Vecchi e nuovi antiangiogenetici Vecchi e nuovi antiangiogenetici

Cesare GridelliDivision of Medical Oncology

“S.G. Moscati” Hospital – Avellino (Italy)cgridelli@libero.it

Proangiogenic Ligands and their ReceptorsProangiogenic Ligands and their Receptors

Jubb AM & Harris AL. Lancet Oncol 2010;11:1172–83.

First-Line Treatment of A-NSCLC First-Line Treatment of A-NSCLC

EGFR-mutationALK analysis

Non-squamous cell carcinoma

Metastatic NSCLC, PS 0-2

Squamous cell carcinoma

EGFR mutation (del 19 or L858R in exon 21)

EGFR wild type (or not done)

EGFR-TKI Radiotherapy• CNS• Central airways• Bone• Soft tissue

Platinum plus• Pemetrexed or gemcitabine or taxanes or

vinorelbine

OR Platinum combination plus

• Bevacizumab* (PS 0,1)

Elderly/PS 2• Platinum combination (preferred in fit elderly) or• Monotherapy (preferred in unfit elderly)

Platinum plus• Gemcitabine or taxane or vinorelbine

Elderly/PS 2• Platinum combination (preferred in fit elderly) or • Monotherapy (preferred in unfit elderly)

1

2

2

3

ALK positive

Crizotinib

First-Line Treatment of Advanced NSCLCFirst-Line Treatment of Advanced NSCLC

• Adenocarcinoma• Large cells• NSCLC NOS

Squamous cell carcinoma

EGFR mutation and ALK negative

EGFR mutation positive

ALK positive

PS 0-1

PS 2

PS 3-4

Gefitinib ErlotinibAfatinib

Crizotinib

Doublet chemotherapy (category 1)

ORCetuximab/vinorelbine/ cisplatin (category 2B)

Chemotherapy

Best supportive care

PS 0-1

PS 2

PS 3-4

Doublet chemotherapy (category 1) OR

Bevacizumab + chemotherapy (if criteria met)

ORCisplatin/pemetrexed (category 1)

(if criteria met)OR

Cetuximab/vinorelbine/cisplatin(category 2B)

Chemotherapy

Best supportive care only

Proangiogenic Ligands and their ReceptorsProangiogenic Ligands and their Receptors

Jubb AM & Harris AL. Lancet Oncol 2010;11:1172–83.

Bevacizumab

Bevacizumab

BPC, bevacizumab-paclitaxel-carboplatin; PC, paclitaxel-carboplatin.The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab versus 10.3 months in the chemotherapy-alone group.Sandler A, et al. N Engl J Med. 2006;355(24):2542-2550.

Hazard ratio, 0.79; P=0.003

100

80

60

40

20

0

Ove

rall

Surv

ival

, %

423024181260

Month

36

BPC group(305 events in 417 patients)

PC group(344 events in 433 patients)

• Avastin-based therapy (n=602)– extends OS to 14.2 months– 31% reduction in the risk of death (HR=0.69)

Duration of OS (months)

Pro

bab

ility

of O

S

0.8

0.6

0.4

0.2

0

0 6 12 18 24 30 36 42 48

Avastin + CP (n=300)

CP (n=302)

10.3 14.2

Antiangiogenic Drugs as Chemosensitizing Agents

• Paclitaxel induces rapid chemotherapy-induced acute endothelial progenitor cell mobilization (CEP), indicating synergy with bevacizumab.

• Gemcitabine does not induce CEP. Shaked Y et al, Cancer Cell 14, 263-273, 2008

DoesDoes the Chemo Partner Make a Difference?: Taxane the Chemo Partner Make a Difference?: Taxane Versus Non-Taxane RegimensVersus Non-Taxane Regimens

• N=29 studies• N=5890 pts.• Median OS: 14.4 vs. 13.7 m, P=0.5

Behera et al, J Thorac Oncol, 2015

First-Line Treatment of Advanced NSCLCFirst-Line Treatment of Advanced NSCLC

• Adenocarcinoma• Large cells• NSCLC NOS

Squamous cell carcinoma

EGFR mutation and ALK negative

EGFR mutation positive

ALK positive

PS 0-1

PS 2

PS 3-4

Gefitinib ErlotinibAfatinib

Crizotinib

Doublet chemotherapy (category 1)

ORCetuximab/vinorelbine/ cisplatin (category 2B)

Chemotherapy

Best supportive care

PS 0-1

PS 2

PS 3-4

Doublet chemotherapy (category 1) OR

Bevacizumab + chemotherapy (if criteria met)

ORCisplatin/pemetrexed (category 1)

(if criteria met)OR

Cetuximab/vinorelbine/cisplatin(category 2B)

Chemotherapy

Best supportive care only

Study designStudy design

Presented By Terufumi Kato at 2014 ASCO Annual Meeting

Primary endpoint: PFS by independent reviewPrimary endpoint: PFS by independent review

Presented By Terufumi Kato at 2014 ASCO Annual Meeting

R

Strata:PS (0-1 vs 2)

Type of mutation (exon19 del vs 21 L858R mut vs others)

1:1

Control arm•Erlotinib 150 mg orally once daily

Experimental arm•Erlotinib 150 mg orally once daily•Bevacizumab 15 mg/kg iv every 21 days

NSCLCNon-squamous Activating EGFR mutation Stadio IIIB o IVPS 0-2

Treatment in both arms will be given until disease progression or unacceptable toxicity or patient’s or physician’s motivated decision to stop

Primary endpoints: investigator-assessed and blinded, indipendent centrally-reviewed PFSSample size: 200 ptsCentres involved: about 60

PI: C. GRIDELLI

BEVERLY : STUDY DESIGN

AvaALL: Trial designAvaALL: Trial design

* SOC2: Labelled agents for 2nd-line treatment of NSCLC (erlotinib, pemetrexed and docetaxel)† SOC3 and beyond: Choice of labelled agents in 3rd-line and beyond is the Investigator’s choice

Enroll

Primary endpoint: OS

PD1

SOC2*+

bevacizumab

SOC3†+

bevacizumab

SOC4±

bevacizumab

SOC2* SOC3† SOC4

PD3

Ran

dom

ize 1

:1

PD2

Stage IIIB/IVnon-squamous NSCLCtreated with platinum-

doublet (4-6 cycles)+ bevacizumab PLUS

> 2 cycles ofbevacizumabmaintenance

N=500

– Global trial conducted in ~20 countries

PI: C. Gridelli

Proangiogenic Ligands and their ReceptorsProangiogenic Ligands and their Receptors

Jubb AM & Harris AL. Lancet Oncol 2010;11:1172–83.

Bevacizumab

Bevacizumab

Ramucirumab

Ramucirumab

VEGFR TKI

REVEL: Study DesignREVEL: Study Design

- Stage IV NSCLC after

one platinum- based

chemo +/-

maintenance- Prior Bev allowed- All histologies - PS 0 or 1- No major blood vessel

invasion, or cavitation

- Stage IV NSCLC after

one platinum- based

chemo +/-

maintenance- Prior Bev allowed- All histologies - PS 0 or 1- No major blood vessel

invasion, or cavitation

Treatment until disease progression

or unacceptable

toxicity

Treatment until disease progression

or unacceptable

toxicity

Ramucirumab 10 mg/kg Ramucirumab 10 mg/kg ++Docetaxel 75 mg/mDocetaxel 75 mg/m22 q3wks q3wks

N=628N=628

Placebo Placebo ++

Docetaxel 75 mg/mDocetaxel 75 mg/m22 q3wks q3wksN=625N=625

RANDOMIZE

1:1

Stratification factors:•ECOG PS 0 vs 1•Gender •Prior maintenance•East-Asia vs. ROW

Stratification factors:•ECOG PS 0 vs 1•Gender •Prior maintenance•East-Asia vs. ROW

Primary endpoint: Overall Survival

Secondary endpoints:PFS, ORR, safety, patient-reported outcomes

Primary endpoint: Overall Survival

Secondary endpoints:PFS, ORR, safety, patient-reported outcomes

Pérol, ASCO 2014; Garon, Lancet 2014

Overall SurvivalOverall SurvivalITT PopulationITT Population

Median (95% CI) Censoring RateRAM+DOC

RAM+DOC vs PL+DOC:

10.5 (9.5-11.2) 31.8%PL+DOC 9.1 (8.4-10.0) 27.0%

Stratified HR (95% CI) = 0.857 (0.751-0.979)Stratified log-rank P = .0235

0

20

40

60

80

100

Ove

rall

Su

rviv

al (

%)

RAM+DOCPL+DOC

Number at risk

0 3 6 9 12 15 18 21 24 27 30 33

527501

415386

329306

231197

156129

10386

7056

4536

2323

119

20

36

Survival Time (months)

628625

00

RAM+DOCPL+DOC

Censored

Pérol, ASCO 2014; Garon, Lancet 2014

OS by HistologyOS by Histology

Nonsquamous OS Squamous OS

Stratified HR (95% CI) = 0.89 (0.70-1.15)

RAM+DOCPL+DOC

RAM+DOC

9.5 (8.0-10.8)8.2 (6.3-9.4)

21.7%19.9%

Median (95% CI)Censoring

Rate

vs PL+DOCStratified HR (95% CI) = 0.84 (0.71-0.98)

RAM+DOCPL+DOC

11.1 (9.9-12.3)9.7 (8.5-10.6)

35.5%29.3%

Median (95% CI)Censoring

Rate

RAM+DOCvs PL+DOC

RAM+DOCPL+DOCCensored

100

0

80

60

Ov

era

ll S

urv

iva

l (%

)

40

20

3 6 9 12 15Survival Time (months)

18 21 24 27 30 33 36

157171

RAM+DOCPL+DOC

Number at risk124132

10399

7875

4948

3131

2320

1614

68

25

14

10

00

00 3 6 9 12 15 18 21 24 27 30 33 36

100

80

60

Ov

era

ll S

urv

iva

l (%

)

40

20

Survival Time (months)

465447

RAM+DOCPL+DOC

Number at risk401362

311282

251226

182144

12594

8064

5440

3927

2118

105

10

00

0

RAM+DOCPL+DOCCensored

Pérol, ASCO 2014; Garon, Lancet 2014

Selected Treatment-Emergent Adverse Events Occurring in ≥20% of Patients or ≥5% Higher in the RAM+DOC Arm Selected Treatment-Emergent Adverse Events Occurring in ≥20% of Patients or ≥5% Higher in the RAM+DOC Arm

Presented By Maurice Perol at 2014 ASCO Annual Meeting

Proangiogenic Ligands and their ReceptorsProangiogenic Ligands and their Receptors

Jubb AM & Harris AL. Lancet Oncol 2010;11:1172–83.

Bevacizumab

Bevacizumab

Ramucirumab

Ramucirumab

PDGFR TKI

FGFR TKI

VEGFR TKINindetanib

Nindetanib

Nindetanib

LUME-Lung 1: Randomised Phase III Study LUME-Lung 1: Randomised Phase III Study

22• Reck M, et al. Lancet Oncol. 2014;15:143-55.

Stratification: ECOG PS (0 vs. 1)Prior bevacizumab (yes vs. no)Histology (squamous vs. non-squamous)Brain metastases (yes vs. no)

Regions: Europe/Asia/South AfricaAccrual: 23 Dec 2008 to 09 Feb 2011

Primary Endpoint: PFS by independent central reviewKey Secondary Endpoint: OS, prespecified hierarchical analyses of patients with adenocarcinoma who

progressed in <9 months after start of first-line therapy, all patients with adenocarcinoma, and ITT population

Nintedanib 200 mg BID po, Days 2–21+ docetaxel 75 mg/m2 IV, Day 1,

21-day cycles (n=655)

Placebo BID po, Days 2–21,+ docetaxel 75 mg/m2 IV, Day 1,

21-day cycles (n=659)

N=1314

RANDOMISE

1:1

PD

PD

Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy

Stage IIIB/IV*or recurrent

NSCLC patients after first-line chemotherapy(all histologies)

All histology

Lume Lung 1: Grade ≥3 AEsLume Lung 1: Grade ≥3 AEs

Reck M, et al. Lancet Oncol. 2014;15:143-55.

Grade ≥3 AEs in Patients with Adenocarcinoma*

Approved by EMA on November 21, 2014Approved by EMA on November 21, 2014

VARGATEF® (nintedanib) is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first-line chemotherapy

LUME-Columbus Phase III Study: 2-line NSCLC LUME-Columbus Phase III Study: 2-line NSCLC

* 75 mg/m2 IV, on Day 1 of every 3-week cycle- No restriction of number of courses

PDPD

PDPD1

1

Placebo: 200 mg BID + Docetaxel *Placebo: 200 mg BID + Docetaxel *

Nintedanib: 200 mg BID + Docetaxel *Nintedanib: 200 mg BID + Docetaxel *

N = 800

RANDOMIZE

RANDOMIZE

Co- Primary Endpoints: OS and PFS (by independent review; 6 weeks CT-schedule)

Secondary Endpoints: OR, DC, HRQOL

Co- Primary Endpoints: OS and PFS (by independent review; 6 weeks CT-schedule)

Secondary Endpoints: OR, DC, HRQOL

Key inclusion criteria

•Stage IIIB/IV NSCLC of adenocarcinoma histology•1 prior treatment line•≥1 measurable target lesion•ECOG PS 0 or 1•EGFR-mutation negative•Alk translocation negative

Key exclusion criteria

•Prior VEGFR inhibitors (except bevacizumab) or docetaxel•Active brain metastases

Stratification • Time since start 1st line (<9mo vs. ≥9mo)• ECOG PS (0 vs. 1)

Study Start Date: September 2014Accrual CompletedEstimated Primary Completion Date: July 2015 (Final data collection date for

primary outcome measure)

ChairmenChairmenF. de MarinisC. Gridelli

PanelistsPanelistsF. CiardielloL. CrinòF. de MarinisJ.Y. DouillardC. GridelliF. GriesingerD. LambrechtsM. PerolS. RamalingamE. Smit

Which selection criteria for Which selection criteria for antiangiogenetic treatment?antiangiogenetic treatment?

• Non-squamous

• PS 0-1

• No serious cardio-vascular comorbidities

• No cavitation

• No major vessel invasion

• No previous hemoptysis

• No recent thromboembolic disease or hemorrhage

• No severe or uncontrolled hypertension

• No recent major surgery (< 4 weeks)• No recent thoracic radiation, including the mediastinum

Any predictive biomarker for Any predictive biomarker for antiangiogenetic treatment ?antiangiogenetic treatment ?

• So far, no biomarker for NSCLC patient selection (as well as other cancers) has been validated for clinical practice.

1 ° Progression of disease

Docetaxel

or

Erlotinib

Squamous NOS Nonsquamous

EGFR mutated

EGFR mutated

EGFR WT/UNK EGFR WT/UNK

ALK Negative/UKN

Pemetrexed or Docetaxel

or

Erlotinib

Gefitinib or Erlotinib

Advanced NSCLC: Old Algorythm (just yesterday) for Second- and Third-line therapy

2° Progression of disease

Erlotinib (if not previously administered)

ALK

positive

Crizotinib

NEW TREATMENT ALGORITHM IN ADVANCED SQUAMOUS NSCLC

1st Line

2nd Line

3rd Line

Platin +Platin +GEM/TXT/TAX/VNRGEM/TXT/TAX/VNR

Sq

uam

ou

s

NivolumabNivolumab

Afatinib > Erlotinib

Afatinib > Erlotinib

Docetaxel ±RamucirumabDocetaxel ±

Ramucirumab

4rd Line

Pembrolizumab(PD-L1 > 50%)

Pembrolizumab(PD-L1 > 50%)

1st Line

Docetaxel ± Nindetanib

Docetaxel ± Nindetanib

2nd Line

3rd Line

P/Pem P/Pem

No

n S

q

WT

ErlotinibErlotinib

P-based CTx + BEVAP-based CTx + BEVA

PemetrexedPemetrexed

BEVA until PDBEVA until PDPem Maintenance

NivolumabNivolumab

Docetaxel ± Ramucirumab Docetaxel ±

Ramucirumab

ErlotinibErlotinibErlotinibErlotinib

4rd Line

5rd Line

NEW TREATMENT ALGORITHM IN ADVANCED NON SQUAMOUS NSCLC

PembrolizumabPD-L1 >50%

PembrolizumabPD-L1 >50%

Consensus for clinical researchConsensus for clinical researchIssueIssue PriorityPriority

Identification, validation and clinical performance of biomarkers HighHigh

How incorporate immunotherapy and antiangiogenic treatment in the overall strategy

High

Efficacy of the combination of antiangiogenic drugs and TKI for EGFR and other mutation NSCLC

High

Efficacy of Ramucirumab for 1° line squamous NSCLC (including maintainance)

High

Efficacy of Bevacizumab beyond progression MediumMedium

Efficacy of new antiangiogenic drugs plus Docetaxel after immunotherapy

Medium

Develop rationale combinations among antiangiogenic drugs Medium

Optimize dose, schedule and timing of antiangiogenic drugs Medium