ASCO Updates 2011 Lung Cancer

ASCO Updates 2011 Lung Cancer
Heather Wakelee, M.D Assistant Professor of Medicine,Oncology Stanford University and Stanford Cancer Institute

Abstracts to be discussed
Metastatic NSCLC Maintenance CRA pemetrexed, LBA7511 – gefitinib Targeted Therapy LBA7512- motesanib, 7502-vadimezan, CRA7506-driver mutations, EURTAC, MetMab, 7507-crizotinib, 7500-ganetespib Early Stage NSCLC 7002-TREAT, 7013-E1505 Small Cell Lung Cancer 7000-amrubicin

Metastatic NSCLC Maintenance CRA pemetrexed, LBA gefitinib Targeted Therapy LBA7512- motesanib, 7502-vadimezan, CRA7506-driver mutations, EURTAC, MetMab, 7507-crizotinib, 7500-ganetespib Early Stage NSCLC 7002-TREAT, 7013-E1505 Small Cell Lung Cancer 7000-amrubicin

Recent Maintenance Trials
Docetaxel early vs. late PFS benefit Strong trend OS benefit Pemetrexed vs placebo PFS + OS benefit Erlotinib vs placebo - Saturn PFS + small OS benefit Erlotinib vs placebo + Bevacizumab (ATLAS) - ~ early vs late (unblinding at PD) Trend OS benefit

Continuation Maintenance
Study/Yr Induction Maintenance MTTP/MPFS Med OS toxicity Belani 2003 Carbo/Tax Paclitaxel wk Obs 38 wk 29 wk 75 wk 60 wk 45% Gr 3/4 Brodowicz 2006 Cis/Gem Gem d1,8 6.6 mo 5.0 mo P<.001 13 mo 11 mo Heme tox in 20%+ Belani 2010 Carbo/Gem 7.4 mo 7.7 mo 8 mo 9.3 mo NS <20% Heme Perol 2010 3.8 mo 1.9 mo NR 28% Gr 3/4 Clear benefit of continuation in PFS in 3/4, and trend in OS in 2/3 trials PFS matters if we will never return to the 1st line drugs which were stopped Fidias/Novello JCO Dec 2010

Continuation Maintenance
Bevacizumab, cetuximab, erlotinib are ALWAYS given w/ maintenance approach Patel’s phase II study of carboplatin/pemetrexed/bevacizumab w/ continuation of pem/bev was very promising We never stop 2nd or 3rd line therapy while it is working, so why do we stop 1st line?

PARAMOUNT: Phase III Study of Maintenance Pemetrexed (Pem) Plus Best Supportive Care (BSC) Versus Placebo Plus BSC Immediately Following Induction Treatment with Pem Plus Cisplatin for Advanced Nonsquamous NSCLC CRA 7510 L. G. Paz-Ares1, F. de Marinis2, M. Dediu3, M. Thomas4, J.L. Pujol5, P. Bidoli6, O. Molinier7, T.P. Sahoo8, E. Laack9, M. Reck10, J. Corral1, S. Melemed11, W. John11, N. Chouaki12, A. H. Zimmermann11, C. Visseren-Grul13, C. Gridelli14 1

PARAMOUNT: Background
Pemetrexed is active nonsquamous NSCLC: In first-line doublet 3 As maintenance agent following a non-pem platinum doublet 4 JMEN: after 4 cycles non-pem platinum doublet pem vs placebo Non-squamous pt results: OS HR .07, p.002 Pemetrexed maintenance has not been studied following pemetrexed-platinum induction in a phase III setting (continuation maintenance) Paz-Ares PASCO 2011, LBA7510 1 2Azzoli CG et al. J Clin Oncol 2009; 27:6251–6266 3Scagliotti GV et al. J Clin Oncol 2008;26: ; 4Ciuleanu T et al. Lancet 2009;374:

PARAMOUNT: Study Design
Paz-Ares PASCO 2011, LBA7510 Study Treatment Period Progression Induction Therapy (4 cycles) Maintenance Therapy (Until PD) 21 to 42 Days 500 mg/m2 Pemetrexed + 75 mg/m2 Cisplatin, d1, q21d CR, PR, SD PD Placebo + BSC, d1, q21d 500 mg/m2 Pemetrexed + BSC, d1, q21d 2:1 Randomization Patients enrolled if: Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0/1 Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD) Randomized, placebo-controlled, double-blind, phase III study Folic acid and vitamin B12 administered to both arms

PARAMOUNT: Investigator Assessed PFS (from Maintenance)
Pem + BSC Placebo + BSC Pemetrexed: median =4.1 mos ( ) Placebo: median =2.8 mos ( ) Log-rank P= Unadjusted HR: 0.62 ( ) Patients at Risk Pem + BSC N=359 132 57 21 4 Placebo + BSC N=180 52 15 5 JMEN: PFS 4.4 mo vs 1.8 mo, HR 0.47, p<.00001 Paz-Ares PASCO 2011, LBA7510

Efficacy and tolerability data from a randomized, placebo-controlled, parallel-group study of gefitinib as maintenance therapy in patients with locally advanced or metastatic NSCLC (INFORM) (C-TONG 0804) L Zhang, SL Ma, XQ Song, BH Han, Y Cheng, C Huang, SJ Yang, XQ Liu, YP Liu, MZ Wang, XW Zhang on behalf of the INFORM investigators # LBA 7511

INFORM: Study design Zhang PASCO LBA7511 Endpoints Primary Secondary
Progression-free survival (PFS) Secondary Objective response rate (ORR) Disease control rate (DCR) Overall survival (OS) Quality of life Safety and tolerability Exploratory Biomarkers EGFR mutation Patients Age ≥18 years Completed 4 cycles of first-line platinum-based chemotherapy without PD or unacceptable toxicity Life expectancy ≥12 weeks WHO PS 0-2 Measurable Stage IIIB/IV disease Gefitinib (250 mg/day) 1:1 randomization Placebo (once daily) EGFR, epidermal growth factor receptor; PD, progressive disease PS, performance status; WHO, World Health Organization

INFORM: PFS (ITT population)
Zhang PASCO LBA7511 100 Gefitinib (n=148) Placebo (n=148) 90 80 Median PFS,† months 6-month PFS rate, % 12-month PFS rate, % No. events, n (%) (83.8) (97.3) 70 60 HR‡ (95% CI) = 0.42 (0.33, 0.55); p<0.0001 Probability of PFS (%) 50 40 30 20 10 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time since randomization (weeks) Patients at risk : Placebo 148 82 46 26 16 10 6 4 3 2 2 2 Gefitinib 148 109 82 70 65 56 49 42 38 31 20 15 6 1 †Estimated using the Kaplan-Meier method ‡Primary Cox analysis with covariates

INFORM PFS by EGFR mut status
Zhang PASCO LBA7511 HR (95% CI) = 0.17 (0.07, 0.42) Gefitinib (n=15) Median PFS†, 16.6 months No. events, 9 (60.0%) Placebo (n=15) Median PFS†, 2.8 months No. events, 15 (100.0%) EGFR mutation-positive HR (95% CI) = 0.86 (0.48, 1.51) Gefitinib (n=25) Median PFS†, 2.7 months No. events, 25 (100.0%) Placebo (n=24) Median PFS†, 1.5 months No. events, 24 (100.0%) EGFR mutation-negative 100 100 80 80 60 60 PFS (%) PFS (%) 40 40 20 20 8 16 24 32 40 48 56 64 72 80 88 96 104 112 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (weeks) Time (weeks) No. of patients at risk No. of patients at risk Placebo 15 9 5 3 3 2 1 1 1 1 1 1 Placebo 24 9 5 3 2 Gefitinib 15 15 14 14 13 11 10 18 7 7 5 3 1 Gefitinib 25 14 6 3 3 1 †Estimated using the Kaplan-Meier method

INFORM OS: (ITT population)
Gefitinib (n=148) Placebo (n=148) 100 90 Median OS, months 6-month survival rate, % 12-month OS rate, % No. events, n (%) (53.4) (62.8) 80 70 HR (95% CI) = 0.84 (0.62, 1.14); p=0.2608 60 Overall survival (%) 50 40 30 20 10 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 Time (weeks) Patients at risk: Placebo 148 147 136 127 115 107 97 91 78 66 47 37 13 6 HR <1 implies a lower risk of death on gefitinib Gefitinib 148 141 129 119 114 108 102 90 84 75 56 39 18 4

Conclusions – Switch Maintenance
PFS improved in ALL switch maintenance studies OS significantly improved w/ PEM in JMEN and erlotinib in Saturn but not gefitinib in INFORM OS strongly trended in favor of early docetaxel Patients receiving delayed 2nd line Rx MAY live just as long IF they receive the effective agent BUT we miss at least 1/3 of them 2nd line therapy works, we should not deny our patients 2nd line therapy

Metastatic NSCLC Maintenance CRA pemetrexed, LBA gefitinib Targeted Therapy LBA7512- motesanib, 7502-vadimezan,CRA7506-driver mutations, EURTAC, MetMab, 7507-crizotinib, 7500-ganetespib Early Stage NSCLC 7002-TREAT, 7013-E1505 Small Cell Lung Cancer 7000-amrubicin, 7001-obatoclax

E4599: Bevacizumab Efficacy
RR: 15% for Carboplatin (CbP) vs 35% for CbP + Bevacizumab PFS OS 100 CbP 100 CbP CbP + bevacizumab CbP + bevacizumab 80 80 P < .001; HR: 0.66 Median PFS: 6.2 mos vs 4.5 mos 6-mos PFS: 55% vs 33% 1-yr PFS: 15% vs 6% P = .003; HR: 0.79 Median OS: 12.3 mos vs mos 1-yr OS: 51% vs 44% 2-yr OS: 23% vs 15% 60 60 Patients With PFS (%) Patients Surviving (%) 40 40 20 20 6 12 18 24 30 36 6 12 18 24 30 36 Mos Mos Sandler A, et al. N Engl J Med. 2006;355: .

Promising Small Molecule Inhibitors of VEGFR and Their Targets
SCA-14 SABCS V pptSCA-10 breast cancer slides_ ppt 4/13/2017 Promising Small Molecule Inhibitors of VEGFR and Their Targets Inhibitor VEGFR-1 VEGFR-2 VEGFR-3 PDGFR cKIT EGFR Other Sunitinib + - FGFR Valatanib cFms Vandetanib +/- ret Cediranib ++ Pazopanib Sorafenib Raf Axitinib Cabozantinib Met Motesanib BIBW1120 Multiple VEGFR-TKIs being developed

VEGFR-TKI activity in NSCLC
Vandetanib improved symptoms combination w/ 2nd line chemo Improved PFS with docetaxel, but no FDA approval Cediranib with 1st line chemo promising (BR.24) Press release that phase III trial halted for toxicity Sorafenib single agent promising results, but toxic w/ carbo/taxol (ESCAPE trial) We are still lacking any biomakers to help us “personalize” VEGF targeted agents.

SCA-14 SABCS V6 02-13-07.pptSCA-10 breast cancer slides_8-21-06.ppt
4/13/2017 An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) 1090 chemo-naïve pts with stage IIIB/IV NSCLC Randomized to 6 cycles of carboplatin/paclitaxel + motesanib 125 mg QD (Arm A) or placebo QD (Arm B) OS was NOT significantly improved w/ motesanib 13 mo vs 11 mo, HR .9, p.14, primary endpoint PFS was improved w/motesanib HR .79, p.0006 ORR was significantly improved with motesanib 40% vs 26%, p<.0001 Incidence of grade 3 AEs in Arms +/- m was 73%/59% Main update at ASCO 2011 on a VEGFR TKI was this negative phase III trial Scagliotti LBA#7512

913 pts w/ stage IIIB/IV NSCLC s/p 1 prior chemo
Aflibercept in combination with docetaxel for 2nd-line treatment of locally advanced or metastatic NSCLC: Final results of a multinational placebo-controlled phase III trial (VITAL) Aflibercept novel fusion protein binding VEGF-A, -B and PIGF acting as a decoy receptor 913 pts w/ stage IIIB/IV NSCLC s/p 1 prior chemo randomized to docetaxel + aflibercept or placebo 83% adenoCA, Med age 60 yo, 66% male OS 10.4 vs 10.0 mo, HR 1.0 w aflibercept, primary endpoint PFS HR .82, p.0035 RR 9% vs 23%, p<.0001 Novello, WCLC 2011, O43.06

Paclitaxel + carboplatin + ASA404 Paclitaxel + carboplatin + placebo
Study Design ASA404 (vadimezan): a small molecule vascular disrupting agent; Causes breakdown of vasculature and hemorrhagic tumor necrosis Stage IIIB/IV NSCLC All histologies First-line chemotherapy-naïve PS 0 or 1 Stratification: Sex Squamous vs non-squamous Paclitaxel + carboplatin + ASA404 N=1200 Randomization 1:1 Paclitaxel + carboplatin + placebo ATTRACT-1 is a randomized, double-blind, placebo-controlled, global Phase III trial, investigating ASA404 in combination with paclitaxel/carboplatin in first-line treatment of advanced NSCLC of all histologies. Stratification was according to sex and histology. Randomization was with a 1:1 ratio. To be consistent with contemporary studies in advanced NSCLC, the paclitaxel dose selected for the ATTRACT 1 trial was 200 mg/m2. Blinded maintenance therapy was given to patients with response or stable disease after 6 cycles of therapy. Paclitaxel 200 mg/m2, carboplatin AUC 6, and ASA mg/m2 or placebo Day 1, q3w, up to six cycles ASA404 maintenance treatment (after completion of six cycles of ASA404 + P/C up to progression) Lara abstr 7502 23

ATTRACT1: Overall Survival
Arm ASA404 + PC Placebo + PC Median survival (95% CI) 13.4 months (11.4, 16.6) 12.7 months (11.3, 14.4) The primary endpoint of this trial was Overall Survival. The study was closed by the DSMC at interim analysis for futility. The final overall survival curves are presented here. HR for survival was 1.0, with a p value of 0.5, corresponding to median survival times of 13.4 and 12.7 months for the ASA404 and placebo arms respectively. Lara abstr 7502

Anti-Angiogensis in NSCLC No biomarkers, small steps forward
Bevacizumab increases RR and PFS when added to 1st line chemotherapy for NSCLC, improved OS in 1/2 trials No VEGFR-TKI to date has improved the efficacy of chemotherapy, including motesanib at ASCO 2011 Decoy receptor-aflibercept – No OS benefit with chemotherapy Vascular disrupting agent ASA404 failed to improve outcomes when added to chemotherapy Single agent promise seen with sorafenib, sunitinib, others, but no confirmatory phase III trial data to date Novel agents in development – other VDAs, other antibodies Predictive and prognostic markers are in development to help guide patient selection- but none validated to date ICAM, VEGF levels, VEGF polymorphisms, C/AFs… We are still lacking any biomakers to help us “personalize” VEGF targeted agents.

Metastatic NSCLC Maintenance CRA pemetrexed, LBA gefitinib Targeted Therapy LBA7512- motesanib, 7502-vadimezan, CRA7506-driver mutations, EURTAC, MetMab, 7507-crizotinib, 7500-ganetespib Early Stage NSCLC 7002-TREAT, 7013-E1505 Small Cell Lung Cancer 7000-amrubicin, 7001-obatoclax

Lung Cancer Mutation Consortium
Kris ASCO 2011, CRA7506

516 Number analyzed for mutation and FISH 1064 FISH
Lung Cancer Mutation Consortium Kris ASCO 2011, CRA7506 Number analyzed for mutation and FISH 516 82 294 172 Mutation profiling FISH Total study group as of 13 May 11 1064 Pending analysis

Incidence of Single Driver Mutations
Lung Cancer Mutation Consortium Incidence of Single Driver Mutations Mutation found in 54% (280/516) of tumors completely tested (CI 50-59%) Kris ASCO 2011, CRA7506

IPASS: Progression-free survival in EGFR mutation + vs - patients
EGFR mutation-positive EGFR mutation-negative Gefitinib (n=132) Carboplatin/paclitaxel (n=129) Gefitinib (n=91) Carboplatin/paclitaxel (n=85) 1.0 1.0 HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 No. events gefitinib, 97 (73.5%) No. events C/P, 111 (86.0%) HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 No. events gefitinib, 88 (96.7%) No. events C/P, 70 (82.4%) 0.8 0.8 0.6 0.6 Probability of progression-free survival Probability of progression-free survival 0.4 0.4 Additional testing on a subset of the IPASS patients led to the discovery of a very different story where it is clear that those with the mutations do benefit more from first line gefitinib, but those without the mutations are better with chemotherapy 0.2 0.2 0.0 0.0 4 8 12 16 20 24 4 8 12 16 20 24 Months Months At risk: Gefitinib 132 108 71 31 11 3 91 21 4 2 1 C/P 129 103 37 7 2 1 85 58 14 1 Treatment by subgroup interaction test, p<0.0001 Incidence of EGFR mutation: 261/437 = 59.7% Mok et al 2008 30

4/13/2017 Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial 174 patients in Europe w/ EGFR mut randomized to receive erlotinib or platinum-based CT as first-line therapy CT Erlotinib P value Response rate 10.5% 54.5% <0.0001 PFS, mo 5.2 (95% CI, ) 9.4 (95% CI, ) HR: 0.42, P<0.0001 Median survival, mo 18.8 22.9 HR: 0.80, P=0.42 Most common toxicities Asthenia: 68.9% Anemia: 45.9% Nausea: 40.5% Neutropenia: 36.5% Diarrhea: 57.3% Asthenia: 53.3% Rash: 49.3% At ASCO 2011 were the results of EURTAC, the first large phase III randomized trial in pts with EGFR mutations done outside of Asia. Again the study showed improved RR and PFS with first line EGFR TKI (erlotinib) versus chemotherapy, but no OS improvement. Rosell PASCO 2011, abstr 7503

EURTAC: PFS in ITT population
Tony Mok, ASCO discussant 2011 1.0 0.8 0.6 0.4 0.2 Erlotinib (n=86) Chemotherapy (n=87) HR=0.37 (0.25–0.54) Log-rank p<0.0001 PFS probability 5.2 9.7 Study Response Rate PFS EURTAC 58% vs 14.9% 9.7 vs 5.2 months (HR 0.37) OPTIMAL 83% vs 36% 13.1 vs 4.6 months (HR 0.16) NEJ 002 74% vs 31% 10.8 vs 5.4 months (HR 0.30) WJTOG 3405 62% vs 31% 9.2 vs 6.3 months (HR 0.49) Time (months) Patients at risk Erlotinib Chemo Data cut-off: 26 Jan 2011

4/13/2017 Final overall survival results of NEJ002, a phase III trial comparing gefitinib to carboplatin (CBDCA) plus paclitaxel (TXL) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) with EGFR mutations 228 patients w/ EGFR+ adv NSCLC were treated with gefitinib or carboplain/paclitaxel Results: MST= 27.7 mo for gef vs mo for C/P 2-year survival: 58% for gef vs. 54% for C/P Eurtac OS: HR=0.80 (0.47–1.37), Log-rank p=0.4170 None of the EGFR-TKI vs chemo as 1st line therapy trials in EGFR mut pts have shown a significant OS benefit Multiple trials in Asia have now focused on pts with EGFR mutations looking at EGFR-TKI versus chemotherapy first line. The results have all been similar with improved RR and PFS with the EGFR TKI in these pts, but no Os benefit. At ASCO 2011 the OS results from a Japanese study was presented with the same conclusions. Inoue PASCO 2011, abstr 7519 Rosell PASCO 2011 abstr 7503

EGFR Resistance Overview
Unfortunately resistance to EGFR TKIs develops T790M ~50% of acquired resistance Approachs like irreversible* EGFR-TKIs in development Afatinib, HKI272*, PF *, BMS690514* Met amplification ~20% of acquired resistance Multiple drugs in development, mostly + an EGFR-TKI XL184 (cabozatinib), MetMab, ARQ197 Other resistance mutations in EGFR reported T854A, D761Y… Kobayashi. NEJM 2005;352:786; Engelman. Science 2007;316:1089; Balak. CCR 2006;12:6494;Bean. CCR 2008;14:7519

Phase II: Erlotinib +/- MetMAb in 2nd/3rd-line NSCLC
(15 mg/kg IV Q3W) + erlotinib (150 mg daily) Arm A R A N D O M I Z A T I O N 1:1 Stratification factors: Tobacco history Performance status Histology n=69 Key eligibility: Stage IIIB/IV NSCLC 2nd/3rd-line NSCLC Tissue required PS 0–2 Placebo (IV Q3W) + erlotinib (150 mg daily) n=137* n=68 Arm B Co-primary objectives: PFS in ‘Met Diagnostic positive’ patients (est. 50%) PFS in overall ITT population PD Add MetMAb n=27 Spigel PASCO 2011, 7505 5

MetMAb + erlotinib - ITT population
Spigel PASCO 2011, 7505 PFS: HR=1.09 OS: HR=0.8 Placebo + erlotinib 2.6 56 MetMAb + erlotinib 2.2 48 Placebo + erlotinib 7.4 41 MetMAb + erlotinib 8.9 34 0.0 0.2 0.4 0.6 0.8 1.0 Median (mo) HR (95% CI) Log-rank p-value No. of events 0.0 0.2 0.4 0.6 0.8 1.0 Median (mo) HR (95% CI) Log-rank p-value No. of events 1.09 (0.73–1.62) 0.69 0.80 (0.50–1.28) 0.34 Probability of progression free Probability of survival 3 6 9 12 15 18 3 6 9 12 15 18 21 Time to progression (months) Overall survival (months) 8

MetMAb plus erlotinib in Met Dx+ pts
Spigel PASCO 2011, 7505 PFS: HR=0.53 OS: HR=0.37 Placebo + erlotinib 1.5 27 MetMAb + erlotinib 2.9 20 Placebo + erlotinib 3.8 26 MetMAb + erlotinib 12.6 16 0.0 0.2 0.4 0.6 0.8 1.0 Median (mo) HR (95% CI) Log-rank p-value No. of events 0.0 0.2 0.4 0.6 0.8 1.0 Median (mo) HR (95% CI) Log-rank p-value No. of events 0.53 (0.28–0.99) 0.04 0.37 (0.19–0.72) 0.002 Probability of progression free Probability of survival 3 6 9 12 15 18 3 6 9 12 15 18 21 Time to progression (months) Overall survival (months) 9

Results (of 55 evaluable):
Afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. Janjigian PASCO 2011, abstr 7525; Horn WCLC 2011, abstr O19.07 Background: T790M resistance common, combined afatinib+ cetuximab may overcome resistance Methods: 61 NSCLC with “acquired resistance” received oral afatinib 40 mg qd + biweekly cetuximab 250 or 500 mg/m2 Results (of 55 evaluable): 100% disease control w/500 mg/m2 dose: 51% PR 11/35 PR in T790M+ pts No dose-limiting toxicities, 8% Gr 3 rash Conclusions: Cetuximab/afatinib combination is tolerable with encouraging clinical activity- study expansion 1st documented activity in T790M population

Tumor Regression by T790M Mutation Status
Horn WCLC 2011, abstr O19.07

Marked Activity of Crizotinib in Patients with Advanced, ALK-positive NSCLC (N=82)
Kwak et al. NEJM 2010;363:1693–703; Bang et al. JCO 2010;28:18S abstract 3 60 40 20 –20 –40 –60 –80 –100 Progressive disease Stable disease Confirmed partial response Confirmed complete response Maximum change in tumor size (%) –30% *

4/13/2017 Impact of crizotinib on survival in patients with advanced, ALK+ NSCLC compared with historical controls 82 ALK+ patients enrolled phase 1 trial of crizotinib were compared to 37 ALK+ patients not treated with crizotinib (many of whom were not trial eligible which was confounder) and 252 ALK-/EGFR- patients Results: OS in ALK+ patients treated with crizotinib did not differ with gender, ethnicity, smoking history, or age Conclusions: in patients with ALK+ NSCLC, crizotinib therapy resulted in a higher OS than that of crizotinib-naïve controls , but confounded by selection of control population ALK+ Crizotinib-treated ALK+ not treated with crizotinib ALK-/EGFR- 1-y OS 77% 73% 49% 2-y OS 64% 33% Median OS Not reached 20 mo Updates this year focused on retrospective comparisons Shaw PASCO 2011 abstr 7507

4/13/2017 An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC) 73 pts 2nd line+ NSCLC - ganetespib (200 mg/m2 qwk 3/4) Mutation status: group A=EGFR; group B=KRAS; group C=EGFR & KRAS wt Results: AEs reported in ≥20% diarrhea, fatigue, nausea, anorexia, constipation, and dyspnea (all generally grade 1-2) Group C: durable PR, and 7 SD; expansion continues Responses seen exclusively in ALK+ patients (all 4 PRs ALK+) Disease stabilization noted in EGFR and KRAS mutated patients Resistance to ALK also develops with some promising new treatment options under investigation Wong PASCO 2011 abstr#7500

Hsp90: Background Heat shock proteins represent 1-2% of all cellular proteins Facilitate protein-folding and stabilization Induced under stress, hypoxia and oxidative damage Ramalingam discussion Soti et al, J Biol Chem, 2002.

Clinical Results: HSP90 Inhibition in ALK+ NSCLC
IPI-504 STA-9090 *simulated waterfall plot based on reported results *Durability of responses not reported N=11 Ramalingam discussion ASCO 2011

Hsp90 Inhibtion in ALK + NSCLC
There is now clear evidence of robust anti-cancer effects with Hsp90 inhibitors in ALK+ NSCLC Durability of responses is not established yet Next steps Combination of Crizotinib with Hsp90 inhibitors Hsp90 inhibition in Crizotinib-resistant ALK +NSCLC Ramalingam discussion ASCO 2011

Targeted Therapy: Summary
The VEGFR-TKI inhibitors show promise, but not with chemotherapy today, and not without biomarkers Other angiogenesis approaches like Aflibercept and ASA404 unfortunately negative to date Driver mutations identified in >50% of adenocarcinomas EGFR-TKI therapy is appropriate first-line therapy for pts with known EGFR activating mutations Strategies to overcome EGFR-TKI promising MetMab, Afatinib/cetuximab EML4-ALK fusion protein inhibitor crizotinib shows great promise in selected patients HSP90 inhibitors may overcome crizotinib resistance

Time Lag- Target Recognition to Drug Therapy
1960 1978 1998 2001 2002 2004 2007 2010 BCR-ABL 41 yrs EGFR 26 yrs KIT 3 yrs BRAF 8 yrs ALK 3 yrs Govindan Discussion ASCO 2011 Gerber and Minna Cancer Cell: 18: 548, 2010

Lace Meta-analysis trials
Trial Stage n Chemo Survival ALPI I-III Cis/MVd No BLT I-III Cis/4 options No IALT I-III Cis/Vinca or VP16 Yes NCIC IB-II Cis/Vin Yes ANITA I-IIIA Cis/Vin Yes NEJM 00; JNCI 03; EuroJTS 04, NEJM 04; NEJM 05; Lancet Onc 2006

NCCN Guidelines Adjuvant Chemotherapy, NSCL-D
Includes 5 published cisplatin regimens Cis 50 d 1,8 + vin 25 d 1, 8, 15, 22 q 28 Cis 100 d 1 + vin 30 d 1,8,15, 22 q 28 Cis d 1 + vin day 1,8 q 21 Cis 100 d 1 + etop 100 day 1-3, q 28 Cis 80 d 1 + vinblastine 4 q wk - q 2 wk q 21 Includes 3 other regimens – all cis 75 q 21 Gem 1250 d 1,8: Doce 75 d 1, Pem 500 d 1

Randomized phase 2 Trial on
Refinement of Early stage NSCLC Adjuvant chemotherapy with cisplatin and pemetrexed (CPx) versus cisplatin and vinorelbine (CVb) - TREAT Kreuter PASCO abstr 7002 M. Kreuter, J. Vansteenkiste, J. Fischer, W. Eberhardt, H. Zabeck, J. Kollmeier, M. Serke, N. Frickhofen, M. Reck, W. Engel-Riedel, S. Neumann, M. Thomeer, C. Schumann, P. De Leyn, T. Graeter, G. Stamatis, I. Zuna, F. Griesinger and M. Thomas on behalf of the TREAT investigators

TREAT Design Cisplatin / Vinorelbine (CVrb) R0
Kreuter PASCO 2011 abstr 7002 Inclusion • NSCLC stages IB, IIA, IIB, T3N1M0 • ≤ 42 days postoperatively, R0, systematic LN-dissection • ECOG 0, 1 • amenable to Cisplatin treatment Stratification • Center • Nodal status (N0 versus N1) • Surgical procedure (lobectomy versus pneumonectomy) Cisplatin / Vinorelbine (CVrb) Cisplatin / Pemetrexed (CPx) 400 mg/m2 over 16 wks 50 mg/m2 d1+8 / 25 mg/m2 d1, 8, 15, 22 q d 29 x 4 75 mg/m2 d1 / mg/m2 d q d 22 x 4 +folic acid, Vitamin B12, Dexa in Cis-Pem Winton et al., N Engl J Med (2005) 352: 258 R0 300 mg/m2 over 12 wks

Very high dose delivery on cis/pem On cis/vin dose delivery lower
TREAT Kreuter PASCO 2011 abstr 7002 CPx safe and feasible less toxicity compared to CVb; Gr 3/4 heme Very high dose delivery on cis/pem 90% of cisplatin or 271 mg/m2 (mean) On cis/vin dose delivery lower 66% of cisplatin still 263 mg/m2 (mean) Dose density improved with cis/pem CVb –Vb delivery d15, d22 difficult Efficacy: longer follow up to be awaited; but 38% stage IB and 45% squamous cell

Which Chemotherapy in the Adjuvant Setting?
Metastatic disease: Carboplatin/paclitaxel = cisplatin/paclitaxel = cisplatin/docetaxel = cisplatin/gemcitabine Cisplatin/docetaxel > cisplatin/vinorelbine Cisplatin/pemetrexed > cisplatin/gemcitabine for non-squam histology Wakelee Discussion ASCO 2011 Schiller NEJM 346:92, 2002; Fossela JCO 21:3016, 2003; Scagliotti JCO 26:3543, 2008

A simple proof in adjuvant chemotherapy
So IF in metastatic disease: Cis/Vin < Cis/Doce Cis/Doce = Cis/Gem Cis/Gem < Cis/Pem (non-squam) Then: either cis/doce, cis/gem or cis/pem (non-squam) > cis/vin for adjuvant therapy But this is BIOLOGY, not simple math Wakelee Discussion ASCO 2011

ECOG 1505 Adjuvant Chemo +/- Bevacizumab
RANDOM I Z E Overall Survival Primary Endpoint Chemotherapy X 4 cycles ELIGIBLE: N=1500 Resected IB-IIIA (1B  4cm) Chemotherapy x 4 cycles + Bevacizumab X 1 year * Investigator Choice : Cis/Vinorelbine, Cis/Docetaxel, Cis/Gem, Cis/Pem

Table 4: E1505 - Preliminary Chemotherapy Administered
Total Arm A Arm B (BEV) Cisplatin + 636 320 316 Vinorelbine 170(27%) 82(26%) 88(28%) Docetaxel 207(33%) 105(33%) 102(32%) Gemcitabine 158(25%) 76(24%) Pemetrexed* 99(16%) 50(16%) 49(16%) *option only since 2009, non-squamous histology only Wakelee abstr 7013, ASCO 2011

Interim E1505 Toxicity Differences
Arm A n=341 Gr 3 /4 Arm B (Bev) n=329 Gr 3/4 P value Neutropenia 57(17%) / 69(21%) 68(21%)/ 76(24%) 0.05 Lymphopenia 3(0.9%)/0 10(3.1%)/1(0.3%) 0.03 Hypertension 7(2.1%) / 0(0%) 64(20.1%)/ 3(0.9%) <0.001 Proteinuria 2 (0.6%) / 0 8(2.5%) / 1 (0.3%) Abdominal pain 1 (0.3%) / 0 12 (3.8%) / 2 (0.6%) Hyponatremia 21(6.3%)/1(0.3%) 31(9.7%)/5(1.6%) 0.04 Hypoxia 1(0.3%)/0 6(1.9%)/0/1 gr 5 (0.3%) Worst grade - any 130 (38%) / 95 (28%) 160 (50%) / 107 (34%) Grade 5 8 (2.4%) 10 (3.1%) NS Enrollment goal: 1500 pts w/ resected stage 1B-IIIA NSCLC; pts are randomized to chemo (cis+vin, doce, gem, or pem) alone or chemo+ bevacizumab Wakelee PASCO Abstr #7013

Adjuvant Chemotherapy Choices
Strongest evidence for adjuvant chemotherapy in NSCLC is w/ cis/vinorelbine TREAT-improved drug delivery/toxicity w/ cis/pem Substitutions of other regimens common Data on other regimens coming; E1505 The future will include more directed therapy based on results of prospective biomarker driven adjuvant trials For now we all have to decide how much “proof” we need to use alternative regimens

Prospective Chemotherapy Biomarker Adjuvant Trials
Stage Therapy Marker SWOG 0720 I (>2cm) +/- Chemotherapy (Cis/Gem) ERCC1 /RRM1 ITACA I-IIIA Cisplatin/Pemetrexed ERCC1/TS TASTE Cisplatin / Erlotinib ERCC1/ EGFR mut SCAT Platinum / Docetaxel BRCA1/ RAP80

S0720: Pharmacogenomic-directed Adjuvant Therapy of NSCLC
Assignment, stage I >2cm RRMI > 40.5 AND ERCC1> 66.0 Active Monitoring All Others (RRM1< 40.5 OR ERCC1 < 66.0 ) Cisplatin-Gemcitabine Primary Endpoint: Feasibility measured as % of patients in whom treatment assignment can be made (>75%=success)

Phase II Pharmacogenomics-Based Adjuvant Therapy Trial in Pts with Stage I NSCLC:S0720
Zinner WCLC 2011 Started Accrual April pts enrolled. 83 eligible Met Primary Endpoint of Feasibility Expression analysis for all 83 eligible pts 72/83 (87%) treatment assignment met requirements Pre-specified target was at least 85% 64/83 (77%) evaluated pts assigned to chemo (95% CI: 67%-86%) Expected: 70% 14/64 pts (22%) declined treatment assignment

RRM1 and ERCC1 (AQUA) 64/83 (77%) eligible for chemo r = 0. 40 (p = 0

S0720 Conclusions Met Primary Endpoint of Feasibility
72/83 (87%) treatment assignments met requirements 64/83 (77%) evaluated pts assigned to chemo 14/64 pts (22%) declined treatment assignment Biomarker RRM1 and ERCC1 levels correlated with each other Neither correlated with gender, age, histology Zinner WCLC 2011

Randomized Phase 3 Trial of Amrubicin versus Topotecan as Second-line Treatment for Small Cell Lung Cancer (SCLC) R. Jotte1, J. von Pawel,2 D.R. Spigel,3 M. Socinski,4 M.E.R. O’Brien,5 E. Paschold,6 J. Mezger,7 M. Steins,8 L. Bosquée9, J. Bubis,10 K. Nackaerts,11 J.M. Trigo,12 P. Clingan,13 W. Schuette,14 P. Lorigan,15 M. Reck,16 M. Domine,17 F. Shepherd,18 R McNally,19 MF Renschler19 Jotte PASCO 2011, abstr 7000

Phase III 2nd-line SCLC: ACT-1
Jotte PASCO 2011, abstr 7000 R A N D O M I Z E 2 to1 Small Cell Lung Cancer (SCLC) Extensive or Limited Disease Sensitive or refractory disease (Progression ≥ 90 or <90 days after completion of 1st line chemotherapy, Response to 1st line chemo) 1 prior chemotherapy regimen ECOG performance status 0-1 Stratified: Sensitive/Refractory; Extensive/Limited AMR IV 40 mg/m2 1x daily on d 1-3 q 3 w Topotecan IV 1.5 mg/m2 1x daily on d 1-5 q 3 w Primary endpoint: Overall Survival Secondary endpoints: ORR, PFS, TTP, quality of life, safety, sparse PK Analyses: Interim (deaths = 294), Final (deaths = 490)

OS – ITT Population Jotte PASCO 2011, abstr 7000 AMR Topo HR P Value*
. AMR Topo HR P Value* N/Events 424/336 213/175 Median OS (months) 7.5 7.8 0.880 0.1701 95% CI 6.8 – 8.5 6.6– 8.5 0.733 – 1.057 . 9 . 8 . 7 . 6 Survival Probability . 5 . 4 * Unstratified log-rank test . 3 Amrubicin Efficacy table Graph . 2 . 1 Topotecan . 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 3 3 Time (months) # at risk Amrubicin 343 250 109 94 50 32 17 7 3 1 Topotecan 164 122 77 43 22 8 4 1 1

Median OS in Sensitive and Refractory Patient Subgroups
Jotte PASCO 2011, abstr 7000 Survival Probability Time (months) Amrubicin Topotecan 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 3 6 9 12 15 18 21 24 27 30 33 AMR Topo HR P Value* N/events 225/168 117/89 OS (mo) 9.2 9.9 0.936 0.6164 95% CI 0.724 – 1.211 Sensitive Patients AMR Topo HR P Value* N/events 199/168 96/86 OS (mo) 6.2 5.7 0.766 0.0469 95% CI 0.589 – 0.997 Survival Probability Time (months) Amrubicin Topotecan 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 3 6 9 12 15 18 21 24 27 Refractory Patients Graph efficacy table * Unstratified log-rank test

PFS – ITT Population Jotte PASCO 2011, abstr 7000 Median PFS (months)
. Amrubicin N=424 Topotecan N=213 HR P Value* N/ Events 424/367 213/167 Median PFS (months) 4.1 3.5 0.802 0.0182 95% CI 3.5– 4.3 2.9 – 4.2 0.667 – 0.965 . 9 . 8 . 7 . 6 Survival Probability . 5 . 4 * Unstratified log-rank test . 3 Graph efficacy table . 2 Amrubicin Topotecan . 1 . 3 6 9 1 2 1 5 1 8 2 1 Time (months) # at risk Amrubicin 236 105 36 13 6 3 Topotecan 102 32 6 1

Conclusions Jotte PASCO 2011 abstr 7000 Primary endpoint of OS in ITT 7.5 mo Amrubicin vs. 7.8 mo topotecan, HR 0.880, p=0.1701 All secondary endpoints favored Amrubicin ORR (31.1 vs. 16.9%, p=0.0001) PFS (median 4.1 mo vs. 3.5, HR 0.802, p=0.0182) Enhanced symptom control and quality of life OS in refractory patients improved (6.2 mo Amrubicin vs. 5.7 mo topotecan, HR 0.766, p=0.0469) Safety profile of Amrubicin is acceptable Increased infections; Fewer transfusions No evidence of significant cumulative cardiotoxicity

Negative trials in orphan diseases
RPhII Carboplatin/etoposide +/- obatoclax ES-SCLC; 165 pts RR 65% vs 54%; PFS 6.0 vs 5.4 mo; OS 10.6 vs 9.9 mo all NS RPhIII maintenance thalidomide post chemo Mesothelioma; 222 pts PFS HR 1.0; OS HR 0.78 favor placebo Langer PASCO 2011; abstr 7001 Baas PASCO 2011; abstr 7006

Abstracts discussed Metastatic NSCLC
Maintenance CRA pemetrexed, LBA7511 – gefitinib Continuation maintenance with pemetrexed promising; await survival results Switch maintenance gefitinib feasible

Abstracts discussed Metastatic NSCLC- Targeted Therapy
LBA7512- motesanib, 7502-vadimezan, CRA7506-driver mutations, EURTAC, 7505-MetMab, 750-crizotinib, 7500-ganetespib Chemo + motesanib, vadimezan, aflibercept all negative trials Driver mutations found in >50% adenoCA EGFR mut tumors do well with EGFR TKI 1st line EGFR resistance better understood Promise w/MetMab and afatinib/cetuximab ALK resistance better understood - ?HSP 90

Abstracts discussed Early Stage NSCLC
7002-TREAT, 7013-E1505 Adjuvant chemotherapy substitutions with some data in support E1505 enrollment ongoing Small Cell Lung Cancer 7000-amrubicin Small steps in small cell and mesothelioma Hope for amrubicin in refractory SCLC pts

ASCO Updates 2011 Lung Cancer

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