advantages and disadvantages of irreversible...
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Advantages and disadvantages ofirreversible EGFR-TKI
Martin ReckDepartment of Thoracic Oncologyepa t e t o o ac c O co ogy
LungClinic GrosshansdorfGermany
Importance of EGFR mutations
Mutations that change the
• Tumours with these mutations have been shown to be highly
Exon 19 deletionsExon 21 L858R
mutation
Commonly termed
‘activating mutations’
change the structure and function of a
protein such that it has a new or greater activity
• Tumours with these mutations have been shown to be highly responsive to EGFR TKIs1
• In the case of EGFR, exon 19 deletions for example, lead to the expression of an EGFR protein that is permanently addicted to signal transduction2,3, even in the absence of stimulating ligands
1. Murray, et al. JTO 20082. Faber, et al. PNAS 2009; 3. Sharma, et al. Nat Rev Can 2007TKIs = tyrosine-kinase inhibitors
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Clinical efficacy of EGFR-TKIs as first-line therapy
Trial Pop. DrugEGFR
Mut + (N)ORR %
TKI vs CTPFS
(HR, 95% CI)
IPASS1 Asia Gefitinib 261 71.2 vs 47.30.48
(0.36, 0.64)(0.36, 0.64)
First-SIGNAL2 Asia Gefinitb 42 84.6 vs 37.50.61
(0,31, 1.22)
WJTOG 34053 Asia Gefitinib 172* 62.1 vs 32.20.49
(0.34, 0.71)
NEJGSG0024 Asia Gefitinib 224** 73.7 vs 30.70.30
(0.22, 0.41)
OPTIMAL5 Asia Erlotinib 154*** 83 vs 360.16
(0.10, 0.26)
EURTAC6,7 Europe Erlotinib 174# 58.1 vs 14.90.37
(0.25, 0.54)(0.25, 0.54)
Lux Lung 38 Europe/Asia Afatinib 34556 vs 23
61 vs 22
0.58(0.34, 0.65)
0.47(0.34, 0.65)
1. Mok et al 2009; 2. Lee, oral presentation at WCLC 2009; 3. Mitsudomi et al 2012; 4. Maemondo et al 2010; 5. Zhou et al 2011;6. Rosell et al 2011; 7. Gervais, oral presentation at WCLC 2011; Yang et al, ASCO 2012
*, modified ITT population; **, PFS population;***, study population; , ITT population
However..
• After 12 – 14 months progression ofdisease in most of the patientsdisease in most of the patients....
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EGFR resistance mediatingmechanisms
Combination
Second GenerationEGFR-TKIs
Change of EGFR-TKI
chemotherapy + EGFR-TKI
Chemotherapy
IGF-Inhibitors
Sequist et al, Sci Transl Med 2011Met Mab
CombinationEGFR-TKI +
EGFR AB
PIK3 TKI
cMet TKI
HGF AB
Rebiopsy for T790M Analysis
Arcila ME et al, Clin Cancer Res 2011; 17: 1169-80
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Standard Testing:• Standard Sequencing
Rebiopsy for T790M Analysis
Standard Sequencing• Fragment AnalysisAdditional Testing• LNA-PCR/Sequencing
Arcila ME et al, Clin Cancer Res 2011; 17: 1169-80
The Advantage of irreversible EGFR-TKIs- another steric form -
Brugger W et al, Lung Cancer 2012; 77: 2-8
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The Advantage of irreversible EGFR-TKIs- another concept of efficacy -
• Reversible TKIs compete with ATP in thekinase domain of EGFRkinase domain of EGFR
• Irreversible TKIs in addition have a covalent binding to one part of ATP binding pocket.Pharmacodynamics of irreversible TKIs arey
determined by target (EGFR) half-life.
Garutti L, Curr Med Chem 2011; 18: 2981-94
The Advantage of irreversible EGFR-TKIs- inhibiton of several receptors-
Example: Afatinib
Li D, Oncogene 2008; 27: 4702-11
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Second Generation EFGR-TKI
• Neratinib
D iti ib• Dacomitinib
• Afatinib
Neratinib
• 167 patients with advanced NSCLC• Most patients pretreated with
chemotherapy and EGFR-TKI• RR: 1.9%, SD 51%• EGFR Mutant: RR: 3.4%, SD 50%• EGFR Wild Type: RR 0%, SD 64%• No Response in T790M+ patients• PFS: 15.3 w• Grade 3 Diarrhea: 50%
Grade 3 Vomiting: 8%• Grade 3 Vomiting: 8%• Grade 3 Nausea: 3%
Sequist L, J Clin Oncol 2010; 28: 3076-3083
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Second Generation EFGR-TKI
• Neratinib
D iti ib• Dacomitinib
• Afatinib
Dacomitinib
Engelman J, Cancer Res 2007; 67:11924-11923
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Dacomitinibrandomized phase II trial
Dacomitinib Erlotinib HR / p
Patients 94 94
M/F 55/39 56/38
Asian 24.5% 25.5%
Non Sm 19.1% 20.2%
Adeno 66% 64.9%
EGFR Mut 20.2% 11.1%
RR 17% 5.3% P: 0.011
Med PFS 2.86m 1.91mHR 0.66P: 0.012
Med OS 9.5 m 7.4 mHR 0.8
P: 0.205
Ramalingam S, J Clin Oncol 2012; 3 0: 3337-3417
Dacomitinib - Toxicity
Ramalingam S, J Clin Oncol 2012; 3 0: 3337-3417
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Ongoing trials
Name / NCT Population Design Phase
ARCHERNCT01360554
Advanced NSCLC2 d/3 d li
Dacomitinib v E l ti ib
IIIP i EP PFSNCT01360554 2nd/3rd line Erlotinib Prim EP: PFS
NCT00818441 EGFR Mut+ orNever/LightSmoker1st line
Dacomitinib II
NCT01000025 Advanced NSCLC2nd/3rd/4th line(Prior EGFR-TKI)
Dacomitinib vPlacebo
IIIPrim EP: OS
Second Generation EFGR-TKI
• Neratinib
D iti ib• Dacomitinib
• Afatinib
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Afatinib: Preclinical data
KEY FEATURE: Afatinib is highly potent and selectively blocks
Molecular potency and selectivity (IC50)
EGFR (nM) 0.5
HER2 (nM) 14
ErbB4 (nM) 1
HGFR (nM) >10,000
VEGFR2 (nM) >100,000
Afatinib selectively and potently blocks the ErbB Family (EGFR, HER2 and ErbB4) (30,32,33)
Afatinib is highly selective for the ErbB Family. Afatinib does not
i ifi tl i hibit f th
Molecular selectivity
Kinase panel 10 μM 0/50
PanLab 10 μM 3/62
CYP450 10 μM 0/6
significantly inhibit a range of other kinases even at 1000 times higher
concentrations (30,32,33)
Li D, et al. Oncogene 2008;27:4702–4711; Data on file; Uttenreuther-Fischer MM, et al. Oral presented at TraFo, Bergisch Gladbach, Germany, 17–19 May 2007
Afatinib: Activity in a NSCLC model
140
ble
cel
ls (
72 h
ou
rs;
%)
120
100
80
60
Afatinib
ErlotinibNCI-H1975 is a human
NSCLC cell line, characterized by two EGFR mutations,
L858R (activating mutation) and T790M (resistance
mutation)
Co
ntr
ol v
ia 40
20
0
10-5 0.0001 0.001 0.01 0.1 1 10
Drug concentration (µM)
Li D, et al. Oncogene 2008;27:4702–4711; Solca F, et al. Poster A242 presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Philadelphia, USA, 14–18 November 2005
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LUX Lung 1: DesignPreselection of Patients
Patients with:• Adenocarcinoma of the lung • Stage IIIB/IV • Progressed after one or two lines of chemotherapy (incl. one platinum-based regimen)
and ≥12 weeks of treatment with erlotinib or gefitinib
Randomization 2:1(Double Blind)
Oral afatinib 50 mg once daily plus BSC
Oral placebo once daily plus BSC
and ≥12 weeks of treatment with erlotinib or gefitinib• ECOG 0–2
N=585
Primary endpoint: Overall survival (OS)
Secondary: PFS, RECIST response, QoL (LC13 & C30), safety
East Asian patients 58%/56%
Never smoker 63%/62%
Median treatment TKI 10.2/9.7 mMiller V, Lancet Oncology 2012;13: 528-38
PFS by independent review
• No significant difference in OS (HR 1.08; p=0.74)• High number of poststudy treatments (68%/79%)
Miller V, Lancet Oncology 2012;13: 528-38
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Study design Lux Lung 3
Stage IIIB (wet)/IV lung adenocarcinoma (AJCC version 6)
EGFR mutation in tumor( t l l b t ti Th EGFR29* RGQ PCR)
Randomization 2:1 Stratified by:
EGFR mutation (Del19/L858R/other) Race (Asian/non-Asian)
Afatinib 40 mg/day†Cisplatin + Pemetrexed 75 mg/m2 + 500 mg/m2
i.v. q21 days, up to 6 cycles
(central lab testing; Therascreen EGFR29* RGQ PCR)
Primary endpoint: PFS (RECIST 1.1, independent review)‡
Secondary endpoints: ORR, DCR, DoR, tumor shrinkage, OS, PRO§, safety, PK
*EGFR29:19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I. †Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10 mg decrements in case of related G3 or prolonged G2 AE.‡Tumor assessments: q6 weeks until Week 48 and q12 weeks thereafter until progression/start of new therapy. §Patient-reported outcomes: Q-5D, EORTC QLQ-C30 and QLQ-LC13 at randomization and q3 weeks until progression or new anti-cancer therapy.
Yang JC, et al. ASCO 2012
Primary endpoint: PFS Independent review ‒ all randomized patients
bilit
y)
1.0
0 8
Afatinib n=230
Cis/pem n=115
PFS event, n (%) 152 (66) 69 (60)
gres
sion
-fre
e su
rviv
al (
prob
ab
0.8
0.6
0.4
0 2
Median PFS (months) 11.1 6.9
Hazard ratio(95% confidence interval)
0.58 (0.43–0.78)p=0.0004
47%
Pro
g 0.2
0.0
Number at riskAfatinib 230 180 151 120 77 50 31 10 3 0Cis/Pem 115 72 41 21 11 7 3 2 0 0
Progression-free survival (months)0 3 6 9 12 15 18 21 24 27
22%
Yang JC, et al. ASCO 2012
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bilit
y)1.0
0 8
Afatinib n=204
Cis/pem n=104
PFS event, n (%) 130 (64) 61 (59)
PFS: Common mutations (Del19/L858R)Independent review – patients with Del19/L858R (n=308)
gres
sion
-fre
e su
rviv
al (
prob
ab
0.8
0.6
0.4
0 2
Median PFS (months) 13.6 6.9
Hazard ratio(95% confidence interval)
0.47 (0.34–0.65)p<0.0001
51%
Pro
g 0.2
0.0
Number at riskAfatinib 204 169 143 115 75 49 30 10 3 0Cis/Pem 104 62 35 17 9 6 2 2 0 0
Progression-free survival (months)0 3 6 9 12 15 18 21 24 27
21%
Yang JC, et al. ASCO 2012
Most frequent related adverse events>20% difference between treatment arms
Afatinib (n=229)
Cis/pem (n=111)
All Gr† (%) Gr 3 (%) Gr 4 (%) All Gr† (%) Gr 3 (%) Gr 4 (%)
Diarrhea 218 (95 2) 33 (14 4) 0 17 (15 3) 0 0Diarrhea 218 (95.2) 33 (14.4) 0 17 (15.3) 0 0
Rash/acne* 204 (89.1) 37 (16.2) 0 7 (6.3) 0 0
Stomatitis/mucositis* 165 (72.1) 19 (8.3) 1 (0.4) 17 (15.3) 1 (0.9) 0
Paronychia 130 (56.8) 26 (11.4) 0 0 0 0
Dry skin 67 (29.3) 1 (0.4) 0 2 (1.8) 0 0
Nausea 41 (17.9) 2 (0.9) 0 73 (65.8) 4 (3.6) 0
Decreased appetite 47 (20.5) 7 (3.1) 0 59 (53.2) 3 (2.7) 0
Fatigue* 40 (17.5) 3 (1.3) 0 52 (46.8) 14 (12.6) 0
Vomiting 39 (17.0) 7 (3.1) 0 47 (42.3) 3 (2.7) 0
Neutropenia 2 (0.9) 1 (0.4) 0 35 (31.5) 17 (15.3) 3 (2.7)
Anemia 7 (3.1) 1 (0.4) 0 31 (27.9) 5 (4.5) 2 (1.8)
*Grouped term. †No grade 5 events for the presented AEs.
Yang JC, et al. ASCO 2012
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Time to deterioration in lung cancer-related symptoms
Cough Dyspnea
Pain
Yang JC, et al. ASCO 2012
Another Benefit: Combination of irreversible EGFR-TKI and EGFR-Antibody?
CetuximabresistantT24PR3
CetuximabSensitiveT24T24PR3
Quesnelle KM, ClinCancer Res 2011; 17: 5935- 44
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Afatinib + CetuximabTumor Regression by T790M Mutation Status
Horn L, WCLC 2011
Conclusions
Advantages:
• Efficacy in EGFR mutated tumorsy
• Efficacy after failure of reversible EGFR-TKI
• Efficacy in combination with EGFR Ab (afatinib)
• Efficacy in HER2 mutated tumors
Disadvantages:
• Higher toxicity
• Efficacy in T790 mutated tumors needs to be confirmed
• Comparative efficacy to reversible EGFR-TKI needs tobe proven (ongoing phase III trials)
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