NSCLC. In
these patients, ALK gene rearrangements serve as a key and strong oncogenic driver for NSCLC and
represent a critical therapeutic target susceptible to targeted ALK kinase inhibition.
2.1.4. Clinical presentation, diagnosis
Patients with ‘ALK-positive’ tumours (tumours harbouring a rearranged ALK gene/fusion protein) tend to have
specific clinical features, including never or light smoking history, younger age, NSCLC with adenocarcinoma
histology, and are highly sensitive to therapy with ALK inhibitors.
2.1.5. Management
Systemic chemotherapy is a cornerstone in the management of locally advanced or metastatic NSCLC.
Standard first-line treatment typically consists of a platinum-based doublet (cisplatin or carboplatin in
combination with other chemotherapy agents), unless a patient has a known mutation, candidate for targeted
therapy (NCCN Guidelines v3.2012, Vansteenkiste et al 2013). The outcomes with this type of chemotherapy
remain poor, with response rates of 15 to 35% and median progression-free survival (PFS) and overall
survival (OS) of 4 to 7 months and 10 to 16 months, respectively (Scagliotti et al 2008, Ciuleanu et al 2009,
Ettinger et al 2010, Paz-Ares et al 2012).
Pemetrexed/cisplatin (or carboplatin) combination therapy and carboplatin/paclitaxel with (or without)
bevacizumab represent a therapeutic option in patients with advanced non-squamous NSCLC. These
regimens are commonly used based on phase III randomised trials (NCCN version 1.2015)
Recently, pemetrexed-based regimens have been used in adenocarcinomas (if patients are not candidate for
targeted therapy), because taxane-based regimens are associated with more toxicity (e.g. neurotoxicity).
The outcomes with second-line chemotherapy are dismal, with response rates of less than 10%, median PFS
of 2 to 3 months, and median OS of 5 to 8 months (Shepherd et al 2000, Fossella et al 2000, Hanna et al
2004).
The ALK-fusion protein is an appropriate target for the treatment of patients with NSCLC harboring ALK gene
rearrangements as demonstrated in nonclinical NSCLC models and in clinical trials with crizotinib and
ceritinib, both of which have received marketing authorization in ALK-positive NSCLC in the EU in 2012 and
2015, respectively.
Crizotinib, an inhibitor of receptor tyrosine kinases including ALK, hepatocyte growth factor receptor (HGFR or
hepatocyte growth factor receptor [c-Met]), recepteur d’origine nantais (RON) and ROS proto-oncogene 1
(ROS1), was the first approved TKI for the treatment of ALK-positive NSCLC. In the EU, crizotinib received
conditional approval for patients with previously treated, ALK-positive, advanced NSCLC (Xalkori SmPC).
Assessment report
EMA/197343/2017 Page 12/122
About the product
Alectinib is a highly selective and potent ALK and RET tyrosine kinase inhibitor. In preclinical studies,
inhibition of ALK tyrosine kinase activity led to blockage of downstream signalling pathways including STAT 3
and PI3K/AKT and induction of tumour cell death (apoptosis).
Alectinib demonstrated in vitro and in vivo activity against mutant forms of the ALK enzyme, including
mutations responsible for resistance to crizotinib. The major metabolite of alectinib (M4) has shown similar in
vitro potency and activity.
Treatment with Alectinib should be initiated and supervised by a physician experienced in the use of
anticancer medicinal products.
A validated ALK assay is necessary for the selection of ALK-positive NSCLC patients. ALK-positive NSCLC
status should be established prior to initiation of Alectinib therapy.
The recommended dose of Alectinib is 600 mg (four 150 mg capsules) taken twice daily with food (total daily
dose of 1200 mg).
Treatment with Alectinib should be continued until disease progression or unacceptable toxicity.
If a planned dose of Alectinib is missed, patients can make up that dose unless the next dose is due within
6 hours. Patients should not take two doses at the same time to make up for a missed dose. If vomiting
occurs after taking a dose of Alectinib, patients should take the next dose at the scheduled time.
Management of adverse events may require dose reduction, temporary interruption, or discontinuation of
treatment with Alectinib. The dose of Alectinib should be reduced in steps of 150 mg twice daily based on
tolerability. Alectinib treatment should be permanently discontinued if patients are unable to tolerate the
300 mg twice daily dose.
Dose modification advice is provided in Tables 1 and 2 below.
Table 1 Dose reduction schedule
Dose reduction schedule Dose level
Starting dose 600 mg twice daily
First dose reduction 450 mg twice daily
Second dose reduction 300 mg twice daily
Table 2 Dose modification advice for specified Adverse Drug Reactions (see sections 4.4 and 4.8)
CTCAE grade Alectinib treatment
ILD/pneumonitis of any severity grade Immediately interrupt and permanently discontinue Alectinib if no other potential causes of ILD/pneumonitis have been identified.
ALT or AST elevation of Grade ≥ 3 (> 5 times ULN) with total bilirubin 2 times ULN
Temporarily withhold until recovery to baseline or Grade 1 (≤ 3 times ULN), then resume at reduced
dose (see Table 1).
ALT or AST elevation of Grade ≥ 2 (> 3 times ULN) with total bilirubin elevation > 2 times ULN in the absence of cholestasis or haemolysis
Permanently discontinue Alectinib.
Bradycardiaa Grade 2 or Grade 3 (symptomatic, may be severe and medically significant, medical intervention indicated)
Temporarily withhold until recovery to Grade 1
(asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm. Evaluate concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive medicinal products. If a contributing concomitant medicinal product is
Assessment report
EMA/197343/2017 Page 13/122
identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to Grade 1
(asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm. If no contributing concomitant medicinal product is identified, or if contributing concomitant medicinal products are not discontinued or dose modified, resume at reduced dose (see Table 1) upon recovery to ≤ Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm.
Bradycardiaa Grade 4 (life-threatening consequences, urgent intervention indicated)
Permanently discontinue if no contributing concomitant medicinal product is identified. If a contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, resume at reduced dose (see Table 1) upon recovery to Grade 1 (asymptomatic) bradycardia or to a heart
rate of ≥ 60 bpm, with frequent monitoring as clinically indicated. Permanently discontinue in case of recurrence.
CPK elevation > 5 times ULN Temporarily withhold until recovery to baseline or to ≤ 2.5 times ULN, then resume at the same dose.
CPK elevation > 10 times ULN or second occurrence of CPK elevation of > 5 times ULN
Temporarily withhold until recovery to baseline or to ≤ 2.5 times ULN, then resume at reduced dose as per Table 1.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; CTCAE = NCI Common Terminology
Criteria for Adverse Events; ILD = interstitial lung disease; ULN = upper limit of normal
a Heart rate less than 60 beats per minute (bpm).
2.2. Quality aspects
2.2.1. Introduction
The finished product is presented as hard capsules containing 150 mg of alectinib hydrochloride as active
substance.
Other ingredients are:
Capsule content: lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate,
carmellose calcium;
Capsule shell: hypromellose, carrageenan, potassium chloride, titanium dioxide (E171), maize starch,
carnauba wax;
Printing ink: red iron oxide (E172), yellow iron oxide (E172), indigo carmine aluminum lake (E132), carnauba
wax, white shellac, glyceryl monooleate.
The product is available in aluminium/aluminium perforated blisters as described in section 6.5 of the SmPC.
Assessment report
EMA/197343/2017 Page 14/122
2.2.2. Active Substance
General information
The chemical name of alectinib hydrochloride (HCl) is 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-
yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride corresponding to the molecular
formula C30H35ClN4O2. It has a relative molecular mass of 519.08 g/mol and the following structure:
Figure 1. Chemical structure of alectinib hydrochloride.
The active substance is an achiral molecule. Its molecular structure has been confirmed by elemental
analysis, IR, NMR (1H and 13C) and UV spectroscopy, and mass spectrometry.
Alectinib HCl is a white to yellow white powder or powder with lumps. The pKa value is 7.05 for the free base
form. It is slightly hygroscopic and has low solubility in aqueous buffers across the pH range. Therefore
particle size is a critical material attribute and it is controlled in the active substance specification. The higher
solubility observed in fed state simulated intestinal fluid (FeSSIF) than in fasted state simulated intestinal
fluid (FaSSIF), suggests a potential food effect (see clinical section).
Alectinib HCl exhibits polymorphism. Multiple crystalline solid forms were identified in screening studies. An
amorphous form of alectinib HCl was also observed. The forms have been studied by differential scanning
calorimetry (DSC), X-ray powder diffraction (XRPD), dynamic vapour sorption (DVS), X-ray single crystal
diffraction (XRSCD) and thermogravimetric analysis (TGA). Alectinib HCl Form I has been confirmed to be the
thermodynamically stable solid form under ambient conditions and was the form selected for development
and commercial use. Form I is consistently produced by the proposed commercial manufacturing process and
does not change upon storage. Although formation of an amorphous fraction can occur during milling of
alectinib HCl, it is controlled to acceptable levels by the milling process (see manufacture section).
Manufacture, characterisation and process controls
Alectinib HCl active substance is manufactured through a six-step synthesis from four starting materials
which are controlled by acceptable specifications. This is followed by a seventh process step in which the
active substance is milled to achieve desired particle size distribution.
The process has been described in detail (e.g. details of order of charging, amounts of ingredients, agitation,
temperatures and in-process controls). Adequate in-process controls are applied during the synthesis. The
specifications and control methods for intermediate products, starting materials and reagents have been
presented.
The characterisation of the active substance and its impurities are in accordance with the EU guideline on
chemistry of new active substances. Potential and observed impurities (including related substances,
genotoxic compounds, reagents, solvents and elemental impurities) have been discussed for each step of the
Assessment report
EMA/197343/2017 Page 15/122
synthesis in relation to their origin, occurrence, possible fate products and purging capacity of the
manufacturing process. All introduced materials for the manufacture of alectinib as well as compounds
formed and having the possibility to be formed during manufacture or during storage, have been screened for
genotoxicity structures using in silico evaluation of structures (using two complementary (Q)SAR
mutagenicity prediction methods (DEREK and MultiCase)), chemical reasoning, and analytical testing. These
include the starting materials and their impurities (observed and potential), reagents, solvents, process
intermediates, potential degradation products, and reasonably expected reaction by-products involved in the
synthesis of alectinib HCl. Several compounds were identified as genotoxic or potentially genotoxic. The
potential for carry-over of these impurities was evaluated. It was demonstrated that the highest carry-over
level is well below the ICH M7 LTL limit (LT 1-10 years) for individual mutagenic impurities. Batch analyses
for the key impurities corroborating the efficient purge of these impurities in the manufacturing process have
been presented. In addition, during commercial manufacture, each key impurity is controlled with an
acceptable specification. Overall, the carry-over and purging studies performed have led to an acceptable
control strategy for these compounds.
Risk assessments were performed to determine the impact of material and process inputs. These were
followed by an FMEA (Failure Mode Effect Analysis) exercise to determine critical process parameters (CPPs)
and a final risk assessment to summarize quality attribute/process parameter functional relationships and
finalize the specifications for starting materials and isolated intermediates. The specifications for all materials
used during the manufacturing process have been provided and are considered satisfactory. Critical material
attributes and CPPs have been identified and are included in the control strategy. Rationales supporting the
commercial process and proven acceptable ranges (PARs) (with indication of targets) have been described
and justified based in development results.
As mentioned above, Form I is consistently produced by the commercial manufacturing process. Formation
of an amorphous fraction can occur during milling of alectinib HCl (Form I). The particle size distribution and
the amorphous content in the milled alectinib HCl are controlled by the milling process. It has been
demonstrated that the amorphous content is adequately controlled when the process is operated within the
established PARs. The available development data, the proposed control strategy and batch analysis data
from commercial scale batches fully support the proposed PARs.
The amorphous content, at levels formed during the milling process, was demonstrated to have no
impact on in vitro dissolution.
The polymorphic form of alectinib HCl is qualitatively confirmed at release by the XRPD identity
test included in the active substance specification. Stability studies also confirmed that Form I is
chemically stable when stored under accelerated and long term conditions (see stability section).
The active substance is packaged in double LDPE-bag in a heat sealed aluminium bag which complies with the EC directive EC 10/2011 as amended and Ph. Eur. 3.1.4.Specification
The active substance specification includes tests for description (colour, appearance-visual), identification
(IR, XRPD, IC), related substances (HPLC), assay (HPLC), hydrogen chloride (IC), water content (KF),
residual solvents (HS GC-MS, IC), residue on ignition (Ph Eur), particle size distribution (LD), microbial
quality (Ph Eur).
The specification has been established based on recommendations in ICH Q3A (R2), Q3C (R5), Q3D, Q6A,
and M7; consideration of analytical data from development and commercial (for Japanese market) batches of
alectinib HCl; and stability data for the primary batches. The acceptance criteria, as well as the rationale for
Assessment report
EMA/197343/2017 Page 16/122
inclusion or exclusion of individual tests have been provided in the dossier and are considered acceptable.
The levels of residual solvents are set in accordance with ICH Q3C. A fluorinated solvent used in the
manufacturing process is not ICH classified. The specification limit established for this solvent was derived
from toxicological studies based on an acceptable daily exposure (ADE) of 50 g using published data from
the European Chemical Agency (ECHA) database.
The specification for the particle size distribution (PSD) of alectinib HCl was based on representative batches
of milled drug substance, knowledge of the relationship between PSD of the drug substance and in vitro
dissolution performance of the finished product, stability results for the PSD, and manufacturing
considerations.
A justification for not including amorphous content in the active substance specification was provided and was
accepted.
The omission of elemental impurities in the active substance specification was justified in line with ICH
Q3D.The analytical methods used have been adequately described and (non-compendial methods)
appropriately validated in accordance with the ICH guidelines. Satisfactory information regarding the
reference standards used for assay testing has been presented.
Batch analysis data from 21 pilot and commercial scale batches of the active substance manufactured by the
intended manufacturers according to the commercial synthetic route has been provided. These batches were
used for development, commercial (for Japanese market), primary stability, clinical and toxicology studies.
The results are within the specifications and consistent from batch to batch.
Stability
Stability data on three commercial scale batches of active substance from the proposed manufacturers stored
in a container closure system representative of that intended for the market for 12 months under long term
conditions at 30 ºC / 75% RH and for 6 months under accelerated conditions at 40 ºC / 75% RH according to
the ICH guidelines were provided. Supportive stability data from one commercial scale batch stored for 24
months at 25°C / 60%RH and for 6 months at 40°C / 75%RH was also provided.
The following parameters were tested: description, identification (XRPD), related substances, assay,
hydrogen chloride, water content, ethyl chloride, PSD and microbial quality. The batches have been analysed
with the same methods as those proposed for release testing, except for XRPD and PSD testing for which
older methods were used.
The long term and accelerated data provided confirms the stability of the drug substance at the studied
conditions. Apart for a yellowing of the powder with time, no significant changes were seen for any
parameter. All samples remained within the proposed acceptance criteria when stored at both long term and
accelerated conditions.
Photostability testing following the ICH guideline Q1B was performed on one batch. Samples were tested for
appearance, identification (XRPD), related substances, water content and assay. The photostability sample
showed an increase in degradation products with a decrease in the assay. Yellowing was observed in the
exposed sample. Other tests (XRPD and water content) did not show any significant change. Therefore it was
concluded that the active substance should be protected from light by its container closure system.
Samples were also exposed to stress conditions (elevated temperature, elevated temperature and humidity,
acidic and basic conditions, and oxidative conditions) Several degradation products were observed. The
Assessment report
EMA/197343/2017 Page 17/122
results The results from these studies demonstrate the stability indicating nature of the release HPLC
method.
The stability results justify the proposed retest period and storage conditions
2.2.3. Finished Medicinal Product
Description of the product and Pharmaceutical development
The proposed commercial formulation is an immediate release hard capsule for oral administration containing
150 mg of alectinib (as hydrochloride) and standard excipients. The capsules are size 1, white, with “ALE”
printed in black ink on the cap and “150 mg” printed in black ink on the body. They are packaged in
aluminium/aluminium perforated blisters. The composition of the capsules is presented in section 6.1 of the
SmPC and in chapter 2.2.1 of this report.
Different formulations were used during clinical studies. Two dosage strengths, 20 mg and 40 mg, were
initially developed for first-in-human study. Since a dose of 600 mg twice a day was clinically required, a
higher strength capsule for Phase II and Phase III studies was developed to reduce the number of capsules
needed to achieve higher doses and increase patient compliance and convenience. This resulted in a 150 mg
capsule formulation which was designed to match the dissolution characteristics of the initial 40 mg capsule.
Comparable release characteristics of the 40 mg capsule and the proposed 150 mg formulation was
demonstrated by the in vitro dissolution studies. The proposed 150 mg formulation was used in the Phase
I/II studies NP28673 (global) and NP28761 (US and Canada), and the ongoing global Phase III study
BO28984.
The development of the product followed a classic development approach and adopted elements of Quality by
Design (QbD) and risk-based methodology.
As described above, alectinib is a poorly water soluble free base with a measured pKa of 7.05. The mono HCl
salt (Form I) was selected for development based on higher solubility in comparison to other salts and
maximum absorbable dose. To enhance dissolution performance, the active substance is milled and the
particle size distribution is controlled. Form I is the only solid form used in non-clinical (toxicological) and
clinical studies conducted throughout development. Form I is consistently produced by the commercial drug
substance manufacturing process. A small amount of amorphous content has been observed in the milled
drug substance, which was shown to have a negligible impact on clinical bioavailability. The amount of
amorphous content is controlled by the milling process parameters to acceptable levels.
The excipients examined during formulation development were selected based on prior use in approved
products manufactured by wet granulation and the physicochemical properties of the active substance. These
were evaluated regarding compatibility. The results indicated that alectinib HCl was compatible with all of the
excipients tested.
Potential excipients were also screened for their suitability to increase the active substance solubility and
possibly in vivo exposure for alectinib HCl. Sodium lauryl sulfate (SLS) showed significantly higher solubility
enhancement compared to the other excipients and was selected as wetting agent. Based on early in vitro
dissolution studies the level of SLS in the dosage form was selected for clinical formulations. This results in a
total daily intake of 600 mg of SLS at the efficacious dose of alectinib (600 mg twice a day [BID]), which is
higher than the amount included in medicinal products approved within the EU. The safety concerns
Assessment report
EMA/197343/2017 Page 18/122
regarding the proposed high amount of SLS were discussed with the applicant as part of a scientific advice
procedure (see non-clinical section). The applicant was advised to reduce the amount of SLS in the
formulation proposed for marketing. In order to explore the possibility of alternate formulations with lower
SLS content, the applicant conducted a bioequivalence study (NP29040) to compare the clinical formulation
proposed for commercial use (alectinib hard capsules, 150 mg with 50% SLS) and three lower SLS
formulations (see clinical section). In order to reduce the intake of SLS, the applicant has been
recommended to introduce an alternative capsule formulation for oral administration containing a lower
amount of SLS post-approval.
From the polymers investigated the binder hydroxypropylcellulose (HPC) was selected Lactose monohydrate
is added as a water-soluble diluent. Carboxymethylcellulose calcium was selected as disintegrant. Magnesium
stearate is used as a lubricant at a level typical in solid dosage formulations. The list of excipients included in
the commercial formulation is included in section 6.1 of the SmPC and in paragraph 2.1.1 of this report.
All excipients are well known pharmaceutical ingredients and their quality is compliant with Ph. Eur
standards. There are no novel excipients used in the finished product formulation.
The discriminatory power of the dissolution method has been demonstrated with regard to different critical
material attributes, CPPs and the effect of stressed storage conditions.
The manufacturing process involves conventional pharmaceutical operations: sieving and blending of drug
substance and internal phase excipients, high-shear wet granulation, wet sieving, fluid-bed drying, dry
sieving, blending of the dried granules and external phase excipients and encapsulation. Early process
development was based on informal risk assessments to identify potential CPPs and potential CMAs, which
served to guide subsequent experimental studies. As mentioned above, the active substance particle size
distribution was found to have a strong effect on dissolution and therefore it is controlled by a milling process
and a specification was established to ensure a satisfactory dissolution performance. With regards to the
process parameters, the higher-shear wet granulation step is the most critical process steps that impacts
product quality and manufacturability.
The primary packaging is aluminium/aluminium perforated blisters. The material complies with Ph.Eur. and
EC requirements. The choice of the container closure system has been validated by stability data and is
adequate for the intended use of the product.
Manufacture of the product and process controls
The finished product is manufactured using conventional pharmaceutical wet granulation and drying
processes. Specifically, the manufacturing process consists of nine main steps: sieving, blending, wet
granulation, wet sieving, drying, dry sieving, blending, encapsulation and packaging. The process is
considered to be a standard manufacturing process. Optimisation of the manufacturing process was
performed based on experience gained from risk assessments and DOE studies.
The in-process controls, frequency of testing, and acceptance criteria for the capsules are adequate for this
type of manufacturing process.
Six process evaluation batches were manufactured to confirm the proposed control strategy and to
demonstrate the reproducibility and robustness of the manufacturing process. These batches were
manufactured at commercial production scale at the proposed commercial manufacturing site. Three
registration batches were manufactured during process development prior to the manufacture of the process
evaluation batches, also at full commercial scale, for stability evaluation and batch analyses. It has been
Assessment report
EMA/197343/2017 Page 19/122
demonstrated that the manufacturing process is capable of producing the finished product of intended quality
in a reproducible manner.
Product specification
The specifications for the drug product at release and shelf-life has been established based on ICH Q3B (R2),
Q6A and M7 requirements, taking into consideration analytical data from clinical and primary stability batches
at release and during stability studies, as well as the USP, Ph. Eur. and JP monographs for capsules.
The finished product release and shelf-life specifications include appropriate tests for this kind of dosage
form. They include: description (visual), description of capsule content (visual), identification of alectinib
hydrochloride (HPLC, IR), content per capsule (HPLC), degradation products (GC-MS, HPLC), uniformity of
dosage units (Ph Eur), dissolution (HPLC), microbial limits (Ph Eur) and water content (KF). The finished
product is released on the market based on the above release specifications, through traditional final product
release testing.
Although the product is formulated as an immediate-release dosage form, the active substance has low
solubility across the entire physiological pH range (pH 2.0–6.8). Therefore a two-point dissolution
specification has been established. The dissolution specification time points and Q values were established
based on statistical analysis of the dissolution data of representative finished product batches at release and
stability.
The analytical methods used have been adequately described and appropriately validated in accordance with
the ICH guidelines. Satisfactory information regarding the reference standard used for assay testing has been
presented.
Batch analysis results are provided for 35 batches confirming the consistency of the manufacturing process
and its ability to manufacture to the intended product specification. These correspond to 6 pilot scale batches
and 3 primary stability batches manufactured at the proposed commercial manufacturing site; and 26
development and clinical batches manufactured at an alternative site.
Stability of the product
Stability data of three commercial scale batches of finished product stored under long term conditions for 24
months at 30°C / 75% RH and for up to 6 months under accelerated conditions at 40 ºC / 75% RH according
to the ICH guidelines were provided. The stability batches are representative of those proposed for marketing
and were packed in the primary packaging proposed for marketing.
Samples were tested for appearance (description of capsules and capsule content), identification of alectinib
HCl (by IR), content per capsule of alectinib HCl (by HPLC), degradation products, dissolution, microbial limits
and water content according to the specification presented above.
All parameters remained within specification during the stability testing at all storage conditions. No
significant changes were observed.
In addition, one batch was exposed to light as per the ICH Guideline on Photostability Testing of New Drug
Substances and Products. Results demonstrated that the finished product is not light sensitive.
Based on available stability data, the proposed shelf-life of 2 years with the storage instructions “store in the
original package in order to protect from moisture” as stated in the SmPC (section 6.3) is acceptable.
Assessment report
EMA/197343/2017 Page 20/122
Adventitious agents
Apart from lactose monohydrate, no other excipients derived from animal or human origin have been used.
It is confirmed that the lactose is produced from milk from healthy animals in the same condition as those
used to collect milk for human consumption and that the lactose has been prepared without the use of
ruminant material other than calf rennet according to the Note for Guidance on Minimising the Risk of
Transmitting Animal Spongiform Encephalopathy Agents Via Human and veterinary medicinal products.
2.2.4. Discussion on chemical, pharmaceutical and biological aspects
Information on development, manufacture and control of the active substance and finished product has been
presented in a satisfactory manner. The active substance has low aqueous solubility across the pH range.
Therefore, suitable specifications for particle size distribution of the drug substance and in vitro dissolution
have been established to ensure drug product performance. Alectinib HCl Form I is consistently produced by
the proposed commercial manufacturing process. Although formation of an amorphous fraction can occur
during milling of alectinib HCl (Form I), the level of amorphous content is suitably controlled by the milling
process parameters to ensure dissolution performance.
In order to increase the solubility of alectinib HCl, the anionic surfactant SLS is used as a wetting agent in the
formulation. The recommended daily dose of Alecensa is 1200 mg (4 capsules twice a day). This results in a
daily intake of SLS of 600 mg, which is higher than approved medicines in the EU. Although at present the
benefit/risk is positive, the applicant is recommended to introduce an alternative formulation containing a
lower amount of SLS post-approval.
The results of tests carried out indicate consistency and uniformity of important product quality
characteristics, and these in turn lead to the conclusion that the product should have a satisfactory and
uniform performance in clinical use.
2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects
The quality of this product is considered to be acceptable when used in accordance with the conditions
defined in the SmPC. Physicochemical and biological aspects relevant to the uniform clinical performance of
the product have been investigated and are controlled in a satisfactory way. Data has been presented to give
reassurance on TSE safety.
2.2.6. Recommendation(s) for future quality development
In the context of the obligation of the MAHs to take due account of technical and scientific progress, the
CHMP recommends the following points for investigation:
The applicant is recommended to introduce an alternative capsule formulation for oral administration
containing a lower amount of SLS post-approval.
Assessment report
EMA/197343/2017 Page 21/122
2.3. Non-clinical aspects
2.3.1. Introduction
2.3.2. Pharmacology
Primary pharmacodynamic studies
In an enzyme assay, alectinib inhibited ALK with an IC50 of 1.9 nM. In addition RET is inhibited with an IC50 of
4.8 nM. No kinase inhibitory effect was seen with a large panel of other tyrosine kinases. This is in contrast to
other ALK inhibitors like crizotinib and ceritinib which show relevant activity at several unrelated kinases.
(CH5424802=alectinib, LDK378=ceretinib)
IC50 (nmol/L)
ALKRETINSR
KDRROS1
ABL
EGFRFGFR2
HER2IGF1R
JAK1
KITMET
PDGFRβRON
SRC
Akt1 Aurora A
CDK1CDK2
MEK1
PKAPKCα
PKCβ1PKCβ2
Raf-1
1101001000 1101001000
ALKRETINSR
KDRROS1
ABL
EGFRFGFR2
HER2IGF1R
JAK1
KITMET
PDGFRβRON
SRC
Akt1 Aurora A
CDK1CDK2
MEK1
PKAPKCα
PKCβ1PKCβ2
Raf-1
1101001000
ALKRETINSR
KDRROS1
ABL
EGFRFGFR2
HER2IGF1R
JAK1
KITMET
PDGFRβRON
SRC
Akt1 Aurora A
CDK1CDK2
MEK1
PKAPKCα
PKCβ1PKCβ2
Raf-1
CH5424802 Crizotinib LDK378
Table 1: Kinase Selectivity of Alectinib compared to Crizotinib and LDK378
The antiproliferative effect of alectinib was investigated in a number of cell lines, including NSCLC,
lymphoma, and neuroblastoma cell lines. These experiments included cell lines with wild-type ALK, ALK
fusion proteins, ALK amplification, ALK mutation, and ALK deletion.
Table 2: Growth Inhibitory Activity of Alectinib on Human NSCLC, Lymphoma and Neuroblastoma Cell Lines with Gene Alterations of ALK
Tumor type Cell line ALK status IC50 (nM)
NSCLC NCI-H2228 EML4-ALK 12 PC-9 WT 400 NCI-H1993 WT >1,000 A549 WT >1,000
Lymphoma KARPAS-299 NPM-ALK 14 SR NPM-ALK 14 U-937 ALK Negative >1,000
Neuroblastoma NB-1 Gene amplification 4.5 KELLY F1174L 62 SK-N-FI WT >10,000
Assessment report
EMA/197343/2017 Page 22/122
Cells were seeded and cultured overnight, and then treated with alectinib for four or five days. Cell growth was measured using the WST-8
or CellTiter-Glo assays, and the IC50 values were calculated.
Alectinib also showed activity against ALK point mutations associated with acquired crizotinib resistance. The
IC50 for these kinases varied between 2-fold lower to 20-fold higher than for native ALK. Alectinib inhibited
the growth of tumor cell lines where ALK activation is due to the formation of a fusion protein (EML4-ALK). A
comparison of the in vitro anti-tumor activity between alectinib and crizotinb was performed with number of
murine Ba/F3-derived cell lines expressing different EML4-ALK mutants (see the following figure and table).
CH5424802 Crizotinib
A B
Ba/F3 parental cell line and Ba/F3 cell lines expressing native or mutated EML4-ALK
were treated with alectinib (CH5424802) (A) or crizotinib (B) for 2 days. Cell viability was analyzed by CellTiter-Glo® Luminescent Cell Viability Assay. Data are shown as mean ± SD (n = 3). Table 3: Anti-Tumour activity of Alectinib or Crizotinib in Ba/F3 Cell Lines Expressing Native and Mutated EML4-ALK
A comparison of the inhibitory activity of alectinib vs crizotinib for unmutated and mutated ALK was
conducted in vitro (Study 1061439). The following table shows the IC50 values for the decrease in cell
viability. In this table are also shown the ratios where the IC50 value with the mutant ALK is divided with the
IC50 value for the WT ALK – thus representing how much each mutant affects the activity of the two ALK
inhibitors.
Table 4: Inhibitory activity of alectinib and crizotinb against Ba/F3 cell lines expressing native and mutated AML4-ALK
Error! Objects cannot be created from editing field codes.
The in vivo anti-tumor effect of alectinib was studied in mouse xenograft models. Alectinib strongly inhibited
the growth of the EML4-ALK expressing cell line NCI-H228 with tumour regression observed from 6
mg/kg/day.
Table 5: Anti-Tumour Effect of Alectinib in NCI-H2228 and A549 Xenografts
Assessment report
EMA/197343/2017 Page 23/122
Cell line Dose (mg/kg/day) TGI (%) P value
NCI-H2228 0.2 34 0.4078
0.6 47 0.0947
2 84 0.0004
6 147 < 0.0001
20 168 < 0.0001
A549 2 < 1 1.0000
6 22 0.5448
20 31 0.2874
Mice bearing NCI-H2228 (A, human NSCLC cell line harboring EML4-ALK) and A549 (B, human NSCLC cell line with wild-type ALK) were administered alectinib (free base) orally once daily for 11 days at the indicated doses. TGI = Tumor growth inhibition
In a further set of studies, crizotinib-resistant EML4-ALK mutants, expressed in the murine Ba/F3 cell line
were implanted subcutaneously in mice, and the anti-tumor effect of alectinib and crizotinib was studied.
Alectinib at 60 mg/kg inhibited the growth of many of these mutants, where crizotinib at 100 mg/kg was
without effect.
0
200
400
600
800
1000
10 17
Tu
mo
r vo
lum
e (m
m3)
Days after tumor implantation
0
200
400
600
800
1000
10 17
Tu
mo
r vo
lum
e (m
m3)
Days after tumor implantation
0
200
400
600
800
1000
7 14
Days after tumor implantation
0
200
400
600
800
10 17
Days after tumor implantation
0
200
400
600
800
1000
10 17
Days after tumor implantation
Vehicle
CH5424802
Crizotinib
G1269A G1202R
1151Tins F1174L S1206Y
***
******
***
N.S.
N.S.
N.S.
N.S.
N.S.
**
Table 6: Anti-tumour activity of Alectinib against EML4-ALK mutant-driven tumours in a subcutaneous mouse model
In a CNS tumour model, with NCI-H228 cells injected intracranially in mice, alectinib significantly prolonged
survival compared to crizotinib.
Assessment report
EMA/197343/2017 Page 24/122
0
20
40
60
80
100
0 20 40 60 80 100 120
Days after implantation
Su
rviv
al r
ate
(%
)
Vehicle
N=5
Crizotinib
N=5
CH5424802
N=4
Treatment
Day20-45
NCI-H2228 cells were injected intracranially into mice at 4 x 105 cells/mouse. Starting 20 days after implantation, mice
were treated with control vehicle (closed circle), alectinib (60 mg/kg/day, free base; open square), or crizotinib (100
mg/kg/day; open triangle) once daily from Day 20 to 45 or until death.
Table 7: Survival Rate of Mice Treated with either Crizotinib or Alectinib in an Intracerebral NCI-H2228 Implantation Model
In a second model using tumour cells expressing the luciferase gene and bioluminescence as readout,
Alectinib showed anti-tumor activity in the brain against these tumors, while crizotinib did not.
The main human metabolite, M4 was determined to have an IC50 of 1.2 nM against human recombinant ALK,
equivalent to that of alectinib (IC50 of 1.9 nM). Moreover, M4 was also tested in enzyme assays against ALK
mutations associated with crizotinib resistance, and found to have similar inhibition to the parental molecule,
alectinib. The kinase selectivity of M4 was also explored in an enzyme assay against various protein kinases,
and found to be very similar to alectinib. The growth inhibiting activity of M4 was also evaluated using EML4-
ALK fusion-positive cell line NCI-H2228. M4 inhibited growth of the NCI-H2228 cell line with an IC50 of 37
nM, which is in the same range as that for alectinib (IC50 of 12 nM)..
Secondary pharmacodynamic studies
In vitro screening assays investigated the effects of a single concentration of alectinib (10 μM, 4826 ng/mL)
on ligand binding to 109 types of receptors, ion channels and transporters, and on the activity of 42 types of
enzymes. The results of these assays showed that at concentrations far exceeding the clinically relevant free
exposure (by ~690 fold), alectinib had an inhibitory effect of >50% on ligand binding (peripheral
benzodiazepine receptors, dopamine receptors, muscarinic receptors, neurokinin receptors, serotonin
receptors, sigma [σ] receptors, glucocorticoid receptors, urotensin receptors, L-type Ca2+ channels, Cl -
channels, serotonin transporters, norepinephrine transporters, dopamine transporters) and enzyme activity
(CaMK2α).
Functional assays were then performed on the basis of the outcomes of these binding assays. The functions
of 20 receptors expressed in cells and the synaptosomal uptake of 2 types of monoamines (norepinephrine
and dopamine) in rats were evaluated at 2 concentrations (1 and 10 μM, 482.6 and 4826 ng/mL). The
receptors evaluated included those with ligand binding inhibited by alectinib, namely dopamine, muscarine,
neurokinin, serotonin, and urotensin receptors that could be tested with functional assays. > 50% inhibition
of synaptosomal uptake of norepinephrine and dopamine occurred at a concentration of 1 μM (53% and 83%,
Assessment report
EMA/197343/2017 Page 25/122
respectively). At 10 μM, % inhibition of uptake was 49% for dopamine and 43% for norepinephrine. For
serotonin, >50% inhibition of serotonin receptor 5-HT2B activity was observed at 10 μM (82%). No other
receptor functions were affected.
To further investigate the inhibitory action seen in these functional assays, inhibition of synaptosomal uptake
of serotonin, norepinephrine, and dopamine was examined at concentrations of 10-3 to 1 μM. The IC50s of
serotonin, norepinephrine, and dopamine uptake were determined to be 0.10, 0.33, and 0.26 μM (48.3,
159.3, and 125.5 ng/mL), respectively, which corresponds to 7- to 22-fold the human relevant free exposure
of approximately 7 ng/mL.
Safety pharmacology programme
Cardiovascular
Alectinib blocked hERG currents with an IC20 of 0.12 μM (58 ng/mL) and an IC50 of 0.45 μM (217 ng/mL).
These concentrations are approximately 8- to 30-fold the anticipated free clinical Cmax of ~7 ng/mL at 600
mg BID. Alectinib has the potential to block the voltage-dependent Cav1.2 channel with an IC20 of 0.203 μM
(98 ng/mL) and an IC50 of 0.461 μM (222 ng/mL)
An exploratory cardiovascular safety pharmacology study was performed in monkeys. At 20 and 60 mg/kg
(group mean Cmax on first dosing day: 719 and 695 ng/mL, respectively; data taken from Day 1 of the 2-
week repeat-dose monkey study), a slight hypotensive effect (approximately -10 mm Hg) was seen, but
there were no effects on the ECG or heart rate. The hypotension occurring after the 20 mg/kg dose resolved
approximately 22 hours after dosing, whereas after the 60 mg/kg dose, it persisted at least until the end of
the recording period (24 hours), showing dose dependence mainly in duration of effect.
A GLP cardiovascular study was performed in monkeys with ascending doses of 1.7, 5, and 15 mg/kg
alectinib. No effects on the cardiovascular system or body temperature were seen at any dose up to
15 mg/kg (4-hour postdose mean plasma drug concentration: 279 ng/mL). Based on these findings, the
NOEL for the hypotension seen in the exploratory telemetry study was deemed to be 15 mg/kg.
To elucidate the mechanism responsible for the alectinib-induced hypotension seen in the exploratory study
of telemetered monkeys, the effects of alectinib (free base) on vasoconstriction of isolated rat aorta induced
by a high-concentration potassium solution were evaluated using Magnus' method. Alectinib inhibited the
vasoconstriction induced by the high-concentration potassium solution with an IC20 of 0.0153 μM (7.38
ng/mL, reaching the free clinical exposure range and the free concentration in the exploratory telemetry
study) and an IC50 of 0.168 μM (81.1 ng/mL). This vasodilatory effect was considered the cause of the
hypotension seen in cynomolgus monkeys
CNS
To investigate the effects of alectinib on the CNS, a single dose of the vehicle (10% w/v HPCD, 0.01 M MSA,
and 0.001 M HCL solution) or 3, 30, or 300 mg/kg alectinib was orally administered to male rats (N = 6 in
each group), and behavior and general condition were observed using the modified Irwin test. A separate
pharmacokinetic group consisting of 3 male rats was used to confirm exposure. No effects on the CNS were
seen at any of the doses up to 300 mg/kg (mean Cmax: 1770 ng/mL).
Respiratory
To investigate the effects of alectinib on the respiratory system, a single dose of the vehicle (10% w/v HPCD,
0.01 M MSA, and 0.001 M HCL solution) or 3, 30, or 300 mg/kg alectinib was orally administered to conscious
Assessment report
EMA/197343/2017 Page 26/122
male rats (N = 8 in each group), and respiratory rate and ventilation volume (tidal volume and minute
volume) were measured (whole-body plethysmography). No effects on the respiratory system were seen at
any of the doses up to 300 mg/kg (for comparison, mean Cmax at 300 mg/kg in the modified Irwin's test
is 1770 ng/mL).
Gastrointestinal
The potential effect of alectinib on gastrointestinal motor function was investigated in male rats using a
phenol red method. Alectinib was orally administered as a single dose to 6 animals per group at 0, 3, 30 and
300 mg/kg (vehicle: 10% w/v HPCD, 0.01 M MSA and 0.001 M HCL solution). Gastric emptying and small
intestinal transit of phenol red, which was orally administrated by gavage 4 hours after test article
administration, were evaluated. No test article-related effects on gastrointestinal motor function were
observed.
Pharmacodynamic drug interactions
No pharmacodynamic drug interaction studies have been conducted.
2.3.3. Pharmacokinetics
The measurement of plasma concentrations of alectinib in rats, rabbit, and monkeys was validated using a
liquid chromatography — tandem mass spectrometry (LC - MS/MS) method with a supernatant obtained after
plasma protein precipitation.
The measurement of plasma concentrations of the metabolite M4 in monkeys was validated using LC -
MS/MS after plasma protein precipitation.
Absorption
Single dose pharmacokinetic studies were performed in rats and monkeys with intravenous and oral
administration. Pharmacokinetic parameters are presented in the following tables:
Table 8: Mean pharmacokinetic parameters after a single intravenous dose of alectinib to rats and cynomolgus monkeys
Species, Sex (Number of animals)
Dose (mg/kg)
CLtot (mL/min/kg)
Vss (L/kg)
t1/2 (h)
SD rat, male (3) [1054082]
1 7.79 ± 0.556 9.33 ± 1.04 17.8 ± 2.4
HccHan:WIST rat, male (3) [1056248] 1 11.0 ± 2.8 13.3 ± 4.3 24.4 ± 10.9
Monkey, male and female (2) [1054083]
0.5 6.04 5.28 10.4
Table 9: Mean pharmacokinetic parameters after a single oral dose of alectinib to rats and cynomolgus monkeys
Species, Sex (Number of animals)
Dose (mg/kg)
Cmax (ng/mL)
Tmax (h)
AUCinf (ng∙h/mL)
t1/2 (h)
F (%)
SD rat, male [1054082] 1 60.8 ± 11.7 7.0 ± 0.0 1400 ± 492 12.6 ± 2.5 65.2 HccHan:WIST rat, male [1056248]
1 60.9 ± 14.0 8.0 ± 0.0 1400 ± 320 32.1 ± 4.9 88.6
Monkey, male and female [1054083]
0.5 55.8 2.0 696 8.38 50.4
Distribution
Assessment report
EMA/197343/2017 Page 27/122
The tissue distribution studies following a single oral dose of [14C]-alectinib to albino, pigmented and
pregnant rats demonstrated that drug-related material:
1) distributed well to all tissues with highest tissue-to-plasma concentration ratios in harderian glands,
adrenal glands, lungs, brown adipose tissue and liver;
2) penetrated into the CNS tissues with brain tissue-to-plasma concentration ratio of approximately 1;
3) had high accumulation in the melanin-containing tissue uveal tract of the eyes;
4) penetrated the foetus with a distribution pattern to that in maternal rats
In vitro plasma protein binding
The plasma protein binding ratios (fb) of [14C]-alectinib at concentrations of 100, 1000, and 10,000 ng/mL
(1000 ng/mL in mice) were all high, > 99%, regardless of species or concentration. The [14C]-alectinib–HSA
binding ratio at concentrations of 100, 300, and 1000 ng/mL was 97%, but the ratio of binding to α1–AAG
was low, ≤ 4.9%, at all concentrations. These findings suggest that albumin is the main binding protein in
human plasma. M4 was highly protein bound, like the parent molecule, with fb>99% in all species and
concentrations tested.
In vitro blood cell distribution
At concentrations of 100 to 1000 ng/mL, the blood/plasma concentration ratio (Rb) values of rats (2.06),
cynomolgus monkeys (3.95 - 3.52), and humans (2.92 - 2.64) were similar. At a concentration of 10,000
ng/mL, the Rb values decreased to 1.40 in rats, 1.68 in cynomolgus monkeys, and 1.29 in humans.
The blood cell distribution of M4 in rat, monkey, and human blood was evaluated in vitro at concentrations of
0.3, 1 and 2 µg/mL. The quantification of M4 was determined by a LC - MS/MS-based method. The Rb
values were 2.70 - 2.45 in rats, 2.26 - 2.18 in monkeys, and 2.58 - 2.50 in humans.
Metabolism
The metabolic pathway of alectinib in humans is proposed based on the results of in vitro metabolism studies
using human hepatocytes, human liver microsomes, microsomes expressing human CYP isoforms (Figure 1)
and the results from the radiolabelled human ADME study.
Assessment report
EMA/197343/2017 Page 28/122
Figure 1: Proposed Metabolic Pathway for Alectinib in Humans
The enzymes involved in the metabolism of alectinib in human hepatocytes were evaluated by reacting [14C]-
alectinib (2 µM) with a human hepatocyte suspension (prepared from cryopreserved hepatocytes) for 60
minutes at 37˚C in the presence of benzylimidazole or ketoconazole. This study suggests that CYP3A is the
primary enzyme responsible formation of M4 and M6 and contributes to 40% - 50% of total hepatic
metabolism.
M4 and M6 exposure levels were measured in cryopreserved plasma samples from the 13-week oral repeat-
dose toxicity study of alectinib in rats from the high dose group (27 mg/kg/day) using a qualified LC -
MS/MS-based method. Exposures (Cmax and AUC0-24) on Days 1 and 91 are shown in In rats, the exposure to
M4 and M6 was higher in male rats, ranging from 1.4 to 2.0 times the levels in females. There was no
pronounced increase in plasma trough level from the Day 28 onward, and Cmax and AUC0-24 on Day 91
were 1.7 - 2.0 times higher (M4) and 1.1 - 1.7 times higher (M6) than on Day 1. M6 had much lower
exposure than M4 (6% - 11% of M4) and is considered a minor/trace metabolite. Based on the mean AUC0-24
(35,300 and 41,100 ng∙h/mL in male and females, respectively) of alectinib on Day 91, the M4-to-parent
AUC ratios were 3 - 5%.
In monkeys, there were no clear sex differences in exposure to metabolites M4 or M6. There was no
pronounced increase in plasma trough level from Day 28 dose onward, and Cmax and AUC0-24 on Day 91 were
1.9 to 2.4 times higher (M4) and 2.1 to 3.7 times higher (M6) than on Day 1. M6 had much lower exposure
than M4 (6% to 10% of M4) and is considered a minor/trace metabolite. Based on the mean AUC0-24 (6990
ng∙h/mL, gender combined) of alectinib on Day 91, the M4-to-parent AUC ratios were 24%.
Excretion
Assessment report
EMA/197343/2017 Page 29/122
The excretion of radioactivity in urine and faeces was evaluated up to 168 hours after a single oral dose of 1
mg/kg [14C]-alectinib in male RccHan™: WIST rats.
The main route of excretion for drug-related substances was via faeces, and cumulative faecal excretion at
24, 48, 72, 96, and 168 hours postdose was 51.9%, 78.5%, 87.2%, 91.3%, and 95.7% of the dose,
respectively. Excretion in urine was minimal and nearly complete within 96 hours of dosing. The total amount
of radioactivity excreted in urine by 168 hours postdose was 0.5% of the dose.
2.3.4. Toxicology
The performed studies include repeat-dose toxicity, genotoxicity, preliminary embryo-foetal development
toxicity, phototoxicity and toxicity evaluation of the clinical formulation in rats. In addition, the major human
metabolite M4 was investigated in genotoxicity studies in vitro. The rat and cynomolgus monkey were the
selected rodent and non-rodent species, respectively, for general toxicity studies based on their suitable
pharmacokinetic profiles and representation of the major metabolism pathways in humans.
Table 10: Summary of main toxicity studies of alectinib.
Type of study Species/cell line Route or
test method Dose (mg/kg/day)
/concentrationa GLP
compliance
Repeat-dose toxicity
4-week dose finding Rat Oral 0, 3, 10, 30 Non-GLP
4 week Rat Oral 0, 6, 20, 60 GLP
13-week Rat Oral 0, 3, 9, 27 GLP
Preliminary 2-week Monkey Oral 0, 6, 20, 60 Non-GLP
4-week dose finding Monkey Oral 0, 1, 3, 10 Non-GLP
4-week Monkey Oral 0, 1.7, 5, 15 GLP
13-week Monkey Oral 0, 1.3, 4, 12 GLP
Genotoxicity
Bacterial reverse mutation S. typhimurium; E. coli In vitro 0, 31.3–1000 µg/plate GLP
Chromosomal aberration CHO cells In vitro 0, 3–10 µg/mL GLP
Micronucleus (mechanism) TK6 cells In vitro 0, 0.4-6.3 µg/mL Non-GLP
Micronucleus Rat Oral 0, 6-2000 GLP
Micronucleus (mechanism) Rat Oral 0, 100-1000 GLP
Reproductive & developmental toxicity
Embryo-fetal development DF Rat Oral 0, 3, 9, 27 GLP
Embryo-fetal development DF Rabbit Oral 0, 3, 9, 27 GLP
Other toxicity
Screening Ames test (M4) S. typhimurium; E. coli In vitro 0, 1.58–500 µg/plate Non-GLP
Micronucleus (M4) TK6 cells In vitro 0, 0.1–2.8 µg/mL Non-GLP
Phototoxicity 3T3 cells In vitro 0, 0.02–50 µg/mL Non-GLP
4-week (±SLS)b Rat Oral 0, 20 GLP a Free-base alectinib was used as the test article in the photosafety study, but alectinib hydrochloride was used in all other studies. All of the
doses/concentrations are shown converted to the free base. b A formulation with ± 10 mg/kg/day SLS for each group has been used.
Single dose toxicity
No dedicated single-dose studies with alectinib have been conducted. However acute toxicity was evaluated
on the basis of general condition, body weight, and food consumption until a day after the second dose in the
Assessment report
EMA/197343/2017 Page 30/122
micronucleus test study in rats and on the basis of general condition the day after the first dose in the
preliminary 2-week toxicity study in monkeys. There were no deaths or deteriorations in general condition at
≤ 2000 mg/kg/day in rats or at ≤ 60 mg/kg/day in monkeys.
Repeat dose toxicity
The repeat-dose toxicity of alectinib after oral administration was investigated in studies up to 13 weeks in
rats and monkeys. Identified target organs in both rats and monkeys were the erythroid system, GI tract,
hepatobiliary system and adrenal cortex. In rats only, additional effects were observed in the respiratory
tract, bone, incisor teeth, and prolongation of clotting time accompanied by haemorrhagic changes in the
ileum. The changes seen in the 4- and 13-week repeat-dose toxicity studies had recovered or had shown a
tendency to recover by the end of the respective 4- and 8-week recovery periods.
Morbidity and mortality
In the preliminary 2-week toxicity study conducted in monkeys, one of two animals in the high dose group
was sacrificed in moribund condition on Day 13. The major cause of the moribund condition was thought to
be GI tract abnormalities including retention of digestive tract contents and digestive tract dilatation.
Therefore, the dose limiting toxicity at 60 mg/kg (AUC0-24 on Day 1, gender combined: 12050 ng·h/mL) in
monkeys was attributed to alectinib’s effect on the GI tract. No deaths or deteriorations in condition due to
toxicity were seen in either species in the 4- and 13-week repeat-dose toxicity studies.
Effects on the erythroid system (rats and monkeys)
Abnormal red blood cell (RBC) morphology (poikilocytosis, i.e., mainly burr cells and fragmented
erythrocytes) was one of the changes seen at a low exposures. In most cases, abnormal RBC morphology
was seen at low dose, and then as the exposure level increased, a tendency to slight anaemia was seen in
monkeys. In rats, changes suggestive of a compensatory response to anaemic stimuli (e.g., increased
reticulocytes, increased extramedullary hematopoiesis in the spleen and mild increase in spleen weight) were
seen. In the 13-week study in rats, in contrast to monkeys, increased extramedullary hematopoiesis in the
spleen was seen at all doses, while abnormal RBC morphology was only seen at higher exposure levels. The
changes in erythroid system parameters were generally mild and no exacerbation was noted with continued
treatment. Similar findings were also seen in rabbits. The findings were considered reversible or showed a
trend towards reversibility after the recovery period.
Effects on the gastrointestinal tract (rats and monkeys)
Effects on GI epithelia (proliferative zone extension in GI mucosa) were seen in both species. In addition, in
rats, degeneration and mucinous hypertrophy of glandular stomach mucosal epithelium, mixed cell infiltration
in mucosa, disarrangement/desquamation of mucosal epithelium in the small intestine, and increased serum
intestinal ALP were noted. The multinucleated giant cells seen in the GI mucosa were similar to macrophages
phagocytizing foreign material. The content in these cells was most likely the test article dosing formulation
(suspension). In monkeys, dilatation of the large intestine was also seen, and, in the preliminary 2-week
study, decreased stool and retention of GI contents were seen in both animals at 60 mg/kg/day and were
accompanied by very slight erosions/ulcers in the stomach, duodenum, caecum and colon at histopathology.
Assessment report
EMA/197343/2017 Page 31/122
One animal in that group was sacrificed moribund due to worsening of GI symptoms. In rats, no exacerbation
of GI changes was seen after 13 weeks treatment when compared to the 4-week study.
Effects on the hepatobiliary system (rats and monkeys)
In rats, increases in liver weight were noted with vacuolation and degeneration/necrosis of bile ductal
epithelium, bile duct proliferation, hepatocellular hypertrophy and necrosis, and, hepatic sinusoidal
swelling/yellow-brown pigmentation. The hepatobiliary changes were associated with increases in serum
hepatic ALP, -GT and total cholesterol. The changes were mostly minimal to mild; the only moderate change
was focal hepatocellular necrosis. In monkeys, increases in serum hepatic ALP, direct bilirubin, inflammatory
cell infiltration in Glisson’s sheath, hypertrophy of hepatocytes or Kupffer cells, and increases in liver weight
were seen in the 4-week repeat-dose toxicity study. In addition, bile duct proliferation and increased serum
-GT were seen in the 13-week study. The histopathological changes were minimal, and the changes in
laboratory values were mild. Hepatocellular hypertrophy was also observed in the 2-week preliminary study
at 20 mg/kg/day accompanied by very slight bile duct proliferation in one animal. Extension of the dosing
period from 4 to 13 weeks did not lead to a marked increase in the severity of hepatobiliary findings, but
findings occurred at lower exposure. The findings showed complete reversibility during the recovery period.
Effects on the adrenal gland (rats and monkeys)
In rats, findings included increased adrenal gland weight and cortical hypertrophy (zona fascicularis and
reticularis) and increased large lipid droplets or decreased lipid droplets in fascicular cells. In monkeys,
cortical hypertrophy of zona fascicularis/reticularis with decreased lipid droplets in fascicular cells was seen.
The histopathological findings were of minimal to mild severity and were reversible. Many of these
histopathological changes are similar to those usually induced by stress. Accordingly, slight increases of blood
glucose, cholesterol, neutrophils and decreases in lymphocytes (rat 4-week repeat-dose study) might have
been responses to adrenal cortical hypertrophy.
Effects on the respiratory system (lung and trachea, rats)
Minimal to mild foamy macrophage infiltration in alveoli was seen in the 4- and 13-week repeat-dose toxicity
studies in rats. There was no clear exacerbation with longer treatment at comparable exposures, but an
increased severity and incidence at higher doses compared to the control groups. Additionally, mixed cellular
infiltration was seen in the tracheal mucosa (macrophages/multinucleated giant cells and/or inflammatory
cells); and in some animals in the 13-week study in rats, minimal or mild disarrangement in tracheal mucosal
epithelium was also seen.
Effects on bone (rats)
Minimal or mild changes in bone were seen in the high dose groups of the 4- and 13-week repeat-dose
toxicity studies in rats (group mean AUCs ≥38000 ng·h/mL) and these changes were reversible. Findings
included increases in activated osteoclasts and decreased trabecular bone in femur and sternum associated
with mild elevations of bone ALP and inorganic phosphorus. The exposure levels in the high dose groups in
the 4- and 13-week studies were approximately the same, but the longer dosing period led to an increased
severity and incidence of histopathological changes.
Effects on teeth (rats)
In rats, effects on incisor teeth were seen in the high dose group (27 mg/kg/day; mean AUC0-24, gender
combined: 38200 ng·h/mL) following 13-weeks treatment. The changes were reversible following the 8-week
recovery period. Findings included white discoloration and shortening of incisor teeth, as well as
Assessment report
EMA/197343/2017 Page 32/122
disarrangement, degeneration, and/or necrosis of ameloblasts, and dilatation of capillaries in the
papillary/odontoblast layers, and disarrangement of odontoblasts. These changes were seen mainly in the
middle region of the incisor, which is where enamel is produced.
Prolongation of clotting time and ileal hemorrhage (rats)
Prolongation of clotting time (PT and APTT) and ileal hemorrhage were seen at 27 mg/kg/day in the 13-week
repeat-dose toxicity study in rats (group mean AUC; 38200 ng·h/mL) and were considered reversible. The
ileal haemorrhage is considered likely secondary to the prolonged clotting time. Other potential consequences
included blackish feces, dark-red/gelatinous content in the large intestine, and blood loss anemia (decreased
RBC parameters, discoloration of eyeballs considered due to anemia).
Other findings (rats)
Mild effects on the thrombopoietic system, pituitary gland, and blood glucose were seen in repeat-dose
toxicity studies in rats but are considered of limited toxicological significance.
Genotoxicity
Alectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay but induced a slight
increase in numerical aberrations in the in vitro cytogenetic assay using Chinese Hamster Lung (CHL) cells
with metabolic activation, and micronuclei in a rat bone marrow micronucleus test. The mechanism of
micronucleus induction was abnormal chromosome segregation (aneugenicity), and not a clastogenic effect
on chromosomes.
Carcinogenicity
No carcinogenicity studies with alectinib have been conducted.
Reproduction Toxicity
Fertility and early embryonic development studies were not conducted with alectinib.
Preliminary embryo-foetal developmental studies were performed in rats and rabbits. In rats, maternal
toxicity was evident at ≥9 mg/kg/day as shown by decreased body weight gain or body weight and
decreased food consumption. As for the reproductive function of dams, increases in embryonic death ratio,
early foetal death ratio and total death ratio were observed resulting in a total litter loss in all dams at 27
mg/kg/day. In foetal examination, decreased foetal weight, decrease in the number of sacral and caudal
vertebrae, and increases in visceral anomalies ratio, including dilation of ureter, thymic cord, small heart
ventricle and thinning of ventricular wall, were observed at 9 mg/kg/day. The findings in heart were seen at a
low incidence, in 2 foetuses from 1 dam. Due to the total litter loss at the highest dose, a potential dose-
response relationship may be masked by the lethality and cannot be evaluated. Based on the absence of
similar observations in the control and low dose groups, a relation to treatment cannot be excluded. In
conclusion, the NOAEL for maternal toxicity and embryo-foetal toxicity in rats was 3 mg/kg/day (AUC0-24h
13900 ng∙h/mL on GD17).
In rabbits, maternal toxicity was observed at 27 mg/kg/day including low food consumption and body weight,
and changes considered to be associated with anaemic changes, deterioration of nutritional condition,
inflammation and/or stress in haematology and blood chemistry. In addition, erythrocyte morphological
Assessment report
EMA/197343/2017 Page 33/122
abnormalities, in which were based mainly on poikilocyte (burr cell) were observed at ≥9 mg/kg/day. At
27 mg/kg/day, one dam aborted and two others had total litter loss. Increased post-implantation loss,
reduced foetal and placental weights, reduced litter size and an increased incidence of foetuses with
additional ribs were also noted in the dams given 27 mg/kg/day. The NOAEL for maternal toxicity in rabbits
was 3 mg/kg/day (AUC0-24h, 2950 ng∙h/mL on GD18), and 9 mg/kg/day for embryo-foetal development.
No studies on pre-and post-natal development have been performed
Toxicokinetic data
Toxicokinetic (TK) assessment was included in all toxicology studies conducted in rats, monkeys and rabbits.
In addition, the exposure of metabolites M4 and M6 was measured in cryopreserved plasma samples from
the 13-week oral repeat-dose toxicity studies using a qualified LC MS/MS-based method. Plasma samples
from the high dose groups only were evaluated, i.e. 27 mg/kg/day and 12 mg/kg/day, in rats and monkeys,
respectively.
Table 11: Mean alectinib exposure levels after repeat dosing in the pivotal in vivo toxicity studies and in patients.
Type of study Dose Cmax AUC0-24a
(mg/kg/day) (ng/mL), M/F (ng·h/mL), M/F
Humana 1200 mg/day 665 14900
Rat, 4-week 6 673/841 9340/13900
20 2190/1770 38100/33200
60 MTD 2200/1990 39800/40300
Rat, 13-week 3 370/524 5100/8450
9 1250/1520 18600/25800
27 MTD 1840/2170 35300/41100
Monkey, 4-week 1.7b 102/92.5 1160/1300
5 205/302 2400/3980
15 456/464 6530/6540
Monkey, 13-week 1.3 83.4/94.3 894/1030
4 243/189 3610/2810
12 461/463 7060/6920
Rat, embryo-fetal development 3 –/827 –/13900
(pregnant rats) 9 –/2140 –/40600
27 –/3590 –/66400
Rabbit, embryo-fetal development 3 –/163 –/2950
(pregnant rabbits) 9 –/385 –/6650
27 –/2090 –/43200
Rat, micronucleus 6c 412/– 6480/–
20c 1560/– 24200/–
60c 1770/– 28400/–
200 1850/– 36700/–
500 3030/– 55800/–
1000 3020/– 59400/–
2000 2810/– 53700/–
Rat, micronucleus 100 2100/– 37000/–
(mechanism elucidation) 200 3210/– 58700/–
500 4140/– 74900/–
1000 4440/– 84200/–
–: Not applicable aHuman AUCSS,24: The value used was 2 times the geometric mean AUCSS,12 from population PK analysis for Phase I/II studies NP28761 and NP28673 on patients who received repeated oral administration of the recommended clinical dose, 1200 mg/day (600 mg administered twice
a day). bClose to NOAEL based on only one animal with poikilocytosis. cCmax and AUC0-24 were extrapolated from the 4-week oral repeat-dose study in rats.
Assessment report
EMA/197343/2017 Page 34/122
Local Tolerance
No dedicated local tolerance studies were performed. The local tolerance after oral administration is
considered adequately assessed in performed oral repeat-dose toxicology studies. Local effects in the GI tract
were seen in both rats and monkeys and are considered dose-limiting.
Other toxicity studies
Phototoxicity
Alectinib shows affinity with eyes and skin and absorbs light in the 290-700 nm range. In the 3T3 NRU assay
in vitro, alectinib was positive suggesting a potential risk of phototoxicity.
4-week rat study with alectinib in the SLS-containing clinical formulation
The clinical formulation contains sodium lauryl sulfate (SLS) at a concentration of 50% (w/w SLS to
alectinib). This formulation was not used in the repeat-dose toxicity studies and therefore, a dedicated 4-
week rat study was performed to assess the tolerability of the clinical formulation and to explore potential
toxicity effects of SLS combined with alectinib. The study showed that there were no remarkable differences
in the alectinib toxicity and plasma concentration time profiles between alectinib in the clinical SLS
formulation compared to alectinib in the formulation used in the toxicology studies. In the group treated with
the clinical formulation (without alectinib but with SLS), no effects were noted. Based on the acceptable non-
clinical and clinical tolerability, the amount of SLS in the formulation is not considered to pose a significant
toxicological concern.
Metabolites
Metabolite M4 was identified as a major metabolite of alectinib in humans representing ~15% of the total
plasma radioactivity in the mass balance study. M4 was not mutagenic in the screening Ames test and nor
was micronucleus induction observed in the in vitro micronucleus test in TK6 cells. M4 was present in both
rats and monkeys and the AUC exposure to M4 in the 13-week repeat-dose studies represents ~33 to 59% of
the clinical M4 exposure.
Impurities
The Applicants proposes to apply the less-than-lifetime (LTL) approach to determine the acceptable daily
intakes for mutagenic impurities as described in Note 7 in the ICH M7 guideline. Based on the daily dose of
alectinib, these intakes correspond to LTL concentration limits of 8 ppm (individual mutagenic impurities) and
23 ppm (total of mutagenic impurities). Considering alectinib’s indication in advanced cancer and longest
expected treatment duration based on patient life expectancy (less than 10 years), this approach is
considered acceptable. The proposed specifications for the Class 1 compounds are considered acceptable and
in agreement with ICH Q3C R(5) and ICH M7, respectively. For the remaining Class 2 or 3 compounds, they
are all considered as likely below the LTL limit for individual mutagenic impurities of 8 ppm. The sum of these
Class 2 and 3 compounds, assuming a worst-case scenario is also below the LTL limit for total mutagenic
impurities of 23 ppm. Although it is unclear what toxicological data was used by the Applicant to calculate the
ADI of the non-classified fluorinated solvent used during drug substance manufacture, robust data on
genotoxicity with negative results are available in the ECHA database.
Assessment report
EMA/197343/2017 Page 35/122
Ecotoxicity/environmental risk assessment
Table 1. Summary of main study results Substance (INN/Invented Name): Alectinib
CAS-number: 1256589–74–8 (Alectinib HCl), 1256580–46–7 (Alectinib free base)
PBT screening Result Conclusion
Bioaccumulation potential- log Kow
OECD117 3.09 (pH 5) 3.86 (pH 7) 3.85 (pH 9)
Potential PBT (N)
PBT-assessment
Parameter Result relevant for conclusion
Conclusion
Bioaccumulation
log Kow 3.86 not B
BCF steady-state 148 (see OECD 305) not B
Persistence DT50 or ready biodegradability
Not ready biodegradable (see OECD 301F)
P
Toxicity CMR T
PBT-statement : The compound is not considered as PBT nor vPvB. However, a ready biodegradability test showed that it is not biodegradable, and hence should be considered as vP.
Phase I
Calculation Value Unit Conclusion
PEC surfacewater , default 6 g/L > 0.01 threshold (Y)
Other concerns (e.g. chemical class)
N/A N/A N/A
Phase II Physical-chemical properties and fate
Study type Test protocol Results Remarks
Adsorption-Desorption OECD 106 Koc = Soil 1 (pH 5.5)= 21575 L/kg Soil 2 (pH 5.0)= 18928 L/kg Soil 3 (pH 7.4)= 14921 L/kg Sludge 1 (pH 6.1)= 7508 L/kg Sludge 2 (pH 6.1)= 5707 L/kg
Koc > 10000 L/kg triggers terrestrial testing
Ready Biodegradability Test OECD 301F Not ready biodegradable
Aerobic and Anaerobic Transformation in Aquatic Sediment Systems
OECD 308
Sediment 1 DT50, water = 2.3 days DT50, whole system = 75 days Sediment 2 DT50, water = 1.5 days DT50, whole system = 273 days >10% shifting to sediment
Anaerobic conditions not tested Shifting to sediment triggers sediment testing
Phase IIa Effect Studies
Study type Test protocol Endpoint value Unit Remarks
Algae, Growth Inhibition Test OECD 201 NOECgrowth rate
NOECbiomass 11.7 mg/L Pseudokirchneriella
subcapitata
Daphnia sp. Reproduction Test OECD 211 NOEC 0.133 mg/L Daphnia magna
Fish, Early Life Stage Toxicity Test
OECD 210 NOEC 1.04 µg/L Danio rerio
Activated Sludge, Respiration Inhibition Test
OECD 209 EC50
EC10 >1000 1000
mg/L
Phase IIb Studies
Bioaccumulation in fish
OECD 305 BCFsteady state,
parent
434 L/kg Danio rerio normalized to 5% lipids
Aerobic and Anaerobic Transformation in Soil
OECD 307 DT50, soil1
DT50, soil2
DT50, soil3 %CO2 in all soils was negligable
4.1 14.9 (276)
days Soil 1: Kenslow loam Soil 2: Lufa Speyer 2.3 loam Soil 3: Lufa Speyer 6S clay
Soil Micro-Organisms: Nitrogen Transformation Test
OECD 216 NOEC 1000 mg/kg dry weight
Assessment report
EMA/197343/2017 Page 36/122
Terrestrial Plants, Growth Test OECD 208 NOEC 31.6 mg/kg dry weight
Allium cepa, Avena sativa, Brassicus napus, cucumis sativus, Lycopersicon esculentum, Pisum sativum
Earthworm, Chronic Toxicity Tests
OECD222 NOEC 1000 mg/kg dry weight
Eisenia fetida
Toxicity to Terrestrial Springtails (Collembola)
OECD232 NOECreproduction 316 mg/kg dry weight
Folsomia candida
Chronic Toxicity to Sediment
Dwelling Organisms OECD218 NOEC 1060
mg/kg dry weight
Chironomus riparius
Alectinib is persistent (P) or very persistent (vP) in the environment but not bioaccumulative (not B) nor very
bioaccumulative (not vB). It is toxic (T) due to mammalian embryotoxicity at dose levels causing maternal
toxicity and potentially T due to chronic aquatic ecotoxicity. As all the three criteria must be fulfilled for a PBT
substance, the conclusion is that alectinib is not a PBT substance.
2.3.5. Discussion on non-clinical aspects
Pharmacology
In an enzyme assay, alectinib inhibits ALK with an IC50 of 1.9 nM. In addition RET is inhibited with an IC50 of
4.8 nM. No kinase inhibitory effect was seen with a large panel of other tyrosine kinases. This is in contrast to
other ALK inhibitors like crizotinib and ceritinib which show relevant activity at several unrelated kinases.
Alectinib also showed activity against ALK point mutations associated with acquired crizotinib resistance. The
IC50 for these kinases varied between 2-fold stronger to 20-fold lower than for native ALK.
The biology of ALK and RET is discussed and it is agreed that current understanding propose a limited role of
these kinases in the adult, whereas they may play critical roles during development; in particular for the
neural development. For RET, there seems to be some role for neural functions also in adults. No findings
related to the functions identified in knockout models have been observed in animal studies or in humans.
Alectinib inhibited the growth of tumor cell lines where ALK activation is due to the formation of a fusion
protein (EML4-ALK). In one study, alectinib was compared to crizotinib for growth inhibition. In this assay
alectinib was about 10-fold more potent than crozitinib in inhibiting the growth of cells expressing the native
EML4-ALK enzyme.
When comparing the activity of alectinib and crizotinib with a series of Ba/F3 cell transfected with EML4-ALK
as well as a number of EML4-ALK mutants there was no difference in the decrease of inhibitory activity for
ALK mutants between alectinib and crizotinb. Thus, the ability of alectinib to show efficacy with crizotinib-
resistant tumors is not due to a qualitative difference in the inhibition of ALK and ALK mutants. An alternative
explanation is proposed: The activity at the parental Ba/F3 cell line, which is independent of ALK for its
growth, represents off target activity and is likely a good surrogate for dose-limiting toxicity. For crizotinib
the ratio between the IC50 for growth inhibition of Ba/F3 and the IC50 for the Ba/F3 EML-ALK (WT ALK
sequence) is only 6.2 while for alectinib the corresponding figure is 48. For crizotinib, dose-limiting toxicity
will limit the dose resulting in an exposure that will be sufficient to inhibit the growth of tumour cells
expressing the WT ALK sequence but not most of the mutant ALK sequences. For alectinib, a higher relative
exposure can be reached, sufficient to act at many of the mutants. For one of the mutants, ALK G12002R,
Assessment report
EMA/197343/2017 Page 37/122
alectinib actually shows a stronger loss of activity than crizotinib (13x vs 2.6x), which is well in line with the
fact that alecctinib lacks activity on tumors harboring this mutation.
These conclusions on the mechanistic background for the activity of alectinib in patients which have failed on
crizotinb, while differing from the view presented by the applicant, will not have any further consequences
from the non-clinical perspective.
Alectinib was active in models with intrancranially injected tumors. These data, and the substantial alectinib
exposure in CNS suggest that alectinib has the potential to be effective against brain metastases.
The main human metabolite, M4 shows a similar or even higher activity to ALK in enzyme assays, and a
similar selectivity. The activity in the cellular assay was somewhat lower (3-fold) which may be due to a
lower cell penetration. This difference may be of importance for clinical PK-PD considerations, where
substantial differences in relations between alectinib and M4 exposures have been observed (see Clinical
section).
In the screening for secondary pharmacology, some secondary targets with an IC50 < 1 μM were observed.
While an in vivo activity on serotonin, norepinephrine and/or dopamine uptake cannot be fully excluded
based on the relatively limited multiples to clinical exposure, no CNS finding were seen in the safety
pharmacology study in rats.
Alectinib has inhibitory activity on the hERG channel as well as on the Cav1.2 channel. At IC20 the multiple to
the free clinical exposure is 8-fold for hERG and 14-fold for the Cav1.2 channel. In an ex-vivo aorta model,
alectinib inhibited vasoconstriction with an IC20 value similar to the free clinical exposure. A mild hypotensive
effect has been observed in monkeys at around clinically relevant exposures. No cardiovascular effects were
observed in a GLP cardiovascular study in monkeys, but in this study the exposure did not reach clinical
exposure (ca 3-fold below free clinical exposure).
Animal data suggest a risk for cardiovascular effects (hypotension). There are no preclinical findings
suggesting a QT liability. However, no or limited exposure multiples to clinical exposure have been obtained
in these studies and cardiovascular effects need to be carefully addressed in the clinical setting.
Pharmacokinetics
The pharmacokinetics of alectinib was adequately evaluated in the two toxicology species rats and
cynomolgus monkeys.
The distribution studies show widespread distribution. Exposure in CNS suggests a potential for treatment of
CNS metastases (as shown in pharmacology studies). There is retention of drug-related material in the eyes
from pigmented animals, but not in skin.
Drug-related material crosses the placenta and the exposure in the foetal tissues exceeded exposure in
maternal plasma. There is a potential for direct interference with the growing foetus.
The metabolism of alectinib was adequately evaluated in humans, rat and monkeys.
Toxicology
The toxicological profile of alectinib has been evaluated in agreement with recommendations in ICH S9. The
rat and cynomolgus monkey were the selected rodent and non-rodent species, respectively, for general
toxicity studies based on their suitable pharmacokinetic profiles and representation of the major metabolism
pathways in humans.
Assessment report
EMA/197343/2017 Page 38/122
The repeat-dose toxicity of alectinib after oral administration was investigated in studies up to 13 weeks in
rats and monkeys. In the repeat-dose studies in rats, the AUC exposure multiples at the highest dose levels
compared to the clinical AUC were 2.4- to 2.8-fold, while in monkeys, the AUC exposure were less than the
clinical exposure in all studies.
Target organs in both rat and monkey at clinically relevant exposures in the repeat-dose toxicology studies
included, but were not limited to the erythroid system, gastrointestinal tract, and hepatobiliary system.
These effects were observed at exposures below that of the recommended clinical dose. However, most
changes were minimal to mild, and changes of moderate or greater severity were only seen in rats at
exposures approximately three times that of the recommended clinical dose. Furthermore, all findings were
considered reversible changes that either recovered or showed a tendency to recover during the recovery
period. It is also possible to monitor the functioning of these organs through clinical testing (haematology
and blood chemistry tests) and clinical symptoms.
Alectinib is a lipophilic drug, with a >1 blood-to-plasma distribution, and this may have contributed to a
reduced membrane integrity and life span of erythrocytes.
Abnormal erythrocyte morphology was observed at exposures equal or greater than 10-60% the human
exposure by AUC at the recommended dose. Erythrocytes are considered particularly sensitive because of
their limited capacity to renew their cytoskeleton due to lack of a nucleus. In the proposed SmPC section 4.8,
anaemia is included as a very common adverse reaction in clinical trials with alectinib.
The effects on the gastrointestinal tract were considered dose-limiting in monkeys as one animal was
sacrificed moribund due to worsening of GI symptoms. Proliferative zone extension in GI mucosa in both
species was observed at exposures equal to or greater than 20-120% of the human AUC exposure at the
recommended dose.
The severity was graded as minimal to mild in all affected animals with exception of one female high dose rat
in the 1-month study (60 mg/kg/day) which was graded as moderate. There was no apparent progression of
the finding by extending the daily dosing period from 4 to 13 weeks. A complete recovery was noted in the 1-
month rat study and in the 1- and 3-month monkey studies while a tendency for reversibility was noted in
the rat 3-month study. In addition to the proliferative zone extension, desquamation of surface epithelia and
inflammatory cell infiltration was observed in the 1- and 3-month rat studies but not in monkeys. In the
preliminary 14-day monkey study, very slight erosions ulcers were noted in the stomach, duodenum, cecum
and colon in both high dose animals (60 mg/kg/day). These findings indicate that alectinib is a slight GI
irritant. In addition, the non-clinical vehicle also seems to have irritative properties as proliferative zone
extension of minimal degree was observed in 18 out of 20 vehicle control rats in the 3-month rat study.
Therefore, it is agreed with the Applicant that the observed proliferative zone extension is considered a
secondary response to irritation. In clinical trials, the GI tolerability is considered as acceptable. Adverse GI
effects are reported as very common and included constipation (36%), nausea (22%), diarrhoea (18%) and
vomiting (13%). Most of these events were of mild or moderate severity and declined in frequency after the
first month of treatment.
Alectinib’s high liver:plasma distribution, its biliary excretion (including metabolite M4) and inhibition of BSEP
(IC50 = 0.9 µM alectinib), may contribute to hepatobiliary toxicity. Increased hepatic alkaline phosphatase
(ALP) and direct bilirubin as well as vacuolation/degeneration/necrosis of bile duct epithelium and
enlargement/focal necrosis of hepatocytes was observed in rats and/or monkeys at exposures equal to or
greater than 20-30% of the human exposure by AUC at the recommended dose.
Assessment report
EMA/197343/2017 Page 39/122
Adverse hepatobiliary reactions are listed as very common in the SmPC section 4.8 and adequate warnings
are included in section 4.4. In addition, bilirubin and hepatic transaminase elevations are included as
important identified risks in the RMP.
The reversible effects on the adrenal glands of minimal to mild severity are similar to those usually induced
by stress. However, as quantitative whole-body autoradiography of rats revealed a high distribution of
radioactivity in the adrenal gland, an effect on the adrenal gland in addition to stress cannot be fully ruled
out.
In rats only, additional effects were observed in the respiratory tract, bone, incisor teeth, and prolongation of
clotting time accompanied by haemorrhagic changes in the ileum. The effects on the respiratory system are
considered likely caused by the oral gavage administration, because similar changes are commonly seen in
oral gavage studies in rats even in vehicle groups and these were not observed in monkeys. The effects were
not associated with any findings seen in pneumonia or bronchitis and were reversible, so they were not
considered to suggest that alectinib causes a clinically significant respiratory disorder. The effects seen in the
rat long bones and incisor teeth are considered of limited relevance for adult humans. However, potential
effects of alectinib on bone and tooth development in children cannot be ruled out. A prolonged of clotting
time (PT and APTT) was seen at a dose higher than the dose causing hepatotoxicity. Since it is known that
blood coagulation factors are produced in hepatocytes and bleeding tendency is seen in hepatic diseases, the
prolongation of clotting time may be secondary to the hepatotoxicity in rats. The ileal haemorrhage is
considered likely secondary to the prolonged clotting time.
Alectinib was tested in a complete package of genotoxicity studies in agreement with ICH S2(R1) guidance,
and in addition, mechanistic in vitro and in vivo micronucleus tests combined with centromere analysis was
conducted. The obtained data indicate that alectinib induces abnormal chromosomal segregation
(aneugenicity). Such abnormal chromosome segregations are considered to have a threshold dose, below
which no increase in DNA damage is expected. Accordingly, the threshold for the induction of micronuclei by
alectinib using the no observed effect level (NOEL) for micronucleus induction in rats was 200 mg/kg/day
(Cmax 1850 ng/mL and AUC0-24h 36700 ng·h/mL) corresponding to 2.5-fold clinical exposure based on AUC.
No carcinogenicity studies were performed which in view of the applied indication is acceptable according to
the guideline ICH S9.
Fertility and early embryonic development studies were not conducted with alectinib in agreement with
ICHS9. No adverse effects on male and female reproductive organs were observed in general toxicology
studies. These studies were conducted in rats and monkeys at exposures equal to or greater than 2.6- and
0.5-fold, respectively, of the human exposure, measured by AUC, at the recommended dose of 600 mg twice
daily.
Alectinib caused embryo-foetal toxicity in pregnant rats and rabbits. In pregnant rats, alectinib caused total
embryo-foetal loss (miscarriage) at exposures 4.5-fold of the human AUC exposure and small foetuses with
retarded ossification and minor abnormalities of the organs at exposures 2.7-fold of the human AUC
exposure. In pregnant rabbits, alectinib caused embryo-foetal loss, small foetuses and increased incidence of
skeletal variations at exposures 2.9-fold of the human AUC exposure at the recommended dose.
Embryo-foetal toxicity is included as an important potential risk in the RMP.
Alectinib absorbs UV light between 200 and 400 nm and demonstrated a phototoxic potential in an in vitro
photosafety test in cultured murine fibroblasts after UVA irradiation. Photosensitivity is listed as a common
Assessment report
EMA/197343/2017 Page 40/122
adverse reaction in the SmPC section 4.8 and adequate warnings are included in section 4.4. Photosensitivity
is also considered an important identified risk for alectinib in the RMP.
The clinical formulation contains amounts of SLS that are than that previously approved within EU. The daily
dose of SLS at the maximum recommended clinical dose of alectinib (1200 mg/day) is 600 mg/day i.e. ~10
mg/kg in a 60 kg patient. This is similar to the SLS dose tested in the 4-week rat study where no SLS-related
effects in any of the examined parameters were observed. Additionally, SLS did not alter the toxicity of
alectinib.
From a toxicological perspective, SLS has protein denaturing properties and may cause damage to cell
membranes. However, no SLS-related histopathological effects were seen in the 4-week rat study. Data from
oral administration of SLS in rats are also described in the literature. Results from 4- and 13-week rat studies
showed the primary effect of SLS to be local irritation of the GI tract, with NOAELs at 100 mg/kg/day. Based
on the available data, the amount of SLS in the formulation is not considered to pose a significant concern
although local toxicity in the GI tract is a potential concern. As adverse GI effects have been noted after
administration of alectinib in both non-clinical studies (without SLS) and in clinical studies (with SLS), the
actual contribution of SLS to the clinical reactions is unclear. Therefore, a reduction in the SLS amount may
be beneficial for the clinical GI tolerability (see also discussion on clinical pharmacology). The applicant is
recommended to introduce an alternative capsule formulation for oral administration containing a lower
amount of SLS post-approval.
Metabolite M4 was present in both rats and monkeys and the AUC exposure to M4 in the 13-week repeat-
dose studies represents ~33 to 59% of the clinical M4 exposure. Although, M4 cannot be considered as fully
qualified from a non-clinical perspective, further non-clinical testing is not warranted based on the intended
target population with advanced cancer. Overall, the characterisation of M4 is in agreement with
recommendations given by CHMP (EMEA/H/SA/2659/1/2013/III).
Based on environmental fate and toxicity data as well as on maximal epidemiology-based predicted amounts
of alectinib on the European market, no significant risks to the environmental compartments sewage
treatment, surface water, groundwater, sediment and soils have been identified. Overall, therefore, no
significant risk has been identified for the intended medical use of alectinib in ALK+ NSCLC cancer patients in
Europe.
2.3.6. Conclusion on the non-clinical aspects
The pharmacologic, pharmacokinetic, and toxicological characteristics of alectinib are well characterized.
In order to reduce the potential SLS-related effect on GI tract, the applicant is recommended to introduce an
alternative capsule formulation for oral administration containing a lower amount of SLS post-approval.
Assessment report
EMA/197343/2017 Page 41/122
2.4. Clinical aspects
2.4.1. Introduction
GCP
The Clinical trials were performed in accordance with GCP as claimed by the applicant.
The applicant has provided a statement to the effect that clinical trials conducted outside the community
were carried out in accordance with the ethical standards of Directive 2001/20/EC.
Tabular overview of clinical studies
Study Objective Population
Dosing regimen n
NP29040 BE (fasted/fed) between four candidate formulations for alectinib
Healthy 600 mg SD 150 mg capsules with different SLS content
n=49 (fasted) n=48 (fed)
NP28989 Absolute bioavailability and mass balance
Healthy Period 1: SD IV 50 µg and PO 600 mg Period 2: 600 mg SD
n=6
NP28990 Posaconazole DDI Healthy Cohort A: Alectinib SD 40 mg±posaconazole 400 mg BID Cohort B: Alectinib SD 300 mg± posaconazole 400 mg BID
Cohort A n=6 Cohort B n=17
NP29042 Rifampin DDI Healthy Period 1: Alectinib SD 600 mg Period 2: Alectinib SD 600 mg + RIF 600-mg QD
n=24
NP28991 Food-effect and esomeprazole DDI
Healthy FE: Alectinib SD 600 mg fasted or high fat meal PPI DDI: Alectinib SD 600 mg +esomeprazole 40 mg QD
FE n=18 DDI n=24
NP28673 Safety, tolerability, efficacy, PK
ALK-positive patients
600 mg oral BID fed n=130
Midazolam DDI substudy in study NP28673
ALK-positive patients
Midazolam SD 2 mg± alectinib: 600 mg BID
n=15
NP28761 Safety, tolerability, efficacy, PK
ALK-positive patients
Phase I: 240 mg SD fasted, 300 (fasted), 460, 600, 760, 900 mg BID fed Phase II: 600mg BID fed
Phase I n=42 Phase II n=85
AF-001JP Safety, tolerability, efficacy, PK
ALK-positive japanese patients
20, 40, 80, 160 (fasted) mg oral BID 240 and 300 (fed/fasted) mg oral BID
n = 55-75
2.4.2. Pharmacokinetics
The pharmacokinetics (PK) of Alecensa has been assessed in subjects with NSCLC who have progressed on or
are intolerant to crizotinib as well as in healthy subjects in five Phase I and two Phase I/II studies (see table
above). Also, the disposition of alectinib has been evaluated in a number of in vitro studies, including
metabolism studies, CYP inhibition and induction studies and studies to evaluate transport, transporter
inhibition, protein binding and blood-plasma ratio.
Assessment report
EMA/197343/2017 Page 42/122
An active metabolite (M4) of alectinib, with an estimated relative contribution to the activity of Alecensa of
30-50% based on target binding, has been quantified in laboratory animals and humans. The PK of M4 was
investigated in most of the submitted in vivo and in vitro studies.
Pharmacokinetic data analysis
Standard statistical methods and non-compartmental methods were used to characterize the PK of alectinib
and M4. The population PK of alectinib was characterised by non-linear mixed effects modelling including data
from the clinical studies in patients (study NP28673 and NP28761). A physiologically based pharmacokinetic
(PBPK) model was built using physiological, in vitro and in vivo data and verified based on available clinical
PK and DDI data for prediction alectinib drug interactions.
Analytical methods
In all the completed clinical pharmacology studies included in the submission, plasma concentrations of
alectinib and the active metabolite M4 were quantified using validated LC-MS/MS bioanalytical methods. The
two applied bioanalysis methods were adequately validated and showed acceptable performance during
analysis of study samples. However, there was a 21% bias observed between the methods in a cross-
validation study. However, as the poor performing method was only used in study NP28761 this is not
considered relevant for the PK assessment and will not affect the efficacy/safety evaluation of alectinib.
Formulations
The majority of the studies have been performed with the intended commercial formulation, 150 mg hard
capsule. In addition, an intravenous solution and an oral suspension formulation containing radiolabeled
alectinib and 20/40 mg hard capsules were used during drug development.
Due to the high SLS content (50%) of the formulation used during drug development, bioequivalence to the
50% SLS formulation was investigated for formulations with lower SLS content (25, 12.5 and 3%).
Absorption
The time to maximum observed plasma concentration (tmax) was reached after approximately 4 to 6 hours.
The in vitro permeability of alectinib was studied in Caco-2 cells and was low at 1.810-6 cm/s. The aqueous
solubility of alectinib was low across the pH range.
• Bioavailability
Absolute bioavailability was investigated as part of study NP28989 in six healthy volunteers.
Assessment report
EMA/197343/2017 Page 43/122
Table 12: Mean (± SD) alectinib concentration versus time profiles following a 600 mg single oral dose of
alectinib and following a 50 μg single IV dose of [14C]-alectinib in period 1
The geometric mean exposure ratio (PO/IV) for dose normalized alectinib AUC0-∞ as a measure of absolute
bioavailability was 36.9% (90% CI: 33.9 to 40.3) under fed conditions in healthy subjects.
Alectinib steady-state is reached within 7 days with continuous 600 mg twice daily dosing. The accumulation
ratio for the twice-daily 600 mg regimen was approximately 6-fold.
• Bioequivalence (Study NP29040)
The bioequivalence of the different alectinib formulations following oral administration in healthy subjects was
investigated in a randomized, open-label, single dose, cross-over study. The bioequivalence of treatments A
(reference, 50% SLS), B (25% SLS), C (12.5% SLS) and D (3% SLS) was investigated both in a fasted and
fed state.
Assessment report
EMA/197343/2017 Page 44/122
Table 13: Statistical estimates of effect of formulation on the PK parameters of alectinib and M4 in part 1
(Fasted)
Table 14: Statistical estimates of effect of formulation on the PK parameters of alectinib and M4 in part 2
(Fed)
Bioequivalence (based on Cmax and AUC) between formulations was also evaluated based on the
pharmacokinetic parameters of the total molar sum of alectinib and M4 since both contributed to the effect of
Alecensa. A similar pattern as presented above for alectinib was seen, only with formulation B (25% SLS)
being bioequivalent to formulation A (50% SLS).
Assessment report
EMA/197343/2017 Page 45/122
• Influence of food
The effect of a high-fat, high-calorie meal on the single oral dose PK of alectinib and M4 in healthy subjects
was investigated as part of Study NP28991.
Table 15: Mean plasma concentration vs time profiles of alectinib (RO5424802) and M4 (RO5468924)
Table 16: Statistical estimates of effect of high-fat meal on the PK parameters of alectinib (RO5424802) and
M4 (RO5468924)
The alectinib median Tmax was prolonged from 4 hours in the fasting state to 8 hours in the fed state. For
M4 the median Tmax was prolonged from 8 hours in the fasting state to 10 hours in the fed state.
The molecular weight-adjusted M/P ratios of AUC0-∞ were similar for fasted and fed conditions.
Distribution
Human plasma protein binding and binding proteins of alectinib were evaluated in vitro by equilibrium dialysis
in studies 1054086 and 1056250. The plasma protein binding ratio of alectinib at concentrations of 100-
Assessment report
EMA/197343/2017 Page 46/122
10000 ng/mL were all >99%. The alectinib–HSA binding ratio was 97% at concentrations of 100-1000
ng/mL, but was only 4.9% for a1–AAG, at all concentrations.
The human plasma protein binding of metabolite M4, evaluated by equilibrium dialysis assay, was >99% at
concentrations of 0.3-2 mg/mL in study 1057255.
The mean in vitro human blood-to-plasma concentration ratios of alectinib and M4 are 2.64 and 2.50,
respectively, at clinically relevant concentrations.
The geometric mean volume of distribution at steady state (Vss) of alectinib following IV administration was
475 L, indicating extensive distribution into tissues.
Alectinib demonstrated penetration into the CNS. CSF samples were collected in 8 patients receiving alectinib
in study NP28761. The alectinib concentration in CSF was 0.2-0.5% of the concentration in plasma, which is
similar to unbound fraction in plasma based on in vitro protein binding (0.3%). Penetration into CNS of M4
has not been demonstrated.
Elimination
Alectinib is suggested to be eliminated by two main primary metabolic clearance pathways, the M4/M6
pathway by CYP3A4 metabolism (estimated to contribute 40-50% of alectinib metabolism) and the M1a/M1b
pathway likely to be catalyzed by a combination of CYP isozymes (including isozymes other than CYP3A) and
aldehyde dehydrogenase (ALDH) enzymes.
Results from the human mass balance study demonstrated that alectinib and M4 were the main circulating
moieties in plasma with 76% of the total radioactivity in plasma. The geometric mean Metabolite/Parent ratio
at steady state is 0.399.
Table 17: Proposed metabolic pathway of alectinib in human
Assessment report
EMA/197343/2017 Page 47/122
Based on the final popPK analysis, the geometric mean of the individual elimination half-life estimates after
single and multiple doses of alectinib is 20 hours and 32.5 hours respectively. The individual elimination half-
life estimates after multiple doses of M4 is 30.7 hours.
The apparent clearance (CL/F) was 81.9 L/hour and 217 L/hour for alectinib and M4 respectively.
The molecular weight adjusted geometric mean M/P (M4/alectinib) ratios for AUC0-t and Cmax were 0.368-
0.515 and 0.324-0.494, respectively, following 600 mg BID repeated dosing of alectinib in phase II studies.
Following administration of a 600 mg single oral dose of [14C]-alectinib in study NP28989, administered orally
to healthy subjects the majority of radioactivity was excreted in faeces (mean recovery 97.8%) with minimal
excretion in urine (mean recovery 0.46%). In faeces, 84% of the dose was excreted as unchanged alectinib.
In faeces and urine 5.8, 0.2 and 7.7% of the alectinib dose was excreted as M4, M6 and M1a/M1b
respectively. The remaining identified radioactivity in excreta was made up by alectinib.
Dose proportionality and time dependencies
Dose proportionality analysis of alectinib and M4 Cmax and AUCinf after single and multiple dose (460-900 mg)
was performed as part of study NP28761.
After single dose administration, Cmax and AUCinf increased with increasing doses in the investigated dose
range. A linear regression was performed and alectinib Cmax and AUCinf had a slope of 0.750 (90% CI: 0.188,
1.313) and 0.752 (90% CI: 0.060, 1.440) across the 460 to 900 mg dose range respectively.
After multiple dose administration, Cmax and AUCinf increased with increasing doses in the investigated dose
range. Linear regression of alectinib Cmax and AUClast resulted in slopes of 0.908 (90% CI: 0.526, 1.290) and
1.110 (90% CI: 0.652, 1.573) across the 460 to 900 mg BID dose range.
In addition, dose proportionality was assessed using popPK modelling. The comparisons of the post hoc
estimate for the PK parameters (Table 18), results confirmed that alectinib is dose proportional from 300 mg
to 900 mg.
Table 18: Post hoc (CL/F and V/F) estimates of the PK parameters for alectinib by dose category
The mean accumulation ratio for alectinib and M4 ranges 4.55-8.87 and 5.23-11.5 respectively across the
300-900 mg dose range without no clear trend in study NP28761. The accumulation ratios in study NP28673,
based on AUC0-10 ratios day 21/day 1 was similar at 6.95 and 8.68 for alectinib and M4 respectively. The
accumulation ratio is higher than than expected based on estimations using alectinib and M4 single-dose half-
lifes (around 3-fold accumulation).
Assessment report
EMA/197343/2017 Page 48/122
Population PK model
The objectives of the population pharmacokinetic (popPK) analysis was to develop a model to describe the PK
of alectinib and M4, explore covariates that contribute to the between-patient variability in PK parameters of
alectinib and M4 and derive individual estimates of PK parameters.
Only data from study NP28673 was used to characterise the PK of alectinib and M4 in this popPK model.
Population PK analyses were performed using the software NONMEM version 7.2.0.
The population PK of alectinib and M4 was described by a one-compartment with first-order elimination. Body
weight statistically influenced both CL/F and V/F of alectinib and M4 and was therefore included in the base
structural PK model for alectinib and M4.
The geometric mean (coefficient of variation %) steady-state Cmax, Cmin and AUC0-12hr for alectinib were
approximately 665 ng/mL (44.3%), 572 ng/mL (47.8%) and 7430 ng*h/mL (45.7%), respectively. The
geometric mean steady-state Cmax, Cmin and AUC0-12hr for M4 were approximately 246 ng/mL (45.4%), 222
ng/mL (46.6%) and 2810 ng*h/mL (45.9%), respectively.
The NONMEM parameter estimates for the final popPK model for alectinib are summarized in Table 19.
Table 19: NONMEM parameter estimates for the final PK model for alectinib
The NONMEM parameter estimates for the final popPK model for M4 are summarized in Table 20.
Assessment report
EMA/197343/2017 Page 49/122
Table 20: NONMEM parameter estimates for the final PK model for M4
An adequate predictive performance of the proposed model was demonstrated by prediction corrected visual
predictive checks.
Special populations
No dedicated renal or hepatic impairment study has been submitted by the applicant.
Negligible amounts of alectinib and the active metabolite M4 are excreted unchanged in urine (< 0.2% of the
dose). Based on a population pharmacokinetic analysis alectinib and M4 exposures were similar in patients
with mild and moderate renal impairment and normal renal function. The pharmacokinetics of alectinib has
not been studied in patients with severe renal impairment.
Table 21: PK parameters (Mean ± SD) in patients with severe, moderate and mild renal impairment and with
normal creatinine clearance based on individual estimates from the popPK model for alectinib
Assessment report
EMA/197343/2017 Page 50/122
Table 22: PK parameters (Mean ± SD) in patients with severe, moderate and mild renal impairment and with
normal creatinine clearance based on individual estimates from the popPK model for M4
As elimination of alectinib is predominantly through metabolism in the liver, hepatic impairment may increase
the plasma concentration of alectinib and/or its major metabolite M4. Based on a population pharmacokinetic
analysis, alectinib and M4 exposures were similar in patients with mild hepatic impairment and normal
hepatic function.
Table 23: PK Parameters in patients with hepatic impairment and with normal hepatic function (NCI Criteria)
based on individual estimates from the final popPK model for alectinib
Table 24: PK Parameters in patients with hepatic impairment and with normal hepatic function (NCI Criteria)
based on individual estimates from the final popPK model for M4
The pharmacokinetics of alectinib and M4 has not been studied in patients with moderate to severe hepatic
impairment.
An exploratory analysis of the effect of race, white (n=6) vs. asian (n=20) populations, on alectinib PK was
included in study NP28673. No statistical significant influence of race on the PK parameters was identified
during covariate model building in the popPK model for either alectinib or M4. However, the clearance was
lower in asian patients as compared to white patients both for alectinib (66±25.7 vs. 91.4±37.8 L/h) and M4
(202.5±72.9 vs. 226.6±111.5).
Assessment report
EMA/197343/2017 Page 51/122
No effect of gender was seen in the popPK model.
Body weight was identified as a significant covariate on both CL/F and V/F for both alectinib and M4 and the
alectinib and M4 exposure decreased with increasing weight (24-30% decrease in exposure for patients 90
kg as compared to patients 60-90 kg). Alectinib has not been dosed in patients > 128 kg.
No studies have been conducted to investigate the pharmacokinetics of alectinib in paediatric patients.
No effect of age was observed in the popPK model.
Age 65-74
(Older subjects number
/total number)
Age 75-84
(Older subjects number
/total number)
Age 85+
(Older subjects number
/total number)
PK Trials including
NP29761 and NP28673
26 9 0
Pharmacokinetic interaction studies
The drug-drug interaction potential of alectinib was investigated in a number of in vitro and in vivo studies.
Based on in vitro data, CYP3A4 is the primary enzyme mediating the metabolism of both alectinib and its
major active metabolite M4, and CYP3A contributes to 40% 50% of total hepatic metabolism. M4 has
shown similar in vitro potency and activity against ALK.
In vitro, neither alectinib nor M4 are considered clinically relevant systemic direct inhibitors of CYP-enzymes.
Alectinib is likely to be a time-dependent and intestinal inhibitor of CYP3A4. A signal of CYP1A2, 2B6 and 3A
in vitro induction was observed.
Alectinib did not inhibit OATP1B1/OATP1B3, OAT1, OAT3 or OCT2 at clinically relevant concentrations in vitro.
Based on in vitro data, alectinib is not a substrate of P-gp. Alectinib and M4 are not substrates of BCRP or
organic anion-transporting polypeptide (OATP) 1B1/B3. M4 was identified as a P-gp substrate.
Co-administration of multiple oral doses of 600 mg rifampicin once daily, a strong CYP3A inducer, with a
single oral dose of 600 mg alectinib reduced alectinib Cmax,and AUCinf by 51% and 73% respectively and
increased M4 Cmax and AUCinf 2.20 and 1.79-fold respectively. The effect on the combined exposure of
alectinib and M4 was minor, reducing Cmax and AUCinf by 4% and 18%, respectively.
Co-administration of multiple oral doses of 400 mg posaconazole twice daily, a strong CYP3A inhibitor, with a
single oral dose of 300 mg alectinib increased alectinib exposure Cmax and AUCinf by 1.18 and 1.75-fold
respectively, and reduced M4 Cmax and AUCinf by 71% and 25% respectively .The effect on the combined
exposure of alectinib and M4 was minor, reducing Cmax by 7% and increasing AUCinf 1.36-fold.
The metabolic ratio (M/P) of M4 and alectinib is 0.3-0.5 at normal conditions. However, when Alectinib is
coadministrated with the potent CYP3A4 inhibitor posaconazole and CYP3A inducer rifampin the M/P of M4 is
altered to 0.22 and 3.74 respectively.
Alectinib and M4 were identified as P-gp and BCRP inhibitors in vitro.
Assessment report
EMA/197343/2017 Page 52/122
As alectinib exhibits pH dependent solubility, a potential interaction with esomeprazole that change gastric pH
has been evaluated. Multiple doses of esomeprazole, a proton pump inhibitor, 40 mg once daily,
demonstrated no clinically relevant effect on the combined exposure of alectinib and M4.
In vitro, alectinib and its major active metabolite M4 are inhibitors of the efflux transporters P-glycoprotein
(P-gp) and BCRP.
In vitro, alectinib and M4 show weak time-dependent inhibition of CYP3A4, and alectinib exhibits a weak
induction potential of CYP3A4 and CYP2B6 at clinical concentrations.
Multiple doses of 600 mg alectinib had no influence on the exposure of midazolam (2 mg), a sensitive CYP3A
substrate.
2.4.3. Pharmacodynamics
Mechanism of action
No mechanism of action studies have been conducted.
Primary and Secondary pharmacology
Primary pharmacology
The EML4-ALK fusion gene product is a chimeric oncoprotein with constitutive tyrosine kinase (TK) activity. A
large number of ALK EML4 fusion variants have been described and there are also additional fusion partners
such as TGF.
ALK positive (ALK+) tumours treated with the first licensed ALK inhibitor (ALKi) invariably develop secondary
resistance that might be related to secondary mutations, fusion gene amplification and activation of
alternative signalling pathways. Alectinib shows in essence full inhibitory activity in the most predictable
secondary mutation (L1196M) associated with resistance to treatment with crizotinib, but less activity in case
of other mutations such as G1202R. Resistance associated mutations related to alectinib treatment have also
been described, in case of the resistance mutation I1171N ceritinib has been shown to be active. Of note in
terms of fold change to the wild type mutation alectinib appears as sensitive to resistance mutations as
crizotinib, the main difference being that higher exposure intensity is tolerated for alectinib (for details see
non-clinical section).
RET (rearranged during transfection), the other TK targeted by alectinib, encodes a receptor tyrosine kinase
of importance for proliferation and differentiation. Mutations in RET have been identified e.g. in NSCLC and
alectinib has shown promising inhibitory potential.
Secondary pharmacology
QTc: Based on non-clinical studies the risk for QT prolongation is considered low, about 8-30 fold margin
based on free Css and Cmax (please refer to the non-clinical section). A total of 221 patients who received
alectinib 600 mg BID were analysed with respect ECG changes without conspicuous findings.
There was no observed exposure – QTcF relationship.
Assessment report
EMA/197343/2017 Page 53/122
Heart rate: The heart rate (HR) decreased with about 10 to 13 beats per minute (see safety). This effect is
considered ALK inhibitor class related. A clear exposure – HR relationship was shown. This was not seen in
non-clinical studies, but might have been masked by hypotension induced increase in HR. Hypotension was
not reported in clinical studies.
Across the dose range of 300 to 900 mg BID in phase studies, graphical analyses showed an exposure-
response relationship for the change in tumour size over time. Lower exposure was associated with less
decrease in tumour size over time. At the 600 mg dose level, the Cox proportional-hazards analysis showed
that the variability in exposure was not associated with differences in PFS.
Assessment report
EMA/197343/2017 Page 54/122
The explorative exposure-response analyses indicate that lower alectinib doses could potentially results in
reduced efficacy, putatively related also to pattern of secondary mutations. If an increase in exposure from
doses higher than 600 BID will result in higher efficacy is difficult to determine from the rather limited data
available. However, an indication that the effect appears to plateau at 900 mg BID is visible in the graphical
analysis of the phase I data.
2.4.4. Discussion on clinical pharmacology
M4, but not alectinib, is a substrate of P-glycoprotein (P-gp). Alectinib, but not the active metabolite M4,
demonstrated penetration into the central nervous system (CNS) with CSF concentrations corresponding to
the unbound concentration in plasma. Even so, Alectinib has shown to be effective also against brain
metastases and therefore the uncertainty of M4 CNS distribution is considered acceptable.
The combined data on absolute bioavailability and mass balance of alectinib in study NP28989 is crucial to
elucidate the elimination pathways of alectinib. Metabolism is the major elimination pathway with some
possible contribution of biliary/intestinal secretion.The major drug interaction risks have been identified and
handled.
The main elimination pathway of alectinib is via metabolism/excretion in the liver. Therefore, the ongoing
clinical study on the effect of hepatic impairment on alectinib and M4 PK is important and planned to be
submitted post-approval. Thus, this study has been included in the risk management plan as a post-approval
commitment.
Population PK analysis supports dose proportionality for alectinib across the dose range of 300 to 900 mg
under fed conditions.
Based on available data, no dose adjustment is required in patients with mild hepatic impairment. Alectinib
has not been studied in patients with moderate to severe hepatic impairment. Therefore, Alectinib is not
recommended in patients with moderate to severe hepatic impairment (see sections 4.2 and 5.2 of the
SmPC).
The effect of hepatic impairment on the pharmacokinetics of alectinib will be further investigated in a
multiple-center, open-label study following single oral dosing of alectinib (study NP29783) in subjects with
hepatic impairment and in matched healthy subjects. The final study report will be submitted by 30 April
2018 (see RMP).
No dose adjustment is required in patients with mild or moderate renal impairment. Alectinib has not been
studied in patients with severe renal impairment. However, since alectinib elimination via the kidney is
negligible, no dose adjustment is required in patients with severe renal impairment (see sections 4.2 and 5.2
of the SmPC).
Age, race and gender had no clinically meaningful effect on the systemic exposure of alectinib and M4.
Exposure of alectinib and M4 decreased with increasing weight after dosing to steady-state. However, the
exposure seems to reach a plateau and no dose adjustments seems warranted. Therefore, it is stated in the
SmPC that although PK simulations do not indicate a low exposure in patients with extreme body weight (i.e.
>130 kg), alectinib is widely distributed and clinical studies for alectinib enrolled patients within a range of
body weights of 36.9-123 kg. There are no available data on patients with body weight above 130 kg.
Assessment report
EMA/197343/2017 Page 55/122
The limited data on the safety and efficacy of Alectinib in patients aged 65 years and older do not suggest
that a dose adjustment is required in elderly patients (see sections 4.2 and 5.2 of the SmPC). There are no
available data on patients over 80 years of age.
Based on the effects on the combined exposure of alectinib and M4, no dose adjustments are required when
Alectinib is co-administered with CYP3A inducers. Appropriate monitoring is recommended for patients taking
concomitant strong CYP3A inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin,
rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum)).
Based on the effects on the combined exposure of alectinib and M4, no dose adjustments are required when
Alectinib is co-administered with CYP3A inhibitors. Appropriate monitoring is recommended for patients
taking concomitant strong CYP3A inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin,
ketoconazole, itraconazole, voriconazole, posaconazole nefazodone, grapefruit or Seville oranges).
No dose adjustments are required when Alectinib is co-administered with proton pump inhibitors or other
medicinal products which raise gastric pH (e.g. H2 receptor antagonists or antacids).
A risk for induction of CYP2B6 and PXR regulated enzymes apart from CYP3A4 cannot be completely excluded
based on the submitted in vitro data. However, given the totality of data regarding CYP3A induction and TDI
(e.g. midazolam study, hepatocyte induction study) the risk for either a clinically relevant PXR/CAR induction
or a clinically relevant TDI of CYP3A4 is considered limited and no dose adjustment is required for co-
administered CYP3A substrates. The effectiveness of concomitant administration of oral contraceptives may
be reduced.
Since alectinib and its major active metabolite M4 are inhibitors of the efflux transporters P-gp and BCRP,
they may have the potential to increase plasma concentrations of co-administered substrates of P-gp or
BCRP. When Alectinib is co-administered with P-gp substrates (e.g., digoxin, dabigatran etexilate, topotecan,
sirolimus, everolimus, nilotinib and lapatinib), or BCRP substrates with narrow therapeutic index (e.g.,
methotrexate, mitoxantrone, topotecan and lapatinib), appropriate monitoring is recommended (see section
4.5 of the SmPC).
Alectinib has shown reproductive toxicity in animal studies and conducting an interaction study between
alectinib and oral contraceptives is not considered feasible. Therefore, the issue of appropriate contraception
during and after alectinib treatment has been solved by clear recommendations in the SmPC.
As part of a scientific advice procedure, the Applicant was recommended to introduce an alternative capsule
formulation for oral administration containing a lower amount of SLS post-approval.
2.4.5. Conclusions on clinical pharmacology
The pharmacokinetic characteristics of alectinib and its active metabolite M4 have been sufficiently
characterized.
The CHMP considers the following measures necessary to address the issues related to pharmacology:
- In order to reduce the potential SLS-related effect on GI tract, the applicant is recommended to introduce
an alternative capsule formulation for oral administration containing a lower amount of SLS post-approval.
- Alecensa has not been studied in patients with moderate to severe hepatic impairment. The applicant will
conduct a study to assess the PK in subjects with hepatic impairment and submit the results by 30 April
2018.
Assessment report
EMA/197343/2017 Page 56/122
2.5. Clinical efficacy
The first in human Phase I/II study, AF-001JP, in ALK-positive crizotinib-naïve NSCLC patients was conducted
by Chugai. Based on data from this study (ORR about 90+%) alectinib was granted marketing access in
Japan on 4 July 2014 with the indication: ALK-fusion gene-positive, unresectable, recurrent / advanced
NSCLC. The dose was 300 mg BID. Further dose escalation was stopped due to regulatory concerns related
to the high dose of the excipient SLS (see quality and non-clinical).
In July 2014, Roche initiated a Phase III global study to evaluate alectinib versus crizotinib in treatment-
naïve patients with advanced ALK-positive NSCLC (BO28984, ALEX study). This trial is currently ongoing and
no data are available. A separate Phase III Chugai-sponsored study (JO28928) with a design similar to the
BO28984 (ALEX) study in patients who were ALK-inhibitor naïve and may have received up to one prior
chemotherapy regimen for ALK–positive NSCLC is ongoing in Japan.
This submission is based on two ongoing Phase I/II studies evaluating alectinib in ALK-positive NSCLC
patients who have progressed on crizotinib treatment (studies NP28673 and NP28761).
2.5.1. Dose response study
Study NP28761 – Phase I
A total of 47 patients with ALK positive NSCLC after failure on crizotinib, were enrolled and treated in cohorts
in a staggered manner at an initial dose level of 600 mg/day (300 mg BID). Patients in Cohort 1 received
alectinib under fasting conditions whereas all other cohorts received alectinib under fed conditions.
Figure 2: Phase I Study Design :
Assessment report
EMA/197343/2017 Page 57/122
Figure 3: Phase I Dosing Schedule :
Figure 4: Phase I Dose Escalation Process:
Table 25: Phase I Cohort Dose Levels
DLTs
DLT was defined as:
1. Grade 4 thrombocytopenia
2. Grade 3 thrombocytopenia with bleeding
3. Grade 4 neutropenia continuing for ≥ 7 consecutive days
4. Non-hematological toxicity of Grade 3 or higher
5. Adverse events that required suspension of treatment for a total of ≥ 7 days
Assessment report
EMA/197343/2017 Page 58/122
Two DLTs were reported in the alectinib 900 mg BID PK bridging cohort: AE of Grade 3 headache in one
patient (progressive but asymptomatic brain metastases) and an AE of Grade 3 neutrophil count decreased in
one patient requiring study drug interruption for a week.
2.5.2. Main studies
Due to the similarity in study designs and patient eligibility criteria in the two pivotal studies NP28761 and
NP28673, data will be presented in parallel.
Study NP28761: A Phase I/II Study of the ALK Inhibitor alectinib (CH5424802/RO5424802) in
patients with ALK-rearranged Non-Small Cell Lung Cancer previously treated with Crizotinib.
Study NP28761 is an on-going multi-centre, single arm, open-label, dose escalation study to determine the
safety, tolerability and activity of alectinib as a single agent in patients with either locally advanced (AJCC
Stage IIIB) and not amenable to curative therapy or metastatic (AJCC Stage IV) ALK-positive NSCLC who had
experienced disease progression on crizotinib with or without prior chemotherapy.
Radiologic assessments in study NP28761 were performed every six weeks from Cycle 1 Day 1 at Cycles 2, 4,
and 6 between Days 14 to 21 and every 9 weeks thereafter.
Methods
• Study participants
Inclusion criteria
1. Provided informed consent
2. ≥ 18 years
3. ECOG PS ≤ 2
4. Patients with locally advanced (AJCC Stage IIIB) not amenable to curative therapy or metastatic (AJCC
Stage IV) NSCLC
5. Histologically-confirmed NSCLC
6. ALK-rearrangement confirmed by a FDA-approved test
7. Prior treatment with crizotinib. A washout period of at least 1 week was required from last crizotinib dose
and dosing with alectinib
7. Measurable disease defined by RECIST 1.1
8. Adequate hematologic function
9. Adequate hepatic function
10. Adequate renal function
11. For women who were not postmenopausal (12 months of amenorrhea) or surgically sterile (absence of
ovaries and/or uterus): agreement to use two adequate methods of contraception, including at least one
method with a failure rate of < 1% per year (e.g., hormonal implants, combined oral contraceptives,
Assessment report
EMA/197343/2017 Page 59/122
vasectomized partner), during the treatment period and for at least 3 months after the last dose of study
drug
12. For men: agreement to use a barrier method of contraception during the treatment period and for at
least 80 days after the last dose of study drug
13. Women of childbearing potential had to have a negative serum or urine pregnancy test result within 7
days of starting study drug
14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study
procedures
Exclusion Criteria
1. History of hypersensitivity to any of the additives in the alectinib formulation (lactose monohydrate,
microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose, sodium lauryl sulfate (SLS),
magnesium stearate)
2. Cytotoxic chemotherapy within 4 weeks or 5 half-lives of previous therapy prior to starting the study drug,
whichever was shorter
3. Radiotherapy within 14 days prior to starting the study drug
4. Prior therapy with an ALK inhibitor other than crizotinib.
5. Not recovered from adverse events (AEs) or hematologic and/or biochemical toxicities due to previous
treatments to a Grade 1 or less specified in NCI − CTCAE v4.0 except for alopecia
6. Brain or leptomeningeal metastases that were symptomatic and/or requiring treatment. Patients were
allowed on study only if the following criteria were met:
● Patients who had previously been treated with whole-brain radiotherapy (WBRT) or gamma-knife
radiosurgery had to have completed treatment and discontinued the use of corticosteroids for this indication
for ≥ 2 weeks and any signs and/or symptoms of brain metastases had to be stable for at least 2 weeks prior
to the first dose of alectinib
● Patients who had not previously been treated with WBRT or gamma knife radiosurgery had to be
asymptomatic without neurological signs and clinically stable for ≥ 2 weeks without steroid treatment for CNS
metastases prior to the first dose of alectinib [Patients who had not previously been treated with WBRT or
gamma knife radiosurgery and who were not asymptomatic were not eligible for the study. However, they
could be re-screened after completing WBRT or gamma-knife treatment. They had to have discontinued the
use of corticosteroids for this indication for ≥ 2 weeks and any symptoms had to be stable without
deterioration for at least 2 weeks prior to the first dose of study drug]
7. History of myocardial infarction or stroke within 6 months, congestive heart failure greater than the New
York Heart Association (NYHA) class II, unstable angina pectoris, cardiac arrhythmia requiring treatment or
family history of sudden death from cardiac-related causes
8. History of or current active infection with HIV, hepatitis B virus, or hepatitis C virus
9. Major surgery within 4 weeks of starting study drug. Surgery for brain metastases within 2 weeks of
starting study drug. Intravenous port placement was not considered as a major surgery
Assessment report
EMA/197343/2017 Page 60/122
10. Clinically significant GI abnormality that would affect the absorption of drug such as malabsorption
syndrome or major resection of the small bowel or stomach
11. Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with
study requirements
12. Currently under alcohol or drug abuse rehabilitation or treatment program
13. History of another malignancy, unless patient had been disease-free for 3 years. Individuals with the
following cancers were eligible if diagnosed and treated within the past 3 years: any carcinoma in situ, and
basal cell or squamous cell carcinoma of the skin
14. Pregnant or lactating women
15. Baseline corrected QT interval (QTc) > 470 ms, or baseline symptomatic bradycardia < 45 beats per
minute
16. Administration of strong/ potent cytochrome P450 3A (CYP3A) inhibitors or inducers within 14 days or 5
half-lives (whichever was longer) prior to first administration of study drug(s) and while on treatment except
for oral corticosteroids up to 20 mg prednisolone equivalent per day, or agents with potential QT prolonging
effects within 14 days prior to first administration of study drug(s) and while on treatment.
• Treatments
Alectinib was administered to the patient orally BID starting on Day 1 through Day 21 of each 21-day
treatment cycle. The RP2D determined in Phase I was 600 mg BID. Patients were treated continuously until
disease progression, death, or withdrawal for any other reason.
Figure 5: Phase II dosing schedule (NP28761)
• Objectives
Primary objective
To evaluate the efficacy of alectinib based on ORR (according to RECIST 1.1) as per independent review
committee (IRC) in patients ALK-positive NSCLC who have failed crizotinib.
Secondary objectives
• ORR according to RECIST 1.1 based on investigator review of radiographs
• DCR, DOR and PFS according to RECIST v1.1 by IRC and investigator review of radiographs
• OS
• safety of alectinib
Assessment report
EMA/197343/2017 Page 61/122
• to characterize the PK of alectinib and metabolite(s)
• to assess QoL using the EORTC QLQ − C30 and − LC13
• CNS ORR (CORR) in patients with CNS metastases who have measurable disease in the CNS at baseline,
based on IRC review of radiographs by RECIST 1.1 and Response Assessment in Neuro-Oncology (RANO)
criteria
• CNS duration of response (CDOR) in patients who have a CNS objective response based on IRC review of
radiographs by RECIST 1.1 and RANO criteria
• CNS progression rates (CPR) at 3, 6, 9 and 12 months based on cumulative incidence by IRC review of
radiographs by RECIST v1.1 and RANO criteria.
Exploratory objectives
• To assess blood based methods to detect point mutations in plasma
• To identify molecular determinants of clinical resistance to ALK inhibitors
• To identify potential genetic determinants of PK variability and safety parameters (pharmacogenomics
research)
• To assess alectinib CNS penetration by measuring the cerebrospinal fluid (CSF): plasma concentration ratio
• Outcomes/endpoints
Primary endpoint
ORR (IRC assessed) - Proportion of patients achieving confirmed CR or PR
Secondary endpoints
ORR (investigator assessed) - Proportion of patients achieving confirmed CR or PR
DCR - Proportion of patients achieving CR, PR or SD lasting ≥ 12 weeks
DOR – duration of response
PFS – progression free survival
OS – Overall survival
CORR (IRC assessed) – CNS ORR
CDOR (IRC assessed) – CNS DOR
CPR (IRC assessed) – CNS progression rate
• Sample size
Assessment report
EMA/197343/2017 Page 62/122
A sample size of 85 was chosen such that the lower limit of the 2-sided 95% confidence interval (CI) (using a
Clopper-Pearson CI) around the point estimate of the ORR allowed identification of a clinically relevant
response in order to reject the null hypothesis (H0) that ORR = 35%. With 85 patients, an observed response
rate of 46% (39/85 responses) would have a lower limit of the two-sided 95% CI of 35% which is considered
to be clinically relevant, and thus the null hypothesis could be rejected.
The primary analysis was to occur once all patients enrolled in Phase II were followed for a minimum of 12
weeks, essentially after two tumour assessments had been performed in order that any observed CR or PR
could be confirmed, unless patients progressed, died or withdrew sooner.
A non-binding interim analysis for futility was planned after 30 patients had been dosed and followed at least
until their first post-baseline tumour assessment (6 weeks post-treatment). The analysis was based on the
investigator-assessed ORR in RE population. If ≥ 9 responders were observed, the Phase II portion would
continue to enrol a planned total of approximately 85 patients. If ≤ 8 responders were observed, accrual
could be discontinued. The futility analysis was performed by an IMC.
• Randomisation
N/A
• Blinding (masking)
N/A
Statistical methods
The following null (H0) and alternative (Ha) hypotheses were tested at a two-sided 5% significance level to
compare ORR according to RECIST per IRC review in the response evaluable (RE) population (i.e., the
primary efficacy endpoint):
H0: ORR = 35% versus Ha: ORR ≠ 35%
A sample size of 85 was chosen such that the lower limit of the 2-sided 95% confidence interval (CI) (using a
Clopper-Pearson CI) around the point estimate of the ORR allowed identification of a clinically relevant
response in order to reject the null hypothesis (H0) that ORR = 35%. With 85 patients, an observed response
rate of 46% (39/85 responses) would have a lower limit of the two-sided 95% CI of 35%.
The primary analysis, reported in this CSR, was to occur once all patients enrolled in Phase II were followed
for a minimum of 12 weeks, i.e., after two tumor assessments had been performed in order that any
observed CR or PR could be confirmed, unless patients progressed, died or withdrew sooner.
A non-binding interim analysis for futility was planned for Phase II after 30 patients had been dosed and
followed at least until their first post-baseline tumor assessment (6 weeks post-treatment). The analysis was
based on the investigator-assessed ORR using RECIST 1.1 in RE population. If ≥ 9 responders were
observed, the Phase II portion would continue to enroll a planned total of approximately 85 patients. If ≤ 8
responders were observed, accrual could be discontinued. The futility analysis was performed by an IMC.
Assessment report
EMA/197343/2017 Page 63/122
Results
Participant flow
Disposition of Patients in Phase II:
Recruitment
Patients were enrolled in 26 centres in the US and one site in Canada. The first patient was enrolled on 03
May 2012 and the last patient was enrolled on 04 August 2014.
The data cut-off date for the primary analysis was 24 October 2014 and the database lock date was 10
December 2014.
Conduct of the study
Six protocol amendments were made and a summary of the major changes relating to study design,
objectives or entry criteria is provided below.
Protocol Version 2: 18 November 2011
In Version 2 “NSCLC that has failed crizotinib treatment” was added to the inclusion criteria for Phase I.
Protocol Version 3: 14 May 2012
Key changes in Version 3 were modifications to the dose-escalation design of Phase I.
Protocol Version 4: 10 August 2012
Version 4 added surgery for brain metastases within two weeks of starting treatment to the list of exclusion
criteria and to allow concurrent radiation therapy for palliation or symptom relief of brain or bone metastases
within 24 hours of last dose of alectinib and re-start of study drug upon resolution of any radiation toxicity to
≤ Grade 1.
Assessment report
EMA/197343/2017 Page 64/122
Version 5: 12 March 2013
Phase II consisted of a single population of patients that had failed crizotinib Phase I (instead of two sub-
populations A [crizotinib-failed] and B [crizotinib-naïve]); the study design was modified to conduct Phase II
under fed conditions only; and measures of efficacy in the CNS (CNS response rate in patients with brain
lesions that were not irradiated and CNS relapse rate) were added to the secondary objectives for Phase II.
Version 6: 24 June 2013
The wash-out period for crizotinib was decreased from 2 weeks to 1 week in order to avoid potential disease
flare ups.
Version 7: 17 December 2013
The study population definition was changed to “Patients with locally advanced (AJCC Stage IIIB) not
amenable to curative therapy or metastatic (AJCC Stage IV) NSCLC” (previously “locally advanced or
metastatic NSCLC”); CORR, CDOR, CPR, and QoL using EORTC QLQ-C30 and QLQ-LC13 were added as
secondary efficacy endpoints for Phase II; measures of efficacy in CNS (CNS response rate in patients with
brain lesions that were not irradiated, and CNS relapse rate), were changed to CNS ORR, CNS DOR, and CNS
progression rate (CPR) assessed using RECIST v1.1 and RANO criteria; the statistical hypothesis for efficacy
and statistical methods (null hypothesis that ORR = 35% instead of ORR = 50%) were clarified.
Protocol violations
One patient had a major protocol violation at baseline. The patient tested ALK-positive with a non FDA-
approved FISH test. In the absence of any safety concerns noted, the patient continued to receive alectinib
and was not excluded from the study or analyses.
During the study ten major protocol violations occurred in eight patients (9%) for the following reasons:
• Use of prohibited medications/procedures (7 violations in five patients). These violations pertained to the
administration of corticosteroids at doses higher than allowed per protocol, potent CYP3A4 inhibitor and
radiosurgery/ radiotherapy. • Study drug not taken according to protocol (2 violations in 2 patients)
• Missing tumour assessment at a scheduled visit (1 violation in 1 patient).
At the time of discovering these violations, no safety concerns were identified. No patient who violated the
study protocol was excluded from any analysis and all patients continued on study drug as planned.
Baseline data
Table 26: Patient demographics and baseline characteristics in the safety population for Phase II
Assessment report
EMA/197343/2017 Page 65/122
Assessment report
EMA/197343/2017 Page 66/122
Table 27: Disease history of NSCLC in safety population (Phase II)
Table 28: Target lesions at baseline (IRC) in response evaluable population (Phase II)
Assessment report
EMA/197343/2017 Page 67/122
Numbers analysed
Table 29: Summary of analysis populations in Phase II
Outcomes and estimation
Primary Endpoint
ORR (IRC Assessed in RE Population)
Table 30: Objective Response Rate (IRC) in Phase II (RE Population)
Assessment report
EMA/197343/2017 Page 68/122
Figure 6: Waterfall Plot of Target Lesions Sum of Longest Diameter Best Change from Baseline (IRC) in RE population
Secondary endpoints
ORR (Investigator Assessed)
Table 31: ORR and DCR in Phase II (Investigator) (RE Population):
Assessment report
EMA/197343/2017 Page 69/122
Figure 7: Waterfall Plot of Target Lesions Sum of Longest Diameter Best Change from Baseline (Investigator) in Phase II (RE Population)
Concordance Analysis between IRC and Investigator Assessments of ORR
Table 32: Concordance Analysis between IRC-Determined and Investigator-Determined Best Overall Response in Phase II (Investigator RE Population)
Table 33: Concordance Analysis between IRC-Determined and Investigator-Determined Best Overall Response in Phase II (IRC RE Population)
Duration of Response (DOR)
Of the 33 patients achieving PR in the IRC assessment of the RE population, six patients experienced
progression of their disease. The median DOR was 7.5 months.
Progression - Free Survival (PFS)
At the time of the data cut off, 35 of 87 patients (40%) had progressed or died based on IRC assessments.
The majority due to PD. The estimated median duration of PFS was about 6 months.
Overall Survival (OS)
At the time of data cut-off, 14% enrolled in Phase II had died. Due to the low number of deaths, the median
OS could not be estimated.
Assessment report
EMA/197343/2017 Page 70/122
Ancillary analyses
Health-Related Quality of Life (HRQoL),
Improvements (changes from baseline of ≥ 10%; Osoba et al 1998, 2005) were seen in the European
Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) items
Global Health Status, Emotional Functioning and Social Functioning and also the symptom scales Fatigue and
Pain, indicating improvement of these symptoms.
Summary of main study(ies)
The following tables summarise the efficacy results from the main studies supporting the present application.
These summaries should be read in conjunction with the discussion on clinical efficacy as well as the benefit
risk assessment (see later sections).
Table 34: Summary of Efficacy for trial NP28761
Title: A Phase I/II Study of the ALK Inhibitor alectinib (CH5424802/RO5424802) in patients with ALK-rearranged Non-Small Cell Lung Cancer previously treated with Crizotinib.
Study identifier NP28761
Design multi-centre, single arm, open-label, dose escalation study
Duration of main phase: 03 May 2012 to 24 October 2014 (first patient screened to data cut-off date for primary analysis)
Hypothesis Exploratory
Treatments groups
Alectinib Alectinib was administered to the patient orally BID starting on Day 1 through Day 21 of each 21-day treatment cycle. The RP2D determined in Phase I was 600 mg BID. Patients were treated continuously until disease progression, death, or withdrawal for any other reason.
Endpoints and definitions
Primary endpoint
IRC assessed ORR
Proportion of patients achieving confirmed* CR or PR, calculated using best overall response
Secondary endpoint
Investigator-assessed ORR
Proportion of patients achieving confirmed CR or PR, calculated using best overall response
Secondary endpoint
DOR Interval between 1st documented response (CR or PR) and 1st documented PD or death
Secondary endpoint
PFS Interval between 1st dose of alectinib and date of 1st documented PD (IRC or investigator) or death
Secondary endpoint
OS
Interval between 1st dose of alectinib and date of death
Results and Analysis
Analysis description Primary Analysis Database lock: 24 October 2014
Analysis population and time point description
Response evaluable population: all patients with measurable disease at baseline who had a baseline tumour assessment and received at least one dose of alectinib.
Descriptive statistics and estimate variability
Treatment group
ALK-positive NSCLC previously treated with crizotinib
ORR (IRC) % N= 69
47.8
95% CI
[35.6, 60.2]
Assessment report
EMA/197343/2017 Page 71/122
ORR (investigator) % N= 87
46.0
95% CI
[35.2, 57.0]
DOR (months) Median N=33
7.5
95% CI
[4.9, NE]
PFS (months) Median N=87
6.3
95% CI
[5.5, NE]
OS (months) Median N=87
NE
95% CI
[10.1, NE]
Analysis description Secondary analysis Database lock: 22 January 2016
Descriptive statistics and estimate variability
Treatment group
ALK-positive NSCLC previously treated with crizotinib
ORR (IRC) % N= 67
52.2
95% CI
[39.7, 64.6]
ORR (investigator) % N=87
52.9
95% CI
[41.9, 63.7]
DOR (months) Median N=35
14.9
95% CI
[6.9, NE]
PFS (months) Median N=87
8.2
95% CI
[6.3, 12.6]
OS (months) Median N=87
22.7
95% CI
[17.2, NE]
Assessment report
EMA/197343/2017 Page 72/122
Study NP28673: An open-label, non-randomized, multicentre Phase I/II trial of alectinib
(RO5424802) given orally to Non-Small Cell Lung Cancer patients who have ALK mutation and
who have failed crizotinib treatment.
This study was conducted in three parts:
● Phase I, Part 1: A dose-escalation phase with the objective of assessing the safety, tolerability, and PK of
alectinib 600 mg BID and 900 mg BID dose regimens. During the conduct of Part 1 for this study, the RP2D
(600 mg BID) was confirmed in study NP28761 and Part 1 and Part 2 were combined.
● Phase II, Part 2: A safety and efficacy evaluation phase
● Phase II, Part 3: A post-progression treatment phase
Radiologic assessments were performed at screening and every 8 weeks in the first year, every 12 weeks in
the second year and every 16 weeks subsequently until disease progression.
Patients in Part 2 that were considered by the investigator to still benefit from treatment, could be included in the treatment beyond progression in Part 3, where they could continue to receive alectinib alone or, if their
tumour harboured an EGFR activating mutation, in combination with erlotinib. However, all patients in Part 3 have continued with alectinib monotherapy only. No patients have received erlotinib in combination with alectinib at this point.
Figure 8: Study design – Part 2 and 3 (Study NP28673)
Methods
Study Participants
See inclusion/exclusion criteria for Study NP28671
Assessment report
EMA/197343/2017 Page 73/122
Treatments
Alectinib as a single agent was administered orally at a dose of 600 mg BID within 30 minutes after meals in
the morning and evening. Patients received alectinib at the stated dose for 5 cycles (28 days) continuously,
starting on Cycle 1, Day 1. When a patient missed a dose of alectinib, it could be taken within 4 hours of the
scheduled time. If the time was greater than 4 hours, or the patient vomited the dose, the patient was
instructed to wait and take the next scheduled dose.
Objectives/endpoints
Co-Primary Efficacy Objectives/endpoints
• ORR as per central IRC using RECIST v1.1 in the overall population (with and without prior exposure of
cytotoxic chemotherapy treatments).
• ORR as per central IRC using RECIST v1.1 in patients with prior exposure of cytotoxic chemotherapy
treatments.
Secondary Efficacy Objectives/endpoints
• ORR as per central IRC using RECIST criteria v1.1 in patients without prior exposure of cytotoxic
chemotherapy treatments
• ORR per investigator review of radiographs using RECIST v1.1
• DCR based on IRC and investigator review of radiographs
• DOR based on IRC and investigator review of radiographs
• PFS based on IRC and investigator review of radiographs
• CNS Objective Response Rate (CORR) in patients with CNS metastases who had measurable disease in the
CNS at baseline, based on IRC review of radiographs
• CNS Duration of Response (CDOR) in patients who have a CNS Objective Response based on IRC review of
radiographs
• CNS Progression Rates (CPRs) at 3, 6, 9 and 12 months based on cumulative incidence by IRC review of
radiographs
• To assess OS
Safety Objectives
• To evaluate the safety profile of alectinib using the NCI-CTCAE v 4.03
• To assess the effect of alectinib on cardiac repolarization (corrected QT interval [QTc])
Exploratory Objectives
• To evaluate ORR in patients with EGFR mutation who had experienced disease progression on alectinib
alone and were subsequently treated with a combination of alectinib and erlotinib (Part 3)
• To evaluate the PK of alectinib and metabolite(s), and erlotinib in patients with EGFR mutation who have
experienced disease progression on alectinib alone and who received the combination of alectinib and
erlotinib (Part 3)
Assessment report
EMA/197343/2017 Page 74/122
• To evaluate the safety profile of alectinib in combination with erlotinib using the NCI-CTCAE v 4.03 (Part 3)
• To evaluate the ALK mutations in tumor and blood samples and correlate it with response to alectinib,
where possible
• To evaluate the co-expression of EGFR mutation with ALK translocation and ALK mutation status
• To investigate potential bypass mechanisms of ALK inhibition, such as cMET, KRAS and cKIT
Sample size
A sample size of 85 was chosen such that the lower limit of the two-sided 95% confidence interval (CI; using
an exact Clopper-Pearson CI) around the point estimate of the ORR allowed identifying a clinically relevant
response in order to reject the null hypothesis that ORR = 35%. With 85 patients, an observed response rate
of 46% (39/85 responses) would have a lower limit of the two-sided 95% CI of 35.02% which is considered
to be clinically relevant and the null hypothesis would be rejected. Therefore, at least 85 patients treated with
prior chemotherapy would need to be enrolled. A total enrolment of 130 patients was planned, with a
maximum of 45 chemo-naïve patients to ensure the minimum number requirement of 85 prior-chemotherapy
patients was met.
With 130 patients, an observed response rate of 44% (57/130 responses) would have a lower limit of the
two-sided 95% CI of 35.2% which is considered to be clinically relevant and the null hypothesis would be
rejected. With 130 patients, there was 93% power, based on an exact test for single proportion, to detect a
15% increase in ORR from 35% to 50% at the 5% two-sided significance level.
Randomisation
N/A
Blinding (masking)
N/A
Statistical methods
Hierarchical testing was used. The primary analysis tested the null hypothesis of the best ORR for alectinib
equal to 35%, against the alternative hypothesis that the best ORR for alectinib was not equal to 35%, with
two-sided alpha of 0.05. This primary analysis was tested in the all patients group (patients with and without
prior exposure to cytotoxic chemotherapy treatment).
If the primary test was significant, then the subsequent test also tested the null hypothesis of the best ORR
for alectinib equal to 35%, against the alternative hypothesis that the best ORR for alectinib was not equal to
35%, with two-sided alpha of 0.05. However this subsequent analysis was tested only in the group of
patients with prior exposure to cytotoxic chemotherapy treatment.
Assessment report
EMA/197343/2017 Page 75/122
Results
Participant flow
Recruitment
A total of 138 patients were enrolled and treated in Phase II of the study at 56 sites in 16 countries globally
(France (11), the US (10), Italy (8), Spain (6), the Republic of Korea (4), Taiwan (3), Germany (3), the
Netherlands (2), Australia (2), UK (1), Luxemburg (1), Belgium (1), Sweden (1), Singapore (1), Denmark (1)
and the Russian Federation(1).
Data cutoff date was 18 August 2014.
Conduct of the study
The initial protocol, dated 12 December 2012, was amended four times. A summary of the main changes
made to the protocol are summarised below.
Protocol Amendment 1 (Version 2): 21 December 2012
Protocol Version 1 was amended to remove exclusion criterion regarding use of anticoagulation or
thrombolytic agent within 2 weeks prior to Day 1.
Protocol Amendments 3 and 4 (Versions 4 and 5): 19 November 2013 (v4) and 30 January 2014 (v5)
During submission of protocol Version 4, additional changes were identified that required the creation of
protocol amendment Version 5. The following changes include those made to Versions 4 and 5:
1. To incorporate a MDZ DDI sub-study to be conducted in approximately 14 additional patients with ALK-
positive NSCLC.
Assessment report
EMA/197343/2017 Page 76/122
2. To clarify the Stage IIIb NSCLC study patients to be included in the study, as per FDA request: Only Stage
IIIb NSCLC patients whose disease was not amenable to curative therapy would be eligible for the study, as
other Stage IIIb patients may be eligible to other multimodality treatments.
3. To remove the restriction for the last dose of crizotinib to be within 60 days from the first dose of alectinib.
This restriction was first put in place to avoid possible resensitization to crizotinib and ensure that all patients
are true crizotinib-failure. However, this limitation was thought to potentially affect enrollment as it may not
have allowed enough time for patients to progress on subsequent chemotherapy treatments.
4. To update the permitted and prohibited medications based on the available DDI information for alectinib
Violations at Baseline
Table 35: Summary of Major Protocol Violations at Baseline (NP28673)
Violations during study
In total, 26 major protocol violations occurred in 23 patients (17%) during the study for the following
reasons:
• Use of prohibited medications/procedures (19 violations [18 medications, 1 procedure] in 16 patients). Of
note, of the 18 violations due to use of prohibited medications, nine were due to use of antacids and P-gp
substrates. While these were considered prohibited concomitant medications at the time these violations
occurred, their use was permitted in the latest version (Version E) of the study protocol.
• Study drug not taken according to protocol (6 violations in 6 patients)
• Missing tumour assessment at a scheduled visit (1 violation in 1 patient).
No patient who violated the study protocol was excluded from any analysis (efficacy or safety) and all
patients continued on study drug as planned.
Assessment report
EMA/197343/2017 Page 77/122
Baseline data
Table 36: Demographics and Baseline Characteristics in the Safety Population (Data Cut-off Date: 18 August 2014) – study NP28673
Assessment report
EMA/197343/2017 Page 78/122
Table 37: Disease History of NSCLC in Safety Population (Data Cutoff Date: 18 August 2014) – study NP28673
Assessment report
EMA/197343/2017 Page 79/122
Table 38: Number of Prior Regimens for Metastatic NSCLC and Prior Crizotinib Treatment (Safety Population)
Numbers analysed
Table 39: Analysis Populations (NP28673)
Assessment report
EMA/197343/2017 Page 80/122
Outcomes and estimation
Primary endpoint
ORR – IRC-Assessed (Overall RE Population)
Table 40: ORR and DCR (IRC) in the RE Population (NP28673)
Figure 9: Waterfall Plot of Target Lesions Sum of Longest Diameter Best Change from Baseline (IRC) in RE Population (NP28673)
Assessment report
EMA/197343/2017 Page 81/122
Updated ORR data were submitted during the procedure.
Table 41: ORR in Response Evaluable Population as Assessed by the IRC (NP28673)
Assessment report
EMA/197343/2017 Page 82/122
ORR – IRC-Assessed (Chemotherapy-Pretreated Patients)
Table 42: ORR and DCR (IRC) in Patients with Prior Chemotherapy in the RE Population (NP28673)
Assessment report
EMA/197343/2017 Page 83/122
Secondary endpoints
ORR (Investigator Assessment)
Table 43: ORR and DCR (Investigator) in the RE Population (NP28673)
Assessment report
EMA/197343/2017 Page 84/122
Updated DCR data were submitted during the procedure.
Table 44: Summary of DCR in Response Evaluable Population as Assessed by the IRC and Investigator (NP28673)
Figure 10: Waterfall Plot of Target Lesions Sum of Longest Diameter Best Change from Baseline (Investigator) in RE Population (NP28673)
Assessment report
EMA/197343/2017 Page 85/122
Table 45: Concordance Analysis Between the IRC-Determined and the Investigator-Determined Best Overall Response (NP28673)
DOR
Table 46: Summary of Duration of Response (NP28673)
Assessment report
EMA/197343/2017 Page 86/122
CNS ORR (CORR, by IRC)
Table 47: CORR Based on RECIST (IRC) in Patients with Measurable CNS Lesions at Baseline (NP28673)
Figure 11: Waterfall Plot of CNS Target Lesions Sum of Longest Diameters Best Change from Baseline for Patients with Measurable CNS Lesions at Baseline Based on RECIST (IRC) – Study NP28673
Assessment report
EMA/197343/2017 Page 87/122
CNS DOR (CDOR, by IRC)
Table 48: CDOR for Patients with Measurable CNS Lesions at Baseline Based on RECIST (IRC) – study NP28673
CNS Progression Rate (CPR, by IRC)
The analysis of CPR was based on the CNS RECIST v1.1 and the full RECIST v1.1 IRC review of scans.
Progressions were identified in target, non-target and new lesions from CNS RECIST v1.1 and from
progressions in the CNS in non-target and new lesions in the full RECIST v1.1 IRC review.
Table 49: CPRs for All Patients Based on CNS RECIST (IRC) in the Safety Population (NP28673)
Assessment report
EMA/197343/2017 Page 88/122
Ancillary analyses
Subgroup analyses
Table 50: – ORR by subgroup (INV) RE population (NP28673)
Summary of main study(ies)
The following tables summarise the efficacy results from the main studies supporting the present application.
These summaries should be read in conjunction with the discussion on clinical efficacy as well as the benefit
risk assessment (see later sections).
Table 51: Summary of Efficacy for trial NP28673
Title: An open-label, non-randomized, multicentre Phase I/II trial of alectinib (RO5424802) given orally to non-small cell lung cancer patients who have ALK mutation and who have failed crizotinib treatment.
Study identifier NP28673
Design An open-label, non-randomized, multicentre Phase I/II trial
Duration of main phase:
20 June 2013 − 18 August 2014 (first patient in until data cut-off date for primary analysis).
Hypothesis Exploratory
Treatments groups
Alectinib
600 mg BID alectinib, orally for 5 cycles (28 days) continuously starting on Cycle 1, Day 1 until disease progression, death, or withdrawal for any other reasons.
Endpoints and definitions
Co-Primary endpoint
ORR by IRC in the response evaluable population
A best overall response (BOR) of complete response (CR) or partial response (PR) in all patients with measurable disease at baseline
Assessment report
EMA/197343/2017 Page 89/122
Co-Primary endpoint
ORR by IRC in the subgroup of patients who received previous chemotherapy
BOR of CR or PR in the subgroup of patients who received previous chemotherapy
Secondary endpoint
ORR by Investigator
Proportion of patients achieving best response of CR or PR
Secondary endpoint
CORR (IRC-assessed)
Proportion of patients achieving CR or PR of BL CNS lesions
Secondary endpoint
DOR Interval between 1st documented response (CR or PR) and 1st documented PD or death
Secondary endpoint
PFS Interval between 1st dose of alectinib and date of 1st documented PD (IRC or investigator) or death
Secondary endpoint
OS
Interval between 1st dose of alectinib and date of death
Results and Analysis
Analysis description Primary Analysis Database lock: 8 January 2015
Analysis population and time point description
Response evaluable population: all patients with measurable disease at baseline who had a baseline tumour assessment and received at least one dose of alectinib.
Descriptive statistics and estimate variability
Treatment group
ALK-positive NSCLC previously treated with crizotinib
ORR (IRC) % N= 122
50.0
95% CI
[40.8, 59.2]
ORR (IRC) in patients pre-treated with chemotherapy % N= 96
44.8
95% CI
[34.6, 55.3]
CORR (IRC-assessed) % N=35
57.1
95% CI
[39.4, 73.7]
DOR (months) Median N=61
11.2
95% CI
[9.6, NE]
PFS (months) Median N=122
8.9
95% CI
[5.6, 11.3]
OS (months) Median N=138
NE
95% CI
[14.6, NE]
Analysis description Secondary analysis Database lock: 1 February 2016
Assessment report
EMA/197343/2017 Page 90/122
Descriptive statistics and estimate variability
Treatment group
ALK-positive NSCLC previously treated with crizotinib
ORR (IRC) % N= 122
50.8
95% CI
[41.6, 59.9]
ORR (IRC) in patients pre-treated with chemotherapy % N= 96
44.8
95% CI
[34.6, 55.3]
CORR (IRC-assessed) % N=34
58.8
95% CI
[40.7, 75.4]
DOR (months) Median N=62
15.2
95% CI
[11.2, 24.9]
PFS (months) Median N=138
8.9
95% CI
[5.6, 12.8]
OS (months) Median N=138
26.0
95% CI
[21.5, NE]
Updated efficacy data
The updated data cut-off date for the NP28761 study was 22 January 2016 providing 17 months of follow-up.
The updated data cut-off date for the NP28673 study was 1 February 2016 providing 21 months of follow-up.
Assessment report
EMA/197343/2017 Page 91/122
Table 52: Overview of efficacy results in pivotal studies
The event rate in regard to PFS is 67 % and 71 % for NP28761 and NP28673 respectively. For OS, the event
rate is 41 % and about 44 % respectively. The level of data maturity is considered acceptable.
The median PFS in the NP28761 study has increased with about 2 months (6→8 months) over time whilst
remaining unchanged in study NP28673 (about 9 months).
Assessment report
EMA/197343/2017 Page 92/122
Analysis performed across trials (pooled analyses and meta-analysis)
CNS ORR and DCR
Table 53: Summary of the pooled analysis of CNS endpoints from studies NP28673 and NP28761
CNS Parameters (NP28673 and NP28761) Alectinib 600 mg twice daily
Patients with measurable CNS lesions at baseline
CNS ORR (IRC)
Responders (%)
[95% CI]
Complete response
Partial response
CNS DOR (IRC)
Number of patients with events (%)
Median (months)
[95%CI]
N = 50
32 (64.0%)
[49.2%, 77.1%]
11 (22.0%)
21 (42.0%)
N=32
18 (56.3%)
11.1
[7.6, NE]
CI confidence interval; DOR duration of response; IRC independent review committee; ORR objective response rate;
NE = not estimable
Clinical studies in special populations
Table 54: Elderly patients included in the pivotal studies (NP28761 and NP28673)
Supportive study
Study AF-001JP is a multicentre, open label Phase I/II Study of CH5424802 in Patients with Non-small Cell
Lung Cancer Harbouring the ALK Fusion Gene.
The study was conducted in 13 sites in Japan. The study period was 24 August 2010 to 18 April 2013.
A total of 24 patients were enrolled in Phase I and were assigned to one of the seven alectinib dose cohorts
(20, 40, 80, 160, 240, and 300 [fed/fasted] mg BID). In Phase II, 46 patients were enrolled and all received
treatment with alectinib 300 mg BID. In phase II at least one prior line of chemotherapy was required. Prior
treatment with an ALK inhibitor was an exclusion criterion.
Assessment report
EMA/197343/2017 Page 93/122
In Phase II, mean age of the population was 49.5 years (range: 26 to 75 years), with 42/46 patients being <
65 years old. There were 52% women and 48% men. The majority of patients (59%) had never smoked (or
hardly smoked). ECOG PS was 0 in 20 patients (44%) and 1 in 26 patients (57%). The histological type was
adenocarcinoma in all 46 patients. Disease stage was IIIB in 2 patients (4%), IV in 31 patients (67%), and
postoperative recurrence in 13 patients (28%).
In Phase I, alectinib 300 mg BID was chosen as the RP2D in Japanese patients on the basis of safety, PK, and
efficacy data. Of the 20 Phase I patients, 18 patients had an investigator-assessed BOR of PR and 2 patients
had SD.
In Phase II, the IRC-assessed response rate in the 46 crizotinib-naïve patients enrolled was 93.5% (95% CI:
82.1% to 98.6%), with 7 of the patients achieving a CR and 36 achieving a PR. Due to the low number of
events, the median values for PFS and OS could not be estimated. One-year PFS rate was 83% (95% CI:
68% to 92%) and 1-year survival rate was 93% (95% CI: 81% to 98%).
Study JO28928 (J-ALEX)
During the procedure, the applicant submitted high-level data from J-ALEX, an open-label, randomized (1:1)
Phase III study comparing alectinib head to head with crizotinib in patients who were ALK-inhibitor naïve and
may have received up to one prior chemotherapy regimen for ALK–positive NSCLC.
This study is conducted in Japanese patients and the dosing is alectinib 300 BID as opposed to the dosing in
the two studies pertinent to this application i.e. 600 BID.
The data presented are from a pre-planned interim analysis with 50% of the targeted PFS events. The
median duration of follow-up at the time of this analysis was 12 months (range: 1 to 23 months) for the
alectinib arm and 12 months (range: 0 to 20 months) for the crizotinib arm.
2.5.3. Discussion on clinical efficacy
Design and conduct of clinical studies
The benefit assessment is based on two Phase I/II studies, NP28761 (n=87, US/ Canada) and NP28673
(n=138, global) that enrolled patients with ALK positive NSCLC previously treated with crizotinib (Xalkori).
The amendments and protocol violations in the two studies are deemed unlikely to have a relevant impact on
the integrity of the study.
In further support of the application the AF-001JP study has been submitted which is a Phase I/II study
performed in Japanese patients with ALK positive NSCLC that had not received prior crizotinib. In this study
conducted in chemotherapy pre-treated but ALK inhibitor naïve patients, the ORR was very high about 94 %
and the 1-year PFS rate was 83%. This study did not report any CORR and CNS DCR data.
The design of the dose finding study (phase I of study NP28761) is considered standard for an oncology
study. The recommended phase 2 dose (RP2D) determined i.e. 600 mg BID, is considered reasonably well
justified. Study NP28673 also had a dose escalation portion (Part 1) but as the RP2D was defined in study
NP28761, patients in the NP28673 Phase I part were included in the Phase II part (n=6).
Both pivotal studies were single arm studies and very similar in study design and patient eligibility criteria.
Patient demographics were consistent with that of a NSCLC ALK positive population. The demographic
Assessment report
EMA/197343/2017 Page 94/122
characteristics of the overall study population were 67% Caucasian, 26% Asian, 56% females, and the
median age was 52 years. The majority of patients had no history of smoking (70%).
The ECOG (Eastern Cooperative Oncology Group) performance status at baseline was 0 or 1 in 90.6% of
patients and 2 in 9.4% of patients. At the time of entry in the study, 99% of patients had stage IV disease,
61% had brain metastases and in 96% of patients tumours were classified as adenocarcinoma. Among
patients included in the study, 20% of the patients had previously progressed on crizotinib treatment only,
and 80% had previously progressed on crizotinib and at least one chemotherapy treatment.
Furthermore the patients enrolled were rather heavily pre-treated with 54% having received ≥ 3 lines of
therapy prior to enrolment (including crizotinib). The majority (74%) had received a previous platinum-based
chemotherapy regimen and 64% had received prior radiotherapy for NSCLC with main targets brain
metastases (47 %), bone and lung. About half of the population had undergone at least one previous surgical
procedure for NSCLC.
As required by the study protocols, all 225 patients in the overall population had previously received
crizotinib. The median time on crizotinib was about 12 months (range 1 day to 4.5 years) and time since last
dose of crizotinib was about a fortnight (range 7 days to 2 years).
The Applicant has provided best response achieved while on crizotinib for the respective studies. For the 87
patients in NP28761: one patient had CR (1.1 %), 28 patients had PR (32.2 %), 22 patients with SD (25.3
%) and 27 patients with PD (31.0 %). A total of nine patients were deemed NE/NA/Unknown (10.3 %). The
corresponding numbers for study NP28673 were: PR 75 patients (54.3 %), SD 30 patients (21.7 %), PD 27
patients (19.6 %) and 6 (4.3 %) patients NA/Unknown. No patient had CR as best reported response on
crizotinib.
Efficacy data and additional analyses
While primary endpoint in NP28761 and NP28673 was ORR by IRC assessment (RECIST 1.1 with 4 week
confirmation), NP28673 also had a co-primary endpoint of ORR by IRC assessment in patients pre-treated
with chemotherapy.
The primary objective was met in both studies and ORR by IRC was 48 % and 49 % in NP28761 and NP
28673 respectively. ORR by IRC for the patients pre-treated with chemotherapy was 44 %.
A partial response was obtained in 48 % and 49 % in in NP28761 and NP 28673 respectively and stable
disease was achieved in 32 % and 30 % respectively. About 16 % had progressive disease, similar in both
studies.
Data cut-off for NP28761 was 24 October 2014. For NP28673 data cut-off for the primary analysis was 18
August 2014 with an update provided with data cut-off date 8 January 2015. Only limited number of
additional events had occurred at the latter.
Among secondary endpoints was ORR by Investigator with 46 % responders in NP28761 and 48 % in
NP28673. ORR (Inv) in patients pre-treated with chemotherapy in NP28673 was 46 %.
Results on ORR based on subgroups (by age, gender, race, ECOG PS, CNS metastasis, smoking status,
baseline body weight, and prior chemotherapy use), were generally consistent with the ORR in the overall
population for both pivotal studies.
Assessment report
EMA/197343/2017 Page 95/122
DCR as assessed by IRC was about 64 % in both studies although the definition of SD varied between the
two studies with duration for at least 12 weeks in NP28761 and 16 weeks in NP28673.
In terms of time-related secondary endpoints such as DOR, PFS and OS, too few events had occurred which
precluded any firm conclusions to be drawn. The Applicant has as requested (former MO Q 22), provided
updates with data cut-off dates of 22 January 2016 for NP28761 and 1 February 2016 for NP28673:
For PFS, with 67% of the patients in study NP28761 experiencing an event, a mature estimate of the median
PFS can be expected. The median PFS as assessed by IRC is about 8 months. In study NP28673, the median
PFS by IRC (71% data maturity) is about 9 months. The pooled analysis shows a median PFS of
approximately 8 months (69% data maturity). These results are considered clinically meaningful compared
with the results obtained with ceritinib in a similar patient population (Study A: 6.9 months and Study B: 5.7
months).
For OS, the pooled updated median OS is 26 months based on 43% data maturity. These results are also
clinically meaningful, and indirect comparison with ceritinib seems to show that alectinib fares at least as
good (Study A: 16.7 months, Study B: 14.0 months). Study 1007 (crizotinib vs chemotherapy, second-line)
showed a median PFS of 7.7 months and a median OS of 20.3 months.
In regard to CNS DOR a total 50 patients had measurable CNS lesions at baseline. The updated analyses
show that the median CNS DOR for these patients is 11 months (which is slightly better than the primary
pooled analysis of 9 months). This is considered of high clinical relevance. In the pivotal trial in the approval
of ceritinib, patients with symptomatic CNS metastases were excluded.
Overall, the updated results from the two pivotal studies continue to demonstrate a clinically relevant effect
of alectinib in the proposed patient population.
The Applicant has also provided data from a pre-planned interim analysis from the alectinib vs. crizotinib
head to head, Japanese J-ALEX study. The comparative data form the J-ALEX study further supports the
results from the two main studies [data not shown].
The Applicant was also requested to provide further data on the NP28673 Part 3. However, only 11 consented
to an optional biopsy for EGFR testing and none of these were found to harbour an EGFR activating mutation.
Hence no data on the combination of alectinib and erlotinib is available. As regards to the 44 patients in part
3 that continued on alectinib monotherapy beyond progression, 33 patients had discontinued alectinib at the
time of the updated 01 February 2016 cut-off (main reason lack of further clinical benefit [26 patients]). The
median treatment duration was 3.4 months (range 0 to 22 months, censored).
Additional efficacy data needed in the context of a conditional MA
The updated information from the phase II studies supporting the ALKi pretreated indication confirm the
efficacy results initially observed, and provide reassurance on the robustness of these results. The high-level
comparative data form the Japanese J-ALEX study further supports the results from the two main studies.
Although a positive benefit-risk profile can be concluded, the data have limitations inherent to the non-
comparative nature of the pivotal studies supporting the recommendation for a conditional MA.
In order to confirm the positive benefit-risk profile, the applicant will submit the results of the ALEX study, a
phase 3, two-arm, randomized study, comparing alectinib and crizotinib in the first line. Although this study
is not in the exact same setting where alectinib is authorised, it will provide comparative efficacy and safety
Assessment report
EMA/197343/2017 Page 96/122
data for alectinib versus crizotinib. The approval of alectinib in the EU is not expected to impact completion of
the ALEX study as it is not conducted in the indication being applied for.
2.5.4. Conclusions on the clinical efficacy
The updated results from the two pivotal studies with now a reasonable level of data maturity continue to
demonstrate a clinically relevant effect of alectinib in the proposed patient population.
The CHMP considers the following measures necessary to address the missing efficacy data in the context of
a conditional MA:
In order to further confirm the efficacy and safety of alectinib in the treatment of patients with ALK-positive
NSCLC, the MAH should submit the clinical study report of the phase III study ALEX comparing alectinib
versus crizotinib in treatment naïve patients with ALK-positive NSCLC. The clinical study report will be
submitted by 30 April 2018.
2.6. Clinical safety
The primary cut-off dates for the MAA were 24 October 2014 and 18 August 2014 for Studies NP28761 and
NP28673, respectively. This safety update assessment provides cumulative safety data with data cut-off
dates of 22 January 2016 and 01 February 2016 for Studies NP28761 and NP28673, respectively.
1. Group 1 includes patients from Phase II of pivotal Study NP28761.
2. Group 2 includes patients from Phase II of pivotal Study NP28673.
3. Group 3 includes patients from Phase I and II of Study NP28761 (only patients in Phase I who received
alectinib at 600 mg twice daily [BID] were included), and Phase II and the midazolam (MDZ) drug-drug
interaction (DDI) substudy of Study NP28673.
The safety of Alectinib has been evaluated in 253 patients in pivotal phase II clinical trials (NP28761,
NP28673) with ALK-positive non-small cell lung cancer (NSCLC) treated with the recommended dose of
600 mg twice daily. The median duration of exposure to Alectinib was 11 months.
Assessment report
EMA/197343/2017 Page 97/122
Patient exposure
Table 55: Patient Status at Time of Data Cut-off Date for the Safety Update
About 1/3 of the patients were still on therapy and slightly more than 40% of the patients were dead at time
of this update meaning that safety data are considered reasonably stable and robust.
Table 56: Study Drug Exposure in Studies NP28761 (Group 1) and NP28673(Group 2) and the Integrated Safety Population (Group 3) (Safety Population)
Mean and median duration of therapy were roughly 1 year at close to 100% dose intensity.
Assessment report
EMA/197343/2017 Page 98/122
Adverse events
Table 57: Overview of Adverse Events in Studies NP28761 (Group 1) and NP28673 (Group 2) and the Integrated Safety Population (Group 3) (Safety Population)
AEs (related or not) leading to withdrawal of treatment is overall about 6%
Table 58: Adverse Events (Grade 3−5) with an Incidence of At Least 2% in Studies NP28761 (Group 1), NP28673 (Group 2), or the Integrated Safety Population (Group 3) (Safety Population)
Assessment report
EMA/197343/2017 Page 99/122
Significant adverse events of special interest
Interstitial lung disease (ILD) / pneumonitis
Severe ILD/pneumonitis occurred in patients treated with Alectinib. In the pivotal phase II clinical trials
(NP28761, NP28673), 1 out of 253 patients treated with Alectinib (0.4%) had a Grade 3 ILD. This event led
to withdrawal from Alectinib treatment. There were no fatal cases of ILD.
Hepatocellular or Cholestatic Adverse Events and Abnormal Liver Function Tests
Hepatotoxicity is considered a class effect of ALK inhibitors and has been classified as an important identified
risk for alectinib.
In the pivotal phase II clinical trials (NP28761, NP28673) two patients with Grade 3-4 AST/ALT elevations
had documented drug induced liver injury by liver biopsy. One of these cases led to withdrawal from Alecensa
treatment. Adverse reactions of increased AST and ALT levels (16% and 14% respectively) were reported in
patients treated with Alectinib in pivotal phase II clinical trials (NP28761, NP28673). The majority of these
events were of Grade 1 and 2 intensity, and events of Grade ≥ 3 were reported in 2.8% and 3.2% of the
patients, respectively. The events generally occurred during the first 3 months of treatment, were usually
transient and resolved upon temporary interruption of Alectinib treatment (reported for 1.2% and 3.2% of
the patients, respectively) or dose reduction (1.6% and 0.8%, respectively). In 1.2% and 1.6% of the
patients, AST and ALT elevations, respectively, led to withdrawal from Alectinib treatment.
Adverse reactions of bilirubin elevations were reported in 17% of the patients treated with Alectinib in pivotal
phase II clinical trials (NP28761, NP28673). The majority of the events were of Grade 1 and 2 intensity;
Grade 3 events were reported in 3.2% of the patients. The events generally occurred during the first 3
months of treatment, were usually transient and resolved upon temporary interruption of Alectinib treatment
(4.7% of the patients) or dose reduction (2.8%). In 4 patients (1.6%), bilirubin elevations led to withdrawal
from Alectinib treatment.
Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin greater
than or equal to two times the ULN, with normal alkaline phosphatase, occurred in one patient (0.2%)
treated in Alectinib clinical trials.
Assessment report
EMA/197343/2017 Page 100/122
Table 59: Hepatocellular or Cholestatic Damage Adverse Events and Abnormal Liver Function Tests by Preferred Term in the Integrated Safety Population in more than one patient (Safety Population)
Two patients with Grade 3-4 AST/ALT elevations had documented drug-induced liver injury (DILI) by liver
biopsy in Group 3:
Patient 1 in Study NP28761: Liver biopsy showed morphological features of autoimmune hepatitis,
but there was no clear diagnostic evidence of a separate autoimmune hepatitis. Since a similar
pattern may also be seen secondary to drug, and in the patient's clinical setting, a drug-induced
hepatitis was favoured as diagnosis. The event let to permanent discontinuation of study drug and
was considered resolved by Day 53.
Patient 2 in Study NP28673: Ultrasound guided biopsy of the liver performed on Day 222 showed
centrilobular hepatic injury deemed compliant with a toxic effect and thus indicative for DILI. The
events of Grade 3 ALT and AST elevations led to study drug interruption on Day 208, and ALT
elevation finally led to permanent discontinuation on Day 215. The events were considered resolved
by Day 268.
In addition
Patient 3 in Study BO28984 (ongoing phase III) was hospitalized with Grade 4 drug induced liver
injury DILI (considered serious). ALP was within normal range. The patient already had an event of
increased AST, ALT and bilirubin (up to a maximum of 17 fold, 14 fold and 4.7 fold the ULN,
respectively), along with subclinical icterus, abdominal pain, nausea, vomiting, loss of appetite and
increased C-reactive protein approximately 2 weeks before study start. The event of DILI led to
permanent discontinuation of study drug and was considered resolved by Day120.
No cases of hepatic failure have been reported.
Bradycardia
Cases of bradycardia (7.9%) of Grade 1 or 2 have been reported in patients treated with Alectinib in pivotal
phase II clinical trials (NP28761, NP28673). There were 44 of 221 patients (20%) treated with Alectinib who
had post-dose heart rate values below 50 beats per minutes. No case of bradycardia led to withdrawal from
Alectinib treatment.
Severe myalgia and CPK elevations
Cases of myalgia (31%) including myalgia events (25%) and musculoskeletal pain (7.5%) have been
reported in patients treated with Alectinib in pivotal phase II clinical trials (NP28761, NP28673). The majority
of events were Grades 1 or 2 and three patients (1.2%) had a Grade 3 event. Dose modifications of Alectinib
treatment due to these adverse events were only required for two patients (0.8%). Alectinib treatment was
not withdrawn due to these events of myalgia. Elevations of CPK occurred in 46% of 219 patients with CPK
Assessment report
EMA/197343/2017 Page 101/122
laboratory data available in pivotal phase II clinical trials (NP28761, NP28673) with Alectinib. The incidence
of Grade 3 elevations of CPK was 5.0%. Median time to Grade 3 CPK elevation was 14 days. Dose
modifications for elevation of CPK occurred in 4.0% of patients; withdrawal from Alectinib treatment did not
occur due to CPK elevations..
Gastrointestinal effects
Constipation (36%), nausea (22%), diarrhoea (18%) and vomiting (13%) were the most commonly reported
gastrointestinal (GI) reactions. Most of these events were of mild or moderate severity; Grade 3 events were
reported for diarrhea (1.2%), nausea (0.4%), and vomiting (0.4%). These events did not lead to withdrawal
from Alecensa treatment. Median time to onset for constipation, nausea, diarrhea, and/or vomiting events
was 18 days. The events declined in frequency after the first month of treatment.
Adverse drug reactions
The safety database related to the dose proposed for marketing represents 253 patients with a median
duration of therapy of approximately 1 year.
Assessment report
EMA/197343/2017 Page 102/122
Table 60: Adverse Reactions in ALK-Positive Patients Treated with Alectinib
Assessment report
EMA/197343/2017 Page 103/122
Serious adverse event/deaths/other significant events
Table 61: Serious Adverse Events Occurring in at Least 2 Patients (Safety Population)
Group 1
Fifteen patients (17%) experienced 19 SAEs. All events were reported in single patients.
SAEs lead to dose reduction (1 patient), dose interruption (8 patients), and study drug withdrawal (1
patient).
The event was considered related in one patient who reported a Grade 3 SAE of tumour necrosis beginning
on Day 465. Study drug therapy was not changed.
Group 2
Thirty-one patients (23%) experienced 48 SAEs. All events were reported in single patients, with the
exceptions of hyperbilirubinemia (3 patients [2%]), pulmonary embolism (3 patients [2%]), dyspnoea (3
patients [2%]), ALT increased (2 patients [1%]), and AST increased (2 patients [1%]).
SAEs leading to dose reduction (5 patients), dose interruption (11 patients), and study drug withdrawal (8
patients).
Assessment report
EMA/197343/2017 Page 104/122
Table 62: Death and Cause of Death in Studies NP28761 (Group 1) and NP28673 (Group 2) and the Integrated Safety Population (Group 3) (Safety Population)
Laboratory findings
The following table displays treatment-emergent laboratory abnormalities occurring in >10% (all grades) of
patients treated with Alectinib.
Table 63: Key Laboratory Abnormalities
Parameter Alectinib N= 250*
All Grades (%) Grade 3 -4 (%)#
Chemistry
Increased Blood Creatinine 99 1.2
Increased AST 61 3.2
Increased ALT 45 4.0
Increased Blood Creatine Phosphokinase 40 4.4
Increased Bilirubin (total) 35 1.6
Haematology
Decreased Hemoglobin 85 2.0 AST - Aspartate Aminotransferase, ALT - Alanine Aminotransferase, * n=203 for Creatine Phosphokinase. #Treatment-Emergent only.
Assessment report
EMA/197343/2017 Page 105/122
Safety in special populations
Table 64: Adverse Events by Age Group in the Integrated Safety Population (Group 3) (Safety Population)
Table 65: Adverse Events by Sex in the Integrated Safety Population (Group 3) (Safety Population)
Assessment report
EMA/197343/2017 Page 106/122
Table 66: Adverse Events by Race in the Integrated Safety Population (Group 3) (Safety Population)
There are no or limited amount of data from the use of Alectinib in pregnant women.
Safety related to drug-drug interactions and other interactions
See clinical pharmacology.
Dose modifications or interruptions
Group 1
In total, 16 patients (18%) experienced AEs that led to a dose reduction.
Since the data cutoff date for the SCS, 4 additional patients reported a total of 5 new AEs leading to dose
reduction of study drug.
The most common reasons for dose reduction were blood CPK increased (5%), AST increased (3%), and ALT
increased and blood bilirubin increased (2% each).
Compared with the SCS, the following new AEs were reported leading to dose reduction: AST increased (1
patient), ALT increased (1 patient), constipation (1 patient), nausea (1 patient), and oedema peripheral (1
patient).
At the time of the data cutoff for the safety update (22 January 2016), the median time to dose reduction
was 46 days (range: 4−644 days).
Group 2
In total, 15 patients (11%) experienced AEs that led to a dose reduction. Since the data cutoff date for the
SCS, 3 additional patients reported a total of 9 new AEs leading to dose reduction of study drug.
The most common reasons for dose reduction were blood bilirubin increased (3%), abdominal pain upper
(1%), and vomiting (1%). Compared with the SCS, the following new AEs were reported leading to dose
Assessment report
EMA/197343/2017 Page 107/122
reduction: abdominal pain upper (2 patients [1%]), blood bilirubin increased (2 patients [1%]), rash maculo-
papular (1 patient [1%]), and urticaria (1 patient [1%]).
At the time of the data cutoff for the safety update (01 February 2016), the median time to dose reduction
was 102.5 days (range: 2−577 days).
Discontinuation due to adverse events
Altogether 15 patients (6%) discontinued due to AEs, hepatic laboratory events dominated, but there were
also single cases of pneumonia, ILD, ligament rupture.
Data from supportive study
J-ALEX was a randomised crizotinib comparative trial conducted in Japan. The dose of alectinib was 300 bid
instead of 600 mg bid. The estimated systemic exposure in this study was about 35% lower than in the
pivotal trials. This is not likely to have a more than minor impact to safety.
Table 67: Summary of AEs
There was no case of death related to AEs.
Assessment report
EMA/197343/2017 Page 108/122
Table 68: Adverse Events Leading to Discontinuation
2.6.1. Discussion on clinical safety
The safety database related to the dose proposed for marketing is small (253) but median duration of
therapy is approximately 1 year. Still the long-term safety of alectinib is not sufficiently characterised and will
be monitored as part of routine pharmacovigilance. The crizotinib comparative trial conducted at a lower dose
of alectinib (J-ALEX) is considered informative and contextualises the safety profile.
Almost every patient in the two pivotal studies experienced at least one AE. There are comparable numbers
of deaths (all cause) and SAEs in the two studies.
The most common adverse drug reactions (ADRs) (≥ 20%) were constipation (36%), oedema (34%,
including oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital oedema), myalgia
(31%, including myalgia and musculoskeletal pain) and nausea (22%).
Cases of ILD/pneumonitis have been reported in clinical trials with Alectinib (see sections 4.4 and 4.8 of the
SmPC). Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Alectinib should be
immediately interrupted in patients diagnosed with ILD/pneumonitis and should be permanently discontinued
if no other potential causes of ILD/pneumonitis have been identified (see section 4.2 of the SmPC).
Gastrointestinal AEs seem to be common. This may be due to the high concentration of SLS in the tablets.
SLS is a known gastrointestinal irritant that can cause the above mentioned common GI AEs, and these same
GI AEs are also observed in patients treated with crizotinib. They are clinically manageable and do not pose
any major concerns. In Group 4 liver related AEs are more common than GI related AEs. Patients in Group 4
Assessment report
EMA/197343/2017 Page 109/122
received only 300 mg BID and thus had a lower exposure to SLS could explain the lower incidence of GI
related AEs.
The applicant is recommended to introduce an alternative capsule formulation for oral administration
containing a lower amount of SLS post-approval.
Hepatotoxicity is a class effect of ALK-inhibitors, and is also observed in patients treated with crizotinib and
ceritinib.
Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 5 times the
ULN as well as bilirubin elevations of more than 3 times the ULN occurred in patients in pivotal phase II
clinical trials (NP28761, NP28673) with Alectinib (see sections 4.4 and 4.8 of the SmPC). The majority (76%
of the patients with hepatic aminotransferase elevations and 60% of the patients with bilirubin elevations) of
these events occurred during the first 3 months of treatment. In the pivotal phase II clinical trials (NP28761
and NP28673), two patients with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by
liver biopsy. Concurrent elevations in ALT or AST greater than or equal 3 times the ULN and total bilirubin
greater than or equal 2 times the ULN, with normal alkaline phosphatase, occurred in one patient treated in
Alectinib clinical trials.
Liver function, including ALT, AST, and total bilirubin should be monitored at baseline and then every 2 weeks
during the first 3 months of treatment. Thereafter, monitoring should be performed periodically, since events
may occur later than 3 months, with more frequent testing in patients who develop aminotransferase and
bilirubin elevations. Based on the severity of the adverse drug reaction, Alectinib should be withheld and
resumed at a reduced dose, or permanently discontinued (see section 4.2 of the SmPC).
Vision disorders were reported in both pivotal and supportive studies. Most common vision disorders are
blurred vision and visual impairment. All events in Group 3 were of Grade 1 or 2, except for one serious
Grade 3 event of retinal detachment.
Myalgia or musculoskeletal pain occurred in 31% of patients in pivotal phase II trials (NP28761, NP28673)
with Alectinib. The incidence of Grade 3 myalgia/musculoskeletal pain was 1.2%. Dose modifications for
myalgia/musculoskeletal pain were required in 0.8% of patients.
Elevations of CPK occurred in 46% of 219 patients with CPK laboratory data available in pivotal phase II trials
(NP28761, NP28673) with Alectinib. The incidence of Grade 3 elevations of CPK was 5.0%. Median time to
Grade 3 CPK elevation was 14 days. Dose modifications for elevation of CPK occurred in 4.0 % of patients
(see sections 4.4 and 4.8 of the SmPC).
Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. CPK levels
should be assessed every two weeks for the first month of treatment and as clinically indicated in patients
reporting symptoms. Based on the severity of the CPK elevation, Alectinib should be withheld, then resumed
or dose reduced (see section 4.2 of the SmPC).
Symptomatic bradycardia can occur with Alectinib (see sections 4.4 and 4.8 of the SmPC). Heart rate and
blood pressure should be monitored as clinically indicated. Dose modification is not required in case of
asymptomatic bradycardia (see section 4.2 of the SmPC). If patients experience symptomatic bradycardia or
life-threatening events, concomitant medicinal products known to cause bradycardia, as well as anti-
hypertensive medicinal products should be evaluated and Alectinib treatment should be adjusted as described
in sections 4.2 and 4.5 of the SmPC (P-gp substrates and BCRP substrates).
Assessment report
EMA/197343/2017 Page 110/122
Photosensitivity to sunlight has been reported with Alectinib administration (see sections 4.4 and 4.8 of the
SmPC). Patients should be advised to avoid prolonged sun exposure while taking Alectinib, and for at least
7 days after discontinuation of treatment. Patients should also be advised to use a broad-spectrum Ultraviolet
A (UVA)/ Ultraviolet B (UVB) sun screen and lip balm (SPF ≥50) to help protect against potential sunburn.
Alectinib may cause foetal harm when administered to a pregnant woman. Women of childbearing potential
must be advised to avoid pregnancy while on Alectinib. Female patients of child-bearing potential receiving
Alectinib, must use highly effective contraceptive methods during treatment and for at least 3 months
following the last dose of Alectinib (see sections 4.4, 4.6 and 5.3 of the SmPC). Female patients, who become
pregnant while taking Alectinib or during the 3 months following the last dose of Alectinib must contact their
doctor and should be advised of the potential harm to the foetus.
It is unknown whether alectinib and its metabolites are excreted in human milk. A risk to the newborn/infant
cannot be excluded. Mothers should be advised against breast-feeding while receiving Alectinib.
Alectinib has minor influence on the ability to drive and use machines. Caution should be exercised when
driving or operating machines as patients may experience symptomatic bradycardia (e.g., syncope, dizziness,
hypotension) or vision disorders while taking Alectinib (see sections 4.7 and 4.8 of the SmPC).
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, a
congenital lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
The recommended daily dose (1200 mg) of Alectinib contains 2.1 mmol (or 48 mg) sodium. To be taken into
consideration by patients on a controlled sodium diet.
There is no specific antidote for overdose with Alectinib. Patients who experience overdose should be closely
supervised and general supportive care instituted.
From the safety database all the adverse reactions reported in clinical trials have been included in the
Summary of Product Characteristics.
Additional safety data needed in the context of a conditional MA
The submission of the final CSR for the global Phase III comparative alectinib versus crizotinib ALEX study
will provide more mature safety data in order to further confirm the safety profile of alectinib.
2.6.2. Conclusions on the clinical safety
The safety profile of alectinib is as expected for ALK inhibitors. Hepatotoxicity, anaemia, bradycardia, ILD and
photosensitivity are observed. However, QT interval prolongation is not observed in patients being treated
with alectinib, while it is observed in patients being treated with other ALK inhibitors. The discontinuation rate
is only 5% and considered relatively low.
Overall, the safety profile of alectinib is acceptable and in line with other ALK inhibitors.
The CHMP considers the following measures necessary to address the missing safety data in the context of a
conditional MA:
In order to further confirm the efficacy and safety of alectinib in the treatment of patients with ALK-positive
NSCLC, the MAH should submit the clinical study report of the phase III study ALEX comparing alectinib
versus crizotinib in treatment naïve patients with ALK-positive NSCLC. The clinical study report will be
Assessment report
EMA/197343/2017 Page 111/122
submitted by 30 April 2018.
2.7. Risk Management Plan
Safety concerns
Table 69: Summary of the Safety Concerns as proposed by the applicant:
Summary of safety concerns
Important identified risks Interstitial lung disease/pneumonitis
Hepatotoxicity
Photosensitivity
Bradycardia
Severe myalgia and CPK elevations
Important potential risks Embryo-foetal toxicity
Missing information Long-term safety
Treatment in lactating women
Treatment in patients with moderate or severe hepatic impairment
Treatment in patients with severe renal impairment
Pharmacovigilance plan
Table 70: Ongoing and planned additional pharmacovigilance studies/activities in the Pharmacovigilance Plan
Study/activity
Type, title and
category (1-3)
Objectives Safety
concerns
addressed
Status Date for submission
of interim or final
reports
Assessment report
EMA/197343/2017 Page 112/122
BO28984
Randomized,
multicenter, Phase III,
open-label study of
alectinib versus
crizotinib in
treatment-naïve
anaplastic lymphoma
kinase-positive
advanced non-small
cell lung cancer (2)
Primary Objective
To evaluate and compare the efficacy
of alectinib compared to crizotinib in
patients with treatment-naive ALK-
positive advanced NSCLC, as
measured by investigator-assessed
PFS.
Secondary Objectives
To evaluate and compare ORR, DOR,
IRC-assessed PFS, OS.
To evaluate and compare the time to
progression in the CNS on the basis
of IRC review of radiographs by
RECIST v1.1 and RANO criteria, as
well as: To evaluate C-ORR in
patients with CNS metastases who
have measurable disease in the CNS
at baseline; To assess C-DOR in
patients who have a CNS Objective
Response; To assess C-PR at 6, 12,
18, and 24 months on the basis of
cumulative incidence.
To evaluate the safety and tolerability
of alectinib compared to crizotinib.
To characterize the pharmacokinetics
of alectinib and metabolite(s).
To evaluate and compare TTD in
patient-reported lung cancer
symptoms of cough, dyspnea (single
item and multi-item subscales), chest
pain, arm and shoulder pain, and
fatigue as measured by the EORTC
Quality of Life Questionnaire−Core
(QLQ-C30) and the supplemental lung
cancer module (QLQ-LC13) as well as
a composite of three symptoms
(cough, dyspnea, chest pain).
To evaluate and compare PROs of
HRQoL, patient functioning, and side
effects of treatment as measured by
the EORTC QLQ-C30 and EORTC QLQ-
LC13.
Does not address
a specific safety
concern.
Provision of
mature safety
data requested
by the EMA.
Ongoing Study start date:
August 2014.
Primary CSR and
related documents:
April 2018.
Assessment report
EMA/197343/2017 Page 113/122
NP29783
The effect of hepatic
impairment on the
pharmacokinetics of
alectinib: a multiple-
center, open-label
study following single
oral dosing of alectinib
to subjects with
hepatic impairment
and matched healthy
subjects with normal
hepatic function (3)
Primary Objective
To assess the PK of alectinib in
subjects with hepatic impairment and
in matched healthy subjects after a
single oral dose.
Secondary Objective
To assess the PK of the major active
metabolite of alectinib, M4, and the
combined exposure of alectinib and
M4 in subjects with hepatic
impairment and in matched healthy
subjects after a single oral dose.
To investigate safety and tolerability
of alectinib in subjects with hepatic
impairment and in matched healthy
subjects.
Exploratory Objective
To evaluate the relationship, if any,
between measures of hepatic
impairment (e.g., Child-Pugh Scores,
NCI Criteria for hepatic impairment
categories, albumin concentration,
etc.) and PK parameters for alectinib
and/or M4, as appropriate.
Treatment of
patients with
moderate and
severe hepatic
impairment
Ongoing Study start date:
December 2015.
Final CSR: Estimated
December 2017
(submission of report:
April 2018).
ALK Anaplastic Lymphoma Kinase; C-DOR CNS Duration Of Response; CSR Clinical Study Report; C-ORR CNS Objective Response
Rate; C-PR CNS Progression Rates; DOR Duration Of Response; EMA European Medicines Agency; EORTC European Organization for
the Research and Treatment of Cancer; HRQoL Health-Related Quality of Life; IRC Independent Review Committee; NCI National
Cancer Institute; NSCLC Non-Small Cell Lung Cancer; ORR Objective Response Rate; OS Overall Survival; PFS Progression-Free
Survival; PK Pharmacokinetics; PROs Patient Reported Outcomes; RANO Revised Assessment in Neuro Oncology; RECIST Response
Evaluation Criteria In Solid Tumors; TTD Time to Deterioration.
Risk minimisation measures
The Table from the RMP section V.3 has been omitted as there is no required additional risk minimisation
measures proposed.
Safety concern Routine risk
minimization measures
Additional risk
minimization
measures
Interstitial Lung Disease (ILD)/Pneumonitis
SmPC sections: 4.2; 4.4; 4.8
None
Assessment report
EMA/197343/2017 Page 114/122
Safety concern Routine risk
minimization measures
Additional risk
minimization
measures
Hepatotoxicity SmPC sections: 4.2; 4.4; 4.8
None
Photosensitivity SmPC section: 4.4
None
Bradycardia SmPC sections: 4.2; 4.4; 4.8
None
Severe myalgia and CPK elevations
SmPC sections: 4.2; 4.4; 4.8 None
Embryo-fetal toxicity SmPC sections: 4.4; 4.6
None
Long-term safety No data available. None
Treatment in lactating women
SmPC section: 4.6 None
Treatment in patients with moderate or severe hepatic impairment
SmPC section: 4.2; 5.2 None
Treatment in patients with severe renal impairment
SmPC section: 4.2; 5.2 None
Conclusion
The CHMP and PRAC considered that the risk management plan version 1.3 dated 15th December 2016 is
acceptable.
2.8. Pharmacovigilance
Pharmacovigilance system
The CHMP considered that the pharmacovigilance system summary submitted by the applicant fulfils the
requirements of Article 8(3) of Directive 2001/83/EC.
2.9. New Active Substance
The applicant compared the structure of alectinib with active substances contained in authorised medicinal
products in the European Union and declared that it is not a salt, ester, ether, isomer, mixture of isomers,
complex or derivative of any of them.
The CHMP, based on the available data, considers alectinib to be a new active substance as it is not a
constituent of a medicinal product previously authorised within the European Union.
Assessment report
EMA/197343/2017 Page 115/122
2.10. Product information
2.10.1. User consultation
The results of the user consultation with target patient groups on the package leaflet submitted by the
applicant show that the package leaflet meets the criteria for readability as set out in the Guideline on the
readability of the label and package leaflet of medicinal products for human use.
2.10.2. Additional monitoring
Pursuant to Article 23(1) of Regulation No (EU) 726/2004, Alecensa (alectinib) is included in the additional
monitoring list as:
- It contains a new active substance which, on 1 January 2011, was not contained in any medicinal product
authorised in the EU
- It is approved under a conditional marketing authorisation [REG Art 14(7)]
Therefore the summary of product characteristics and the package leaflet includes a statement that this
medicinal product is subject to additional monitoring and that this will allow quick identification of new safety
information. The statement is preceded by an inverted equilateral black triangle.
3. Benefit-Risk Balance
3.1. Therapeutic Context
The original proposed indication for alectinib was “adult patients with anaplastic lymphoma kinase (ALK)-
positive, locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed on or are
intolerant to crizotinib”.
Intolerance to crizotinib as part of the label was questioned by the CHMP and it has been shown that only a
very limited number of patients were in fact included in the studies based on crizotinib-intolerance (five in
NP28761, none in NP28673). Consequently, the Applicant has proposed a revision of the indication wording
to state “Alectinib as monotherapy is indicated for the treatment of adult patients with ALK-positive,
advanced NSCLC previously treated with crizotinib”.
For a new ALKi to be used after failure on prior ALKi treatment it is clinically relevant to define whether
resistance is related to secondary ALK mutations or other mechanisms underlying resistance; a priori activity
e.g., in case of resistance due to activation of alternative signalling pathways bypassing ALK appears remote.
Similarly, to what degree the secondary mutation affects the activity of the new compound is of importance.
Such data are presently available to a very limited and non-informative extent. The applicant is
recommended to provide final analysis on secondary ALK mutation positive/negative samples and correlation
with clinical outcome.
Assessment report
EMA/197343/2017 Page 116/122
3.1.1. Disease or condition
NSCLC is the leading cause of cancer-related mortality worldwide and represents a major health problem.
Approximately 5% of patients with NSCLC have tumours that contain an inversion in chromosome 2 that
juxtaposes the 5' end of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the 3' end of
the ALK gene, resulting in the novel fusion oncogene EML4-ALK. EML4-ALK fusion, and ALK fusions with other
genes (Kinesin Family member 5B [KIF5B]), KLC1 and others define a distinct clinicopathologic subset of
NSCLC.
Patients with ‘ALK-positive’ tumours (tumours harboring a rearranged ALK gene/fusion protein) tend to have
specific clinical features, including never or light smoking history, younger age, NSCLC with adenocarcinoma
histology, and are highly sensitive to therapy with ALK inhibitors.
ALK positive tumours are addicted to ALK signalling meaning that inhibition leads to rapid cell death and early
tumour responses. Loss of activity invariably follows and may be related to secondary ALK resistance
mutations, but also fusion gene amplification and activation of alternative signalling pathways.
3.1.2. Available therapies and unmet medical need
After the licensure of crizotinib and ceritinib, alectinib is the third ALK inhibitor (ALKi) submitted for
marketing authorisation for the treatment of ALK+ NSCLC.
The kinase inhibitory profiles of these compounds are clearly different; alectinib inhibits ALK and RET,
crizotinib has a broader profile: ALK, ROS1, MET, etc. and ceritinib ALK, ROS1, IGF1R (for details please refer
to the non-clinical pharmacology section). Of potential clinical relevance for the activity in different tumour
types/subsets, apart from ALK is inhibition of RET, ROS1, MET and IGF1R, but a broader inhibition profile is
also of importance from a safety perspective.
3.1.3. Main clinical studies
The Applicant initially applied for full approval for alectinib based on two single arm Phase I/II studies,
NP28761 (n=87, US/ Canada) and NP28673 (n=138, global) supported by data from a pre-planned interim
analysis from the 1st line, Japanese, crizotinib comparative study (J-ALEX).
3.2. Favourable effects
Whilst primary endpoint in both studies was ORR by IRC assessment (RECIST 1.1 with confirmation),
NP28673 also had a co-primary endpoint of ORR by IRC assessment in patients pre-treated with
chemotherapy.
The studies met their primary endpoints with ORR, in the updated analyses; IRC 52 % and 51 % in NP28761
and NP 28673, respectively. The co-primary endpoint ORR by IRC for the patients pre-treated with
chemotherapy in NP28673 was 45 %. About 16 % had progressive disease as best response, similar in both
studies.
For both pivotal studies, ORR by subgroups (age, gender, race, ECOG PS, CNS metastasis, smoking status,
baseline body weight, and prior chemotherapy use), were generally consistent with the ORR in the overall
population.
Assessment report
EMA/197343/2017 Page 117/122
Updated median PFS was 8.9 months in both studies, at event rates of 67 and 71%. Data are thus highly
likely to be stable after prolonged follow up.
Out of the 50 patients with measurable CNS lesions in the overall efficacy population, the overall response
rate was 64%, thereof CR in 22% (IRC).
In the supportive Japanese study J-ALEX in ALKi naïve patients alectinib 300 mg BID was compared with
crizotinib in the EU licensed dose. In the interim anaysis at event rates of 24% vs. 56% the PFS HR was 0.34
(p<0.0001)(IRC) and response rates were 92% vs. 79%.
3.3. Uncertainties and limitations about favourable effects
The major uncertainty in the assessment of optimised benefit of alectinib is absence of informative data on
mechanisms underlying resistance to crizotinib; secondary ALK resistance mutations, fusion gene
amplification and activation of alternative signalling pathways as such data may guide the proper use of
alectinib in the now targeted indication.
Out of 225 patients enrolled in the studies, baseline plasma samples were available from 178 individuals and
now data are presented from 49 samples.
Based on the existence of alternative mechanisms of resistance unlikely to be responsive to alectinib therapy,
a higher ORR would be expected in case of tumours with secondary ALK mutation positive samples, but ORR
was similar (1/3) in patients with ALK mutation positive and negative liquid samples and apparently lower
than in the full study population (1/2). Whether the analysed 49 samples are representative for the full study
population could obviously be questioned and the sensitivity of liquid biopsies to detect tumour tissue
mutations is unknown and circulating tumour DNA may relate to tumour burden/invasiveness.
Of some interest, PD as best response was more commonly reported in patients with ALK mutation negative
samples than ALK mutation positive samples (12/35 vs. 2/21).
Patients with CNS progression only should have been excluded from the group of patients with mutation
negative liquid biopsies due to the postulated poorer uptake of crizotinib in CNS metastases. This will not be
further pursued at this stage.
Available data cannot be used to guide the use of alectinib, second line to crizotinib.
The final study report on secondary ALK-mutation positive/negative samples and correlation with clinical
outcome should be submitted (please refer to Section 7 Proposed list of recommendation).
3.4. Unfavourable effects
Tolerability is considered possible to estimate with reasonable certainty at the dose proposed for marketing,
even though the number of patients is low, roughly 250 individuals treated for a for median about 1 year.
The most common side effects are constipation, oedema (including peripheral oedema, generalised oedema,
eyelid oedema, periorbital oedema), myalgia (including myalgia and musculoskeletal pain) and nausea.
Tolerability in terms of discontinuations (6%, related or not) and dose reductions (about 15%, mainly
laboratory events among likely related) are considered favourable when contextualised. This refers not only
to ALKi but to anti-cancer therapy in general.
Assessment report
EMA/197343/2017 Page 118/122
Hepatic events and CPK/myalgia events need to monitored in clinical practice and proper guidance is
provided in the SmPC.
3.5. Uncertainties and limitations about unfavourable effects
Events such as pulmonary embolism and haemorrhages always occur in patients with advanced malignancies,
including ALK+NSCLC. Whether treatment with alectinib increases or decreases the risk cannot be assessed,
but good control of the underlying disease should decrease the disease related event rate.
As only single arm or active, reference controlled trials are possible, the absolute risk increase or decrease
cannot be assessed. The Japanese, first-line, crizotinib comparative trial is considered informative and
indicates a favourable safety profile, with the caveat that the dose of alectinib was lower (estimated exposure
reduced about 35%). The only signal of increased toxicity related to alectinib was myalgia/CPK increase.
There is another ongoing first-line, crizotinib comparative trial at the “EU dose”.
3.6. Effects Table
Table 71: Effects Table for Alectinib in ALK+ NSCLC
Effect Short Description
data cut-off: Updated data cut-off
Uncertainties/ Strength of evidence
Favourable Effects
NP28761 24 October 2014 22 January 2016
ORR by IRC [95% CI]
Proportion of patients achieving best response of CR or PR (%)
48 % (35.6%, 60.2%)
52 % (39.7%, 64.6%)
Overall, the updated results confirm the findings in the primary analyses.
CNS ORR by IRC [95% CI]
Proportion of patients achieving CR or PR of BL CNS lesions
69 % (41.3%, 89.0%)
75 % (47.6%, 92.7%)
CNS DOR (months) [95% CI]
NE (NE, NE)
11 (5.8, NE)
PFS IRC (months) [95% CI]
6 (5.5, NE)
8 (6, 13)
OS (months) [95% CI]
NE (10, NE)
23 (17, NE)
NP28673 08 January 2015 01 February2016
ORR by IRC [95% CI]
50 % (40.8%, 59.2%)
51 % (41.6%, 59.9%)
Overall, the updated results confirm the findings in the primary analyses.
CNS ORR by IRC [95% CI]
57 % (39%, 74%)
59 % (41%,75%)
CNS DOR (months) [95% CI]
9 (5.8, NE)
11 (7.1, NE)
PFS IRC (months) [95% CI]
9 (5.6, 11.3)
9 (5.6, 13)
OS (months) [95% CI]
NE (14.6, NE)
26 (21.5,NE)
Assessment report
EMA/197343/2017 Page 119/122
Unfavourable Effects: Group 3 (pooled safety dataset: NP28761 (Phase I/II), NP28673 (Phase II) and MDZ
N=253 SCS Update Comments
At least 1 AE 97% 99 %
AE grade 3-5 28% 39.5
SAE 16% 22 %
“Related” SAE 5% 6 %
AE leading to dose reduction/interruption
26% 33 %
AE leading to withdrawal 5% 6 %
Number of deaths (all causes)
17% 41.5 %
Number of AE with fatal outcome 2% 2.8 %
Hepatocellular AEs Grade >=3 6%
Visions disorders 12%
Photosensitivity 32%
GI AEs Grade 3
55% 3 %
31% had GI events considered by the investigator to be related to study drug. The relevance of the high dose of SLS is unknown.
Kidney AEs 15%
Bradycardia 5.9% 7.9 %
Abbr: NE – Not estimated, SCS – Summary of Clinical Safety
3.7. Benefit-risk assessment and discussion
3.7.1. Importance of favourable and unfavourable effects
Available clinical data illustrate the likely benefit of targeting the driver mutation of the malignancy only. Very
high activity in terms of ORR and superior PFS compared with crizotinib has thus been reported in the first-
line J-ALEX trial. This is interpreted as indicative of anti-tumour activity not being restricted by dose limiting
side effects not related to inhibition of ALK (and RET). It is easily understood why the Applicant views the
currently proposed indication as a first step only, with an ongoing comparative study versus crizotinib at the
EU recommended dose. In this context it is of interest to notice that fold change in relation to the wild type
translocation is similar to fold change for crizotinib for crizotinib resistance related mutations.
The reported benefit in terms of ORR and PFS after failure on crizotinib is considered clinically meaningful.
Actually, it has been shown that tumour responses at much lower rates than 50% are associated with
measurable symptomatic benefit in clinical studies. Similarly, delayed progression by imaging is associated
with delayed symptomatic progression of similar magnitude. This means that treatment with alectinib is
highly likely to provide symptomatic benefit on a group level. At the reported high frequency of tumour
responses in case of brain metastases, symptomatic benefit is expected also in this group of patients, very
commonly encountered in ALK+ NSCLC.
Reported adverse reactions are considered manageable and reversible and unlikely to affect the tolerability of
the product in more than a small proportion of patients. There are obvious caveats in relation to hepatic and
muscular events and, by convention, ILD. Proper guidance is provided in the SmPC.
To contextualise, the ORR is of similar magnitude to that reported for ceritinib after crizotinib failure. Despite
brain metastases in a high proportion of patients in the ceritinib studies, only 11 patients had brain
metastasis assigned as target lesions resulting in poor estimates of ORR: 45.5% (95% CI: 16.7, 76.6)
Assessment report
EMA/197343/2017 Page 120/122
(EPAR). Selection “bias” should also be taken into account when small proportions of lesions are assigned as
target lesions.
It should also be noticed that tumours addicted to a driver mutation tend to show higher response rates to
conventional chemotherapy. In the confirmatory crizotinib study, second-line to chemotherapy, the response
rate in patients treated with pemetrexed or docetaxel was 20% (vs. 65% in the crizotinib arm).
Altogether benefit clearly outweighs the risk in the target population. As activity is unlikely in case of
resistance to crizotinib if related to signalling bypassing ALK, there is likely room to improve B/R by proper
patient selection. This issue may not be possible to resolve within this procedure, and should be a post
approval commitment.
3.7.2. Balance of benefits and risks
Benefit-risk is considered positive.
3.7.3. Additional considerations on the benefit-risk balance
Alectinib has shown a clinically relevant ORR rate in patients that have previously been treated with
crizotinib.
Conditional marketing authorisation
As comprehensive data on the product are not available, a conditional marketing authorisation was proposed
by the CHMP during the assessment, after having consulted the applicant.
The CHMP considered that ALECENSA falls under the scope of Article 2 of Commission Regulation (EC) No.
507/2006 as eligible for a Conditional Marketing Authorisation as it belongs to:
b) Medicinal products which aim at the treatment, the prevention or the medical diagnosis of seriously
debilitating diseases or life-threatening diseases.
Furthermore, the CHMP considers that the product fulfils the requirements for a conditional marketing
authorisation:
The benefit-risk balance is positive. The ORR of 51-52% obtained with alectinib in pivotal studies is
significant in patients with relapsed and refractory ALK+ NSCLC, whose prior therapy included crizotinib.
Together with an acceptable safety-profile in patients in the proposed indication, the benefit-risk balance
is considered positive.
It is likely that the applicant will be able to provide comprehensive data. The applicant will provide
further comprehensive clinical data to confirm efficacy and safety of alectinib in the proposed indication.
More specifically the applicant will provide:
Study ALEX, a phase 3, two-arm, randomized study, comparing alectinib and crizotinib in the first
line.
This phase 3 study is not in the exact same setting where alectinib is authorised, but it will provide
comparative efficacy and safety data for alectinib versus crizotinib.
Unmet medical needs will be addressed. In view of the positive benefit-risk balance, alectinib fulfils an
Assessment report
EMA/197343/2017 Page 121/122
unmet medical need for patients with poor long-term prognosis and limited treatment alternatives.
Although alectinib has not a new mechanism of action, the safety profile is manageable, and treatment
with alectinib was associated with high ORR and durable responses in patients with CNS metastases. In
this context it should be noted that ceritinib (Zykadia) licensed in the same indication as currently
applied for by the Applicant (i.e. after prior crizotinib treatment), is conditionally approved at the time of
the CHMP opinion.
The benefits to public health of the immediate availability outweigh the risks inherent in the fact that
additional data are still required.
In view of the favourable benefit-risk profile, the high ORR, especially in patients with CNS metastases,
the immediate availability of Alecensa on the market outweighs the risk inherent in the fact that
additional data are still required.
3.8. Conclusions
The overall B/R of Alecensa is positive.
4. Recommendations
Outcome
Based on the CHMP review of data on quality, safety and efficacy, the CHMP considers by consensus that the
risk-benefit balance of Alecensa is favourable in the following indication:
Alecensa as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase
(ALK) positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib.
The CHMP therefore recommends the granting of the conditional marketing authorisation subject to the
following conditions:
Other conditions or restrictions regarding supply and use
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).
Conditions and requirements of the marketing authorisation
Periodic Safety Update Reports
The requirements for submission of periodic safety update reports for this medicinal product are set out in
the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and
any subsequent updates published on the European medicines web-portal.
The marketing authorisation holder shall submit the first periodic safety update report for this product within
6 months following authorisation.
Assessment report
EMA/197343/2017 Page 122/122
Conditions or restrictions with regard to the safe and effective use of the medicinal product
Risk Management Plan (RMP)
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed
RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the
RMP.
An updated RMP should be submitted:
At the request of the European Medicines Agency;
Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result of an
important (pharmacovigilance or risk minimisation) milestone being reached.
Specific Obligation to complete post-authorisation measures for the conditional marketing authorisation
This being a conditional marketing authorisation and pursuant to Article 14(7) of Regulation (EC) No
726/2004, the MAH shall complete, within the stated timeframe, the following measures:
Description Due date
In order to further confirm the efficacy and safety of alectinib in the treatment of
patients with ALK-positive NSCLC, the MAH should submit the clinical study report of
the phase III study ALEX comparing alectinib versus crizotinib in treatment naïve
patients with ALK-positive NSCLC.
30 April 2018
Conditions or restrictions with regard to the safe and effective use of the medicinal product to be implemented by the Member States
Not applicable.
New Active Substance Status
Based on the CHMP review of the available data, the CHMP considers that alectinib is considered to be a new
active substance as it is not a constituent of a medicinal product previously authorised within the European
Union.