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 • CRA7510 - pemetrexed, LBA7511 – gefitinib – Targeted Therapy • LBA7512- motesanib, 7502-vadimezan, CRA7506driver mutations, 7503- EURTAC, 7505- MetMab, 7507-crizotinib, 7500-ganetespib • Early Stage NSCLC • 7002-TREAT, 7013-E1505 • Small Cell Lung Cancer • 7000-amrubicin Abstracts to be discussed • Metastatic NSCLC – Maintenance • CRA7510 - pemetrexed, LBA7511 - gefitinib – Targeted Therapy • LBA7512- motesanib, 7502-vadimezan, CRA7506driver mutations, 7503- EURTAC, 7505- 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) – PFS benefit – Trend OS benefit Continuation Maintenance •Study/Yr Induction Maintenance MTTP/MP FS Med OS toxicity Carbo/Ta x Paclitaxel wk Obs 38 wk 29 wk 75 wk 60 wk 45% Gr 3/4 Brodowicz Cis/Gem 2006 Gem d1,8 Obs 6.6 mo 5.0 mo P<.001 13 mo 11 mo Heme tox in 20%+ Belani 2010 Carbo/Ge m Gem d1,8 Obs 7.4 mo 7.7 mo 8 mo 9.3 mo NS <20% Heme Perol 2010 Cis/Gem Gem d1,8 Obs 3.8 mo 1.9 mo P<.001 NR 28% Gr 3/4 Belani 2003 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 http://seer.cancer.gov/statfacts/html/lungb.html; 2Azzoli CG et al. J Clin Oncol 2009; 27:6251–6266 3Scagliotti GV et al. J Clin Oncol 2008;26:3543-51.; 4Ciuleanu T et al. Lancet 2009;374:1432-40. PARAMOUNT: Study Design Paz-Ares PASCO 2011, LBA7510 Study Treatment Period Progression Induction Therapy (4 cycles) Patients enrolled if: • Nonsquamous NSCLC • No prior systemic treatment for lung cancer • ECOG PS 0/1 500 mg/m2 Pemetrexed + 75 mg/m2 Cisplatin, d1, q21d 21 to 42 Days Maintenance Therapy (Until PD) 500 mg/m2 Pemetrexed + BSC, d1, q21d CR, PR, SD 2:1 Randomization Placebo + BSC, d1, q21d Stratified for: •PS (0 vs 1) •Disease stage (IIIB vs IV) prior to induction •Response to induction (CR/PR vs SD) PD Randomized, placebo-controlled, double-blind, phase III study Folic acid and vitamin B12 administered to both arms PARAMOUNT: Investigator Assessed PFS (from Maintenance) 1.0 Pem + BSC 0.9 Placebo + BSC 0.8 SurvivalProbability 0.7 Pemetrexed: median =4.1 mos (3.2-4.6) Placebo: median =2.8 mos (2.6-3.1) Log-rank P=0.00006 Unadjusted HR: 0.62 (0.49-0.79) 0.6 0.5 Patients 0.4 at Risk Pem + BSC 0.3 N=359 132 57 21 4 0 Placebo + BSC 0.2 N=180 52 15 5 0 0 0.1 0.0 0 JMEN: PFS 4.4 mo vs 1.8 mo, HR 0.47, p<.00001 3 Paz-Ares PASCO 2011, LBA7510 6 9 Tim e(M onths) 12 15 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 Patients • Age ≥18 years • Completed 4 cycles of first-line platinumbased chemotherapy without PD or unacceptable toxicity • Life expectancy ≥12 weeks • WHO PS 0-2 • Measurable Stage IIIB/IV disease Primary 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 • 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 INFORM: PFS (ITT population) Zhang PASCO LBA7511 100 90 Probability of PFS (%) 80 Median PFS,† months 6-month PFS rate, % 12-month PFS rate, % No. events, n (%) 70 60 Gefitinib (n=148) Placebo (n=148) 4.8 47.3 33.2 124 (83.8) 2.6 15.0 2.9 144 (97.3) HR‡ (95% CI) = 0.42 (0.33, 0.55); p<0.0001 50 40 30 20 10 0 0 8 16 24 32 40 48 56 64 72 80 88 96 2 15 0 6 104 112 Time since randomization (weeks) Patients at risk : Placebo 148 82 46 26 Gefitinib 148 109 82 70 †Estimated using the Kaplan-Meier method ‡Primary Cox analysis with covariates 16 65 10 56 6 49 4 42 3 38 2 31 2 20 0 1 0 0 INFORM PFS by EGFR mut status Zhang PASCO LBA7511 EGFR mutation-positive EGFR mutation-negative 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%) 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%) HR (95% CI) = 0.17 (0.07, 0.42) 100 100 80 PFS (%) PFS (%) 80 HR (95% CI) = 0.86 (0.48, 1.51) 60 40 20 60 40 20 0 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (weeks) No. of patients at risk 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (weeks) No. of patients at risk Placebo 15 9 1 1 1 1 1 0 0 0 Placebo 24 9 5 3 2 0 0 0 0 0 0 0 0 0 0 Gefitinib 15 15 14 14 13 11 10 18 7 7 5 3 1 0 0 Gefitinib 25 14 6 3 3 1 0 0 0 0 0 0 0 0 0 †Estimated 5 3 3 2 1 using the Kaplan-Meier method INFORM OS: (ITT population) Gefitinib Placebo (n=148) (n=148) 100 16.9 Median OS, months 18.7 84.9 6-month survival rate, % 82.2 66.0 12-month OS rate, % 68.8 No. events, n (%) 79 (53.4) 93 (62.8) 90 Overall survival (%) 80 70 HR (95% CI) = 0.84 (0.62, 1.14); p=0.2608 60 50 40 30 20 10 0 0 8 16 24 32 40 48 56 Patients at risk: 72 80 88 96 104 112 120 128 Time (weeks) Placebo 148 147 136 127 115 107 97 91 Gefitinib 148 141 129 119 114 108 102 90 HR <1 implies a lower risk of death on gefitinib 64 78 84 66 47 75 56 37 13 39 18 6 4 0 0 0 0 0 0 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 Abstracts to be discussed • Metastatic NSCLC – Maintenance • CRA7510 - pemetrexed, LBA7511 - gefitinib – Targeted Therapy • LBA7512- motesanib, 7502-vadimezan,CRA7506driver mutations, 7503- EURTAC, 7505- 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 Patients With PFS (%) 80 60 40 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% 20 0 0 6 12 18 24 30 36 Mos Sandler A, et al. N Engl J Med. 2006;355:2542-2550. . 100 CbP CbP + bevacizumab CbP CbP + bevacizumab 80 Patients Surviving (%) 100 OS P = .003; HR: 0.79 Median OS: 12.3 mos vs 10.3 mos 1-yr OS: 51% vs 44% 2-yr OS: 23% vs 15% 60 40 20 0 0 6 Mos 12 18 24 30 36 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 - + + + + - Axitinib + + + + + - Cabozantinib + + + Motesanib + + + + BIBW1120 + + + + - + Raf Met + FGFR 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) 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% Scagliotti LBA#7512 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 Study Design ASA404 (vadimezan): a small molecule vascular disrupting agent; Causes breakdown of vasculature and hemorrhagic tumor necrosis Randomization 1:1 • Stage IIIB/IV NSCLC • All histologies • First-line chemotherapynaïve N=1200 • PS 0 or 1 • Stratification: • Sex • Squamous vs non-squamous • • • Lara abstr 7502 Paclitaxel + carboplatin + ASA404 Paclitaxel + carboplatin + placebo Paclitaxel 200 mg/m2, carboplatin AUC 6, and ASA404 1800 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) ATTRACT1: Overall Survival Arm Median survival (95% CI) Lara abstr 7502 ASA404 + PC Placebo + PC 13.4 months (11.4, 16.6) 12.7 months (11.3, 14.4) 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… Abstracts to be discussed • Metastatic NSCLC – Maintenance • CRA7510 - pemetrexed, LBA7511 - gefitinib – Targeted Therapy • LBA7512- motesanib, 7502-vadimezan, CRA7506driver mutations, 7503- EURTAC, 7505- 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 Lung Cancer Mutation Consortium Kris ASCO 2011, CRA7506 Number analyzed for mutation and FISH Mutation profiling 82 294 Total study group as of 13 May 11 1064 FISH 516 172 Pending analysis 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 Gefitinib (n=132) Carboplatin/paclitaxel (n=129) 0.8 HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 0.6 No. events gefitinib, 97 (73.5%) No. events C/P, 111 (86.0%) 0.4 0.2 0.0 0 4 8 12 16 20 24 Gefitinib (n=91) Carboplatin/paclitaxel (n=85) 1.0 Probability of progression-free survival 1.0 Probability of progression-free survival EGFR mutation-negative 0.8 HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 0.6 No. events gefitinib, 88 (96.7%) No. events C/P, 70 (82.4%) 0.4 0.2 0.0 0 4 8 Months At risk: Gefitinib 132 C/P 129 108 103 71 37 31 7 12 16 20 24 1 0 0 0 0 0 Months 11 2 3 1 0 0 91 85 21 58 4 14 2 1 Treatment by subgroup interaction test, p<0.0001 Incidence of EGFR mutation: 261/437 = 59.7% Mok et al 2008 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 Response rate PFS, mo Median survival, mo Most common toxicities CT Erlotinib P value 10.5% 54.5% <0.0001 5.2 (95% CI, 4.4-5.8) 9.4 (95% CI, 7.9-12.3) HR: 0.42, P<0.0001 18.8 22.9 HR: 0.80, P=0.42 Asthenia: 68.9% Anemia: 45.9% Nausea: 40.5% Neutropenia: 36.5% Rosell PASCO 2011, abstr 7503 Diarrhea: 57.3% Asthenia: 53.3% Rash: 49.3% EURTAC: PFS in ITT population Tony Mok, ASCO discussant 2011 1.0 Erlotinib (n=86) Chemotherapy (n=87) 0.8 HR=0.37 (0.25–0.54) PFS probability 0.6 Log-rank p<0.0001 0.4 0.2 5.2 0 9.7 0 Study 3 6Response 9 12 Rate Time (months) EURTAC Patients at risk Erlotinib 86 63 OPTIMAL Chemo 87 49 58% vs 14.9% 54 83% 20 32 21 vs8 36% 5 15 PFS 18 21 24 27 30 33 2 0 0 0 9.7 vs 5.2 months (HR 0.37) 17 413.1 9 7 4 2 vs3 4.6 months 1 0(HR 0.16) 0 DataNEJ cut-off:002 26 Jan 2011 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) Final overall survival results of NEJ002, a phase III trial comparing gefitinib to carboplatin (CBDCA) plus paclitaxel (TXL) as the firstline 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. 26.6 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 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*, PF00299804*, 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 MetMAb Arm A 1:1 Key eligibility: • Stage IIIB/IV NSCLC • 2nd/3rd-line NSCLC • Tissue required • PS 0–2 n=137* R A N D O M I Z A T I O N Stratification factors: • Tobacco history • Performance status • Histology (15 mg/kg IV Q3W) + n=69 erlotinib (150 mg daily) Placebo (IV Q3W) + Arm B Co-primary objectives: • PFS in ‘Met Diagnostic positive’ patients (est. 50%) • PFS in overall ITT population n=68 erlotinib (150 mg daily) 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 + MetMAb + erlotinib erlotinib Probability of progression free 0.8 2.6 2.2 1.0 1.09 (0.73–1.62) 0.69 56 48 0.8 Probability of survival Median (mo) HR (95% CI) Log-rank p-value No. of events 1.0 Placebo + MetMAb + erlotinib erlotinib 0.6 0.4 0.2 0.0 7.4 8.9 Median (mo) 0.80 HR (0.50–1.28) (95% CI) 0.34 Log-rank p-value 41 34 No. of events 0.6 0.4 0.2 0.0 0 3 6 9 12 15 Time to progression (months) 18 0 3 6 9 12 15 18 21 Overall survival (months) 8 MetMAb plus erlotinib in Met Dx+ pts Spigel PASCO 2011, 7505 PFS: HR=0.53 OS: HR=0.37 Placebo + MetMAb + erlotinib erlotinib Probability of progression free 0.8 1.5 2.9 1.0 0.53 (0.28–0.99) 0.04 27 20 0.8 Probability of survival Median (mo) HR (95% CI) Log-rank p-value No. of events 1.0 Placebo + MetMAb + erlotinib erlotinib 0.6 0.4 0.2 0.0 3.8 12.6 Median (mo) 0.37 HR (0.19–0.72) (95% CI) 0.002 Log-rank p-value No. of events 26 16 0.6 0.4 0.2 0.0 0 3 6 9 12 15 Time to progression (months) 18 0 3 6 9 12 15 18 21 Overall survival (months) 9 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 Progressive disease Stable disease Maximum change in tumor size (%) 40 Confirmed partial response Confirmed complete response 20 0 –20 –30% –40 –60 –80 –100 * 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: ALK+ Crizotinibtreated ALK+ not treated with crizotinib ALK-/EGFR- 1-y OS 77% 73% 49% 2-y OS 64% 33% 33% Not reached 20 mo Not reached Median OS 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 Shaw PASCO 2011 abstr 7507 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 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 Response(% change from baseline) 30 20 10 0 -10 IPI-504 -20 STA-9090 -30 -40 *simulated waterfall plot based on reported results -50 -60 Patients N=11 *Durability of responses not reported Ramalingam discussion ASCO 2011 Hsp90 Inhibtion in ALK + NSCLC • There is now clear evidence of robust anticancer 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 Govindan Discussion ASCO 2011 ALK 3 yrs Gerber and Minna Cancer Cell: 18: 548, 2010 Abstracts to be discussed • Metastatic NSCLC – Maintenance • CRA7510 - pemetrexed, LBA7511 – gefitinib – Targeted Therapy • LBA7512- motesanib, 7502-vadimezan, CRA7506driver mutations, 7503- EURTAC, 7505- MetMab, 7507-crizotinib, 7500-ganetespib • Early Stage NSCLC • 7002-TREAT, 7013-E1505 • Small Cell Lung Cancer • 7000-amrubicin Lace Meta-analysis trials n Chemo Survival Trial Stage ALPI BLT IALT NCIC I-III I-III I-III IB-II 1209 381 1867 482 Cis/MVd Cis/4 options Cis/Vinca or VP16 Cis/Vin No No Yes Yes ANITA I-IIIA 840 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 75-80 d 1 + vin 25-30 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 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 Kreuter PASCO 2011 abstr 7002 Design 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) 400 mg/m2 over 16 wks Cisplatin / Vinorelbine (CVrb) 50 mg/m2 d1+8 / 25 mg/m2 d1, 8, 15, 22 q d 29 x 4 Winton et al., N Engl J Med (2005) 352: 258 R0 Cisplatin / Pemetrexed (CPx) 300 mg/m2 over 12 wks 75 mg/m2 d1 / 500 mg/m2 d1 q d 22 x 4 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 ELIGIBLE: N=1500 Resected IB-IIIA (1B 4cm) R A N D O M I Z E Overall Survival Primary Endpoint Chemotherapy X 4 cycles 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) 636 320 316 Vinorelbine 170(27%) 82(26%) 88(28%) Docetaxel 207(33%) 105(33%) 102(32%) Gemcitabine 158(25%) 82(26%) 76(24%) Pemetrexed* 99(16%) 50(16%) 49(16%) Cisplatin + *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%) 0.03 Abdominal pain 1 (0.3%) / 0 12 (3.8%) / 2 (0.6%) <0.001 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%) 0.03 Worst grade - any 130 (38%) / 95 (28%) 160 (50%) / 107 (34%) <0.001 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 2011. 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 SWOG 0720 ITACA Therapy Marker I (>2cm) +/- Chemotherapy ERCC1 (Cis/Gem) /RRM1 I-IIIA Cisplatin/Pemetrexed ERCC1/TS TASTE I-IIIA SCAT I-IIIA Cisplatin / Erlotinib ERCC1/ EGFR mut Platinum / Docetaxel BRCA1/ RAP80 S0720: Pharmacogenomic-directed Adjuvant Therapy of NSCLC Assignment, stage I >2cm RRMI > 40.5 AND ERCC1> 66.0 All Others (RRM1< 40.5 OR ERCC1 < 66.0 ) Active Monitoring 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 2009. 85 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 = 0.0002) ERCC1 <65 RRM1 <40 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 Abstracts to be discussed • Metastatic NSCLC – Maintenance • CRA7510 - pemetrexed, LBA7511 – gefitinib – Targeted Therapy • LBA7512- motesanib, 7502-vadimezan, CRA7506driver mutations, 7503- EURTAC, 7505- MetMab, 7507-crizotinib, 7500-ganetespib • Early Stage NSCLC • 7002-TREAT, 7013-E1505 • Small Cell Lung Cancer • 7000-amrubicin 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 • 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 R A N D O M I Z E 2 to 1 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 1.0 Survival Probability 0.9 0.8 N/Events 0.7 Median OS 0.6 (months) 0.5 95% CI HR P Value* 7.8 0.880 0.1701 6.6– 8.5 0.733 – 1.057 AMR Topo 424/336 213/175 7.5 6.8 – 8.5 0.4 * Unstratified log-rank test 0.3 Amrubicin 0.2 0.1 Topotecan 0.0 0 3 6 9 12 15 18 21 24 27 30 33 17 4 7 1 3 1 1 0 0 0 Time (months) # at risk Amrubicin Topotecan 343 164 250 122 109 77 94 43 50 22 32 8 Median OS in Sensitive and Refractory Patient Jotte PASCO 2011, abstr 7000 Subgroups 1.0 Sensitive Patients Survival Probability 0.9 HR P Value* 9.9 0.936 0.61 64 8.5-10.6 8.5-11.5 0.724 – 1.211 AMR Topo HR P Value* 199/168 96/86 6.2 5.7 0.766 0.04 69 5.5-6.7 4.1-7.0 0.589 – 0.997 AMR Topo 225/168 117/89 9.2 0.8 0.7 N/events 0.6 OS (mo) 0.5 0.4 0.3 Amrubicin 0.2 95% CI Topotecan 0.1 0.0 0 3 6 12 9 15 18 21 24 27 30 33 Time (months) Survival Probability 1.0 Refractory Patients 0.9 0.8 0.7 N/events OS (mo) 0.6 0.5 0.4 0.3 95% CI Amrubicin 0.2 0.1 Topotecan 0.0 0 3 6 9 12 15 Time (months) 18 21 24 27 * Unstratified log-rank test PFS – ITT Population 1.0 Survival Probability 0.9 Jotte PASCO 2011, abstr 7000 Amrubicin Topotecan N=424 N=213 0.8 N/ Events 424/367 213/167 0.7 Median PFS (months) 4.1 3.5 3.5– 4.3 2.9 – 4.2 0.6 0.5 95% CI 0.4 HR P Value* 0.802 0.0182 0.667 – * Unstratified 0.965 log-rank test 0.3 0.2 Amrubicin Topotecan 0.1 0.0 0 3 6 9 12 15 18 21 6 0 3 0 0 0 Time (months) # at risk Amrubicin Topotecan 236 102 105 32 36 6 13 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 • CRA7510 - 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, CRA7506driver mutations, 7503- EURTAC, 7505-MetMab, 750crizotinib, 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