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

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Presentation on theme: "ASCO Updates 2011 Lung Cancer Heather Wakelee, M.D. Assistant Professor of Medicine,Oncology Stanford University and Stanford Cancer Institute."— Presentation transcript:

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

2 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

3 Abstracts to be discussed 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

4 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

5 Continuation Maintenance Study/YrInductionMaintenanceMTTP/MP FS Med OStoxicity Belani 2003 Carbo/Ta x Paclitaxel wk Obs 38 wk 29 wk 75 wk 60 wk 45% Gr 3/4 Brodowicz 2006 Cis/GemGem d1,8 Obs 6.6 mo 5.0 mo P< 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/GemGem d1,8 Obs 3.8 mo 1.9 mo P<.001 NR28% Gr 3/4 Fidias/Novello JCO Dec 2010 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 1 st line drugs which were stopped

6 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 2 nd or 3 rd line therapy while it is working, so why do we stop 1 st line?

7 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-Ares 1, F. de Marinis 2, M. Dediu 3, M. Thomas 4, J.L. Pujol 5, P. Bidoli 6, O. Molinier 7, T.P. Sahoo 8, E. Laack 9, M. Reck 10, J. Corral 1, S. Melemed 11, W. John 11, N. Chouaki 12, A. H. Zimmermann 11, C. Visseren-Grul 13, C. Gridelli 14 1

8 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) 1 2 Azzoli CG et al. J Clin Oncol 2009; 27:6251– Scagliotti GV et al. J Clin Oncol 2008;26: ; 4 Ciuleanu T et al. Lancet 2009;374: Paz-Ares PASCO 2011, LBA7510

9 PARAMOUNT: Study Design  Randomized, placebo-controlled, double-blind, phase III study  Folic acid and vitamin B 12 administered to both arms Study Treatment Period Progression Induction Therapy (4 cycles)Maintenance Therapy (Until PD) 21 to 42 Days 500 mg/m 2 Pemetrexed + 75 mg/m 2 Cisplatin, d1, q21d CR, PR, SD PD Placebo + BSC, d1, q21d 500 mg/m 2 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) Paz-Ares PASCO 2011, LBA7510

10 PARAMOUNT: Investigator Assessed PFS (from Maintenance) Pemetrexed: median =4.1 mos ( ) Placebo: median =2.8 mos ( ) Log-rank P= Unadjusted HR: 0.62 ( ) Patients at Risk Pem + BSCN= Placebo + BSC N= Pem + BSC Placebo + BSC JMEN: PFS 4.4 mo vs 1.8 mo, HR 0.47, p< Paz-Ares PASCO 2011, LBA7510

11 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

12 INFORM: Study design Gefitinib (250 mg/day) Placebo (once daily) 1:1 randomization EGFR, epidermal growth factor receptor; PD, progressive disease PS, performance status; WHO, World Health Organization 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 Endpoints Primary 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 Zhang PASCO LBA7511

13 INFORM: PFS (ITT population) † Estimated using the Kaplan-Meier method ‡ Primary Cox analysis with covariates HR ‡ (95% CI) = 0.42 (0.33, 0.55); p< Gefitinib (n=148) Placebo (n=148) Median PFS, † months 6-month PFS rate, % 12-month PFS rate, % No. events, n (%) (83.8) (97.3) Gefitinib Placebo Probability of PFS (%) Patients at risk : Time since randomization (weeks) Zhang PASCO LBA7511

14 INFORM PFS by EGFR mut status † Estimated using the Kaplan-Meier method 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 PFS (%) Time (weeks) Placebo Gefitinib No. of patients at risk PFS (%) Time (weeks) Placebo Gefitinib No. of patients at risk Zhang PASCO LBA7511

15 INFORM OS: (ITT population) Overall survival (%) Time (weeks) Placebo Patients at risk: Gefitinib HR (95% CI) = 0.84 (0.62, 1.14); p= Gefitinib (n=148) Placebo (n=148) Median OS, months 6-month survival rate, % 12-month OS rate, % No. events, n (%) (53.4) (62.8) HR <1 implies a lower risk of death on gefitinib

16 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 2 nd line Rx MAY live just as long IF they receive the effective agent BUT we miss at least 1/3 of them 2 nd line therapy works, we should not deny our patients 2 nd line therapy

17 Abstracts to be discussed 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

18 E4599: Bevacizumab Efficacy RR: 15% for Carboplatin (CbP) vs 35% for CbP + Bevacizumab 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% Patients Surviving (%) OS Patients With PFS (%) Mos 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% PFS CbP CbP + bevacizumab. CbP CbP + bevacizumab Sandler A, et al. N Engl J Med. 2006;355: Mos

19 Promising Small Molecule Inhibitors of VEGFR and Their Targets InhibitorVEGFR-1VEGFR-2VEGFR-3PDGFRcKITEGFROther Sunitinib++-++-FGFR Valatanib+++++-cFms Vandetanib-+++/--+ret Cediranib Pazopanib+++- Sorafenib-++++-Raf Axitinib Cabozantinib ++++ Met Motesanib BIBW FGFR

20 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)

21 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

22 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

23 Study Design Randomization 1:1 Paclitaxel + carboplatin + placebo Paclitaxel + carboplatin + ASA404 N=1200 Stage IIIB/IV NSCLC All histologies First-line chemotherapy- naïve PS 0 or 1 Stratification: Sex Squamous vs non-squamous Paclitaxel 200 mg/m 2, carboplatin AUC 6, and ASA mg/m 2 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 ASA404 (vadimezan): a small molecule vascular disrupting agent; Causes breakdown of vasculature and hemorrhagic tumor necrosis

24 ATTRACT1: Overall Survival ArmASA404 + PCPlacebo + PC Median survival (95% CI) 13.4 months (11.4, 16.6) 12.7 months (11.3, 14.4) Lara abstr 7502

25 Anti-Angiogensis in NSCLC No biomarkers, small steps forward Bevacizumab increases RR and PFS when added to 1 st 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…

26 Abstracts to be discussed 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

27 Lung Cancer Mutation Consortium Kris ASCO 2011, CRA7506

28 Mutation profiling FISH Pending analysis Lung Cancer Mutation Consortium Number analyzed for mutation and FISH Total study group as of 13 May Kris ASCO 2011, CRA7506

29 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

30 IPASS: Progression-free survival in EGFR mutation + vs - patients EGFR mutation-positiveEGFR mutation-negative Treatment by subgroup interaction test, p< HR (95% CI) = 0.48 (0.36, 0.64) p< No. events gefitinib, 97 (73.5%) No. events C/P, 111 (86.0%) Gefitinib (n=132) Carboplatin/paclitaxel (n=129) HR (95% CI) = 2.85 (2.05, 3.98) p< No. events gefitinib, 88 (96.7%) No. events C/P, 70 (82.4%) Gefitinib C/P Probability of progression-free survival At risk: Probability of progression-free survival Gefitinib (n=91) Carboplatin/paclitaxel (n=85) Months Mok et al 2008 Incidence of EGFR mutation: 261/437 = 59.7%

31 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 CTErlotinibP value Response rate 10.5%54.5%< PFS, mo 5.2 (95% CI, )9.4 (95% CI, ) HR: 0.42, P< Median survival, mo 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% Rosell PASCO 2011, abstr 7503

32 EURTAC: PFS in ITT population PFS probability Erlotinib (n=86) Chemotherapy (n=87) HR=0.37 (0.25–0.54) Log-rank p< Time (months) Patients at risk Erlotinib Chemo Data cut-off: 26 Jan StudyResponse RatePFS EURTAC58% vs 14.9%9.7 vs 5.2 months (HR 0.37) OPTIMAL83% vs 36%13.1 vs 4.6 months (HR 0.16) NEJ 00274% vs 31%10.8 vs 5.4 months (HR 0.30) WJTOG % vs 31%9.2 vs 6.3 months (HR 0.49) Tony Mok, ASCO discussant 2011

33 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= None of the EGFR-TKI vs chemo as 1 st line therapy trials in EGFR mut pts have shown a significant OS benefit Inoue PASCO 2011, abstr 7519 Rosell PASCO 2011 abstr 7503

34 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

35 MetMAb (15 mg/kg IV Q3W) + erlotinib (150 mg daily) Phase II: Erlotinib +/- MetMAb in 2 nd/ 3 rd -line NSCLC RANDOMIZATIONRANDOMIZATION 1:1 n=137* n=69 n=68 Arm A Arm B PD n=27 Key eligibility: Stage IIIB/IV NSCLC 2 nd /3 rd -line NSCLC Tissue required PS 0–2 Stratification factors: Tobacco history Performance status Histology Placebo (IV Q3W) + erlotinib (150 mg daily) Add MetMAb Co-primary objectives: PFS in ‘Met Diagnostic positive’ patients (est. 50%) PFS in overall ITT population 5 Spigel PASCO 2011, 7505

36 MetMAb + erlotinib - ITT population Time to progression (months) Probability of progression free Placebo + erlotinib MetMAb + erlotinib Median (mo) HR (95% CI) Log-rank p-value No. of events Overall survival (months) Probability of survival Placebo + erlotinib MetMAb + erlotinib Median (mo) HR (95% CI) Log-rank p-value No. of events PFS: HR=1.09OS: HR= (0.73–1.62) (0.50–1.28) 0.34 Spigel PASCO 2011, 7505

37 MetMAb plus erlotinib in Met Dx+ pts Time to progression (months) Probability of progression free Placebo + erlotinib MetMAb + erlotinib Median (mo) HR (95% CI) Log-rank p-value No. of events Overall survival (months) Probability of survival Placebo + erlotinib Median (mo) HR (95% CI) Log-rank p-value No. of events PFS: HR=0.53OS: HR= MetMAb + erlotinib (0.28–0.99) (0.19–0.72) Spigel PASCO 2011, 7505

38 Afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. 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 1 st documented activity in T790M population Janjigian PASCO 2011, abstr 7525; Horn WCLC 2011, abstr O19.07

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

40 –20 –40 –60 –80 –100 Progressive disease Stable disease Confirmed partial response Confirmed complete response Maximum change in tumor size (%) –30% 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 *

41 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 crizotinibALK-/EGFR- 1-y OS 77%73%49% 2-y OS 64%33% Median OS Not reached20 moNot reached Shaw PASCO 2011 abstr 7507

42 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 2 nd line+ NSCLC - ganetespib (200 mg/m 2 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

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

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

45 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

46 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

47 Time Lag- Target Recognition to Drug Therapy BCR-ABL 41 yrs EGFR 26 yrs BRAF 8 yrs ALK 3 yrs KIT 3 yrs Gerber and Minna Cancer Cell: 18: 548, Govindan Discussion ASCO 2011

48 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

49 Lace Meta-analysis trials NEJM 00; JNCI 03; EuroJTS 04, NEJM 04; NEJM 05; Lancet Onc 2006 Trial Stage n Chemo  Survival ALPII-III1209Cis/MVd No BLTI-III 381Cis/4 optionsNo IALTI-III1867Cis/Vinca or VP16 Yes NCICIB-II 482Cis/Vin Yes ANITA I-IIIA 840Cis/Vin Yes

50 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

51 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 Kreuter PASCO abstr 7002

52 TREAT Design Cisplatin / Vinorelbine (CVrb) Cisplatin / Pemetrexed (CPx) 50 mg/m 2 d1+8 / 25 mg/m 2 d1, 8, 15, 22 q d 29 x 4 75 mg/m 2 d1 / 500 mg/m 2 d1 q d 22 x 4 R0 Winton et al., N Engl J Med (2005) 352: 258 Inclusion Inclusion NSCLC stages IB, IIA, IIB, T3N1M0 ≤ 42 days postoperatively, R0, systematic LN-dissection ECOG 0, 1 amenable to Cisplatin treatment Stratification Stratification Center Nodal status (N0 versus N1) Surgical procedure (lobectomy versus pneumonectomy) 400 mg/m2 over 16 wks 300 mg/m2 over 12 wks Kreuter PASCO 2011 abstr 7002

53 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 TREAT Kreuter PASCO 2011 abstr 7002

54 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 Schiller NEJM 346:92, 2002; Fossela JCO 21:3016, 2003; Scagliotti JCO 26:3543, 2008 Wakelee Discussion ASCO 2011

55 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

56 ECOG 1505 Adjuvant Chemo +/- Bevacizumab RANDOMIZERANDOMIZE 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 Overall Survival Primary Endpoint

57 Table 4: E Preliminary Chemotherapy Administered TotalArm AArm B (BEV) Cisplatin Vinorelbine170(27%)82(26%)88(28%) Docetaxel207(33%)105(33%)102(32%) Gemcitabine158(25%)82(26%)76(24%) Pemetrexed*99(16%)50(16%)49(16%) *option only since 2009, non-squamous histology only Wakelee abstr 7013, ASCO 2011

58 Interim E1505 Toxicity Differences Arm A n=341 Gr 3 /4 Arm B (Bev) n=329 Gr 3/4 P value Neutropenia57(17%) / 69(21%)68(21%)/ 76(24%)0.05 Lymphopenia3(0.9%)/010(3.1%)/1(0.3%)0.03 Hypertension7(2.1%) / 0(0%)64(20.1%)/ 3(0.9%)<0.001 Proteinuria2 (0.6%) / 08(2.5%) / 1 (0.3%)0.03 Abdominal pain1 (0.3%) / 012 (3.8%) / 2 (0.6%)<0.001 Hyponatremia21(6.3%)/1(0.3%)31(9.7%)/5(1.6%)0.04 Hypoxia1(0.3%)/06(1.9%)/0/1 gr 5 (0.3%)0.03 Worst grade - any130 (38%) / 95 (28%)160 (50%) / 107 (34%)<0.001 Grade 58 (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

59 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

60 Prospective Chemotherapy Biomarker Adjuvant Trials StageTherapyMarker SWOG 0720 I (>2cm)+/- Chemotherapy (Cis/Gem) ERCC1 /RRM1 ITACAI-IIIACisplatin/PemetrexedERCC1/TS TASTEI-IIIACisplatin / ErlotinibERCC1/ EGFR mut SCATI-IIIAPlatinum / DocetaxelBRCA1/ RAP80

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

62 Phase II Pharmacogenomics-Based Adjuvant Therapy Trial in Pts with Stage I NSCLC:S0720 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 Zinner WCLC 2011

63 RRM1 and ERCC1 (AQUA) 64/83 (77%) eligible for chemo r = 0.40 (p = ) ERCC1 <65 RRM1 <40

64 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

65 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

66 Randomized Phase 3 Trial of Amrubicin versus Topotecan as Second-line Treatment for Small Cell Lung Cancer (SCLC) R. Jotte 1, 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. Bosquée 9, 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 Renschler 19 Jotte PASCO 2011, abstr 7000

67 Phase III 2 nd -line SCLC: ACT-1 AMR IV 40 mg/m 2 1x daily on d 1-3 q 3 w Small Cell Lung Cancer (SCLC)Small Cell Lung Cancer (SCLC) Extensive or Limited DiseaseExtensive or Limited Disease Sensitive or refractory disease (Progression ≥ 90 or <90 days after completion of 1 st line chemotherapy, Response to 1 st line chemo)Sensitive or refractory disease (Progression ≥ 90 or <90 days after completion of 1 st line chemotherapy, Response to 1 st line chemo) 1 prior chemotherapy regimen1 prior chemotherapy regimen ECOG performance status 0-1ECOG performance status 0-1 Stratified: Sensitive/Refractory; Extensive/LimitedStratified: Sensitive/Refractory; Extensive/Limited RANDOMIZE 2 to 1 Topotecan IV 1.5 mg/m 2 1x daily on d 1-5 q 3 w 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) Jotte PASCO 2011, abstr 7000

68 OS – ITT Population AMRTopoHR P Value* N/Events424/336213/175 Median OS (months) % CI6.8 – – – * Unstratified log-rank test Survival Probability Time (months) Amrubicin Topotecan # at risk Amrubicin Topotecan Jotte PASCO 2011, abstr 7000

69 Median OS in Sensitive and Refractory Patient Subgroups AMRTopoHR P Value* N/events199/16896/86 OS (mo) % CI – * Unstratified log-rank test Sensitive Patients Refractory Patients AMRTopoHR P Value* N/events225/168117/89 OS (mo) % CI – Jotte PASCO 2011, abstr 7000

70 PFS – ITT Population Amrubicin N=424 Topotecan N=213 HRP Value* N/ Events424/367213/167 Median PFS (months) % CI3.5– – – * Unstratified log-rank test Survival Probability Time (months) Amrubicin Topotecan # at risk Amrubicin Topotecan Jotte PASCO 2011, abstr 7000

71 Conclusions Primary endpoint of OS in ITT 7.5 mo Amrubicin vs. 7.8 mo topotecan, HR 0.880, p= 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 Jotte PASCO 2011 abstr 7000

72 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

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

74 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 1 st line EGFR resistance better understood –Promise w/MetMab and afatinib/cetuximab ALK resistance better understood - ?HSP 90

75 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


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