Cytotoxic Maintenance Therapy in Advanced NSCLC: Update State of the Art or State of Confusion

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1 Cytotoxic Maintenance Therapy in Advanced NSCLC: Update State of the Art or State of Confusion Corey J Langer MD, FACP Director Thoracic Oncology Abramson Cancer Center Professor of Medicine Hematology-Oncology Division University of Pennsylvania Philadelphia, PA Corey.langer@uphs.upenn.edu

2 Disclosures: Past 5 yrs Grant/Research Support: Bristol Myers Squibb, Pfizer, Imclone, Lilly, Schering Plough Research Institute, SanofiAventis, Amgen, Cell Therapeutics Inc., Celgene, Genentech, OSI, Astra Zeneca, Active Biothech, Scientific Advisor: Bristol Myers Squibb, Imclone, Sanofi-Aventis, Pfizer- Pharmacia, GlaxoSmithKline, Abbott, Pharmacyclics, Amgen, AstraZeneca, Novartis, Genentech, OSI, Bayer/Onyx, Abraxis; Biodesix; Clarient; Agennix Speakers Bureau: curtailed as of 12/10 Bristol Myers Squibb, Imclone, Sanofi- Aventis, Lilly, Genentech, OSI

3 Maintenance Therapy Platin based doublet chemotherapy 4-6 cycles Induction Same agent A until POD or toxicity Continuous Maintenance Different agent B until POD or toxicity Switch Maintenance

4 Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus BSC: A Phase III Study in NSCLC Ciuleanu T et al The Lancet, Volume 374, Issue 9699, Pages , 24 October 2009 C.P. Belani 1, T. Brodowicz 2, 3, T. Ciuleanu 3, 4, J.H. Kim 5, M. Krzakowski 3, 6*, E. Laack 7, Y.L. Wu 8, P. Peterson 9, K.Krejcy 10, C. Zielinski 2, 3 1 Penn State Hershey Cancer Institute, Hershey, PA, USA; 2 Medical University, Vienna, Austria; 3 Central European Cooperative Oncology Group (CECOG); 4 Institutul Oncologic I Chiricuta, Cluj, Romania; 5 Yonsei Cancer Center, Seoul, Korea; 6 Maria Sklodowska-Curie Memorial Cancer Center & Institute Of Oncology, Warsaw, Poland; 7 Cancer Center, University Hospital Hamburg-Eppendorf, Germany; 8 Guangdong General Hospital, Guangzhou, China; 9 Eli Lilly and Co. IN, USA; 10 Lilly Regional Operations, Vienna, Austria Ciuleanu T et al The Lancet, Volume 374, Issue 9699, Pages , 24 October 2009

5 Study Design Double-blind, Placebo-controlled, Multicenter, Phase III Trial Stage IIIB/IV NSCLC ECOG PS prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD 2:1 Pemetrexed 500 mg/m 2 (d1,q21d) + BSC (N=441)* Randomization factors: gender PS stage Randomization Primary Endpoint = PFS best tumor response Placebo (d1, q21d) + BSC (N=222)* non-platinum drug brain mets *B 12, folate, and dexamethasone given in both arms

6 Objectives Primary Objective Progression-free survival Secondary Objectives Overall survival Objective response rate (CR+PR) Disease control rate (CR+PR+SD) Safety

7 Eligibility Criteria Age 18 years ECOG performance status of 0 or 1 Histologic or cytologic diagnosis of stage IIIB or IV NSCLC prior to initial therapy No progression during four 21-day cycles of an initial platinum doublet regimen Adequate organ function Treated and stable brain metastases were allowed

8 Baseline Characteristics Pemetrexed N=441 % Placebo N=222 % Median age, years Male/Female 73/27 73/28 Caucasian/Asian/Other 63/32/4 67/30/3 Ever-smoker/Never-smoker 74/26 71/28 Disease stage (IIIB/IV) 18/82 21/79 ECOG PS 0/1 40/60 38/62 Histology Non-squamous Adenocarcinoma Large cell carcinoma 2 5 Other or indeterminate Squamous Ciuleanu T et al The Lancet, Volume 374, Issue 9699, Pages , 24 October 2009

9 Initial Therapy Pemetrexed N=441 % Placebo N=222 % Docetaxel-carboplatin 5 3 Docetaxel-cisplatin 2 2 Paclitaxel-carboplatin Paclitaxel-cisplatin 6 9 Gemcitabine-carboplatin Gemcitabine-cisplatin Best response to initial therapy CR + PR/SD 48/52 52/48

10 Study Treatment Pemetrexed N=441 Placebo N=222 No. patients treated Median no. cycles (range) 5 (1-34) 3.5 (1-30) Dose reductions, % 5 1 Discontinuations due to drug-related toxicities, % 5 1 Patients completing 6 cycles, % Patients completing 10 cycles, % 23 9 Dose intensity % Median follow-up time (months)

11 Progression-free Probability Progression-free Survival HR=0.60 (95% CI: ) P < Pemetrexed 4.0 mos Placebo 2.0 mos Time (months) Ciuleanu T et al The Lancet, Volume 374, Issue 9699, Pages , 24 October 2009

12 Progression-free Probability Progression-free Survival by Histology Non-squamous HR=0.47 (95% CI: ) P < Squamous HR=1.03 (95% CI: ) P = Placebo 1.8 mos Pemetrexed 4.4 mos Time (months) Placebo 2.5 mos Pemetrexed 2.4 mos Time (months) Ciuleanu T et al The Lancet, Volume 374, Issue 9699, Pages , 24 October 2009

13 Survival Probability Overall Survival (Intent-to-treat Population) 1.0 HR=0.79 (95% CI: ) P = Pemetrexed 13.4 mos Placebo 10.6 mos Time (months) Ciuleanu T et al The Lancet, Volume 374, Issue 9699, Pages , 24 October 2009

14 Survival Probability Overall Survival by Histology Non-squamous (n=481) Squamous (n=182) HR=0.70 (95% CI: ) P =0.002 HR=1.07 (95% CI: ) P = Pemetrexed 15.5 mos Placebo 10.3 mos Time (months) Placebo 10.8 mos Pemetrexed 9.9 mos Time (months) Ciuleanu T et al The Lancet, Volume 374, Issue 9699, Pages , 24 October 2009

15 Efficacy by Histologic Groups Histology Groups Median OS, mos P-value Pem Plac (HR) Median PFS, mos P-value Pem Plac (HR) Non-squamous (n=481) (0.70) < (0.47) Adeno (n=329) (0.73) < (0.51) Large cell (n=20) (0.98) (0.40) Other (n=133) (0.61) (0.44) Squamous (n=182) (1.07) (1.03) There was a statistically significant treatment-by-histology interaction with both PFS (P=0 036) and OS (P=0 033)

16 Treatment HRs for Overall Survival in Subgroups of the ITT Population Hazard Ratio Overall ITT Population (n=663) Adenocarcinoma (n=328) Large Cell Carcinoma (n=20) Other Histology* (n=133) Squamous Cell Carcinoma (n=182) Age < 65 (n=443) Age >= 65 (n=220) Female (n=180) Male (n=483) Caucasian (n=428) East Asian (n=154) Other Ethnic Origin (n=81) Ever-smoker (n=482) Never-smoker (n=176) ECOG PS 0 (n=261) ECOG PS 1 (n=400) Induction Cisplatin (n=288) Induction Carboplatin (n=374) Induction Response CR/PR (n=322) Induction Response SD (n=337) Stage IIIB (n=126) Stage IV (n=536) Favors pemetrexed Favors placebo Ciuleanu T et al The Lancet, Volume 374, Issue 9699, Pages , 24 October 2009

17 Conclusions First randomized, double-blind, placebocontrolled study to demonstrate a significant overall survival benefit for maintenance treatment in patients with advanced NSCLC Pemetrexed yielded a statistically significant and clinically meaningful PFS and OS advantage, confined to non-squamous histology Administration of pemetrexed in the maintenance setting is fairly well tolerated and is devoid of any cumulative toxicity

18 Potential Criticisms Significant percentage of pts will not get to enjoy the fruits of maintenance pemetrexed Early 2 nd line vs 2 nd line at progression, ie. mandatory crossover at time of progression not instituted Toxicity of pemetrexed, though mild, is not entirely trivial Early institution of 2 nd line Tx unnecessary in sizable proportion of pts Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. Cost?!

19 Potential Criticisms Significant percentage of pts will not get to enjoy the fruits of maintenance pemetrexed Early 2 nd line vs 2 nd line at progression, ie. mandatory crossover at time of progression not instituted Toxicity of pemetrexed, though mild, is not entirely trivial Early institution of 2 nd line Tx unnecessary in sizable proportion of pts Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. Cost?!

20 Immediate Versus Delayed Docetaxel After Induction Eligibility & Treatment Plan Chemonaϊve Stage IIIb/IV NSCLC N = 562 ORR 29% Immediate Docetaxel N = 153 Immediate Treated N = 142 GCb Phase N = 552 (388 (69%) received 4 cycles) SD, PR, CR N = 307 (56%) Randomized Treated Off Study N = 245 Delayed Docetaxel N = 154 Delayed Treated N = 91* *Only 59% of patients randomized to delayed docetaxel received treatment. Fidias et al, ASCO 2007

21 Limited Applicability If we look at the Fidias trial, only 56% of those started on first-line Tx were randomized to maintenance Reasons: Therapeutic reality Disease progression Intercurrent Co-moribidities Pt opt-out Benefits of Pemetrexed are confined to the nonsquamous population, ~ 2/3 of the remainder So the benefits of pemetrexed maintenance apply to only 44% of the entire advanced stage good PS NSCLC population (38% if we use Fidias as our reference)

22 Potential Criticisms Significant percentage of pts will not get to enjoy the fruits of maintenance pemetrexed Benefits confined to <50% of those who start first-line therapy, maybe < 40% Early 2 nd line vs 2 nd line at progression, ie. mandatory crossover at time of progression not instituted Toxicity of pemetrexed, though mild, is not entirely trivial Early institution of 2 nd line Tx unnecessary in sizable proportion of pts Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. Cost?!

23 Systemic Post-study Therapy Pemetrexed (N=441) % Placebo (N=222) % Patients with post-study therapy Most common post-study therapies Carboplatin 7 10 Cisplatin 5 6 Docetaxel Erlotinib Gefitinib Gemcitabine 9 14 Paclitaxel 4 6 Pemetrexed 1 19 Vinorelbine Total Validated 2 nd Line Tx Higher rate of follow-up treatment on the placebo arm Balanced selection of therapies between arms and low rate of crossover

24 Systemic Post-study Therapy Pemetrexed (N=441) % Placebo (N=222) % Patients with post-study therapy Most common post-study therapies Carboplatin 7 10 Cisplatin 5 6 Docetaxel Erlotinib Gefitinib Gemcitabine 9 14 Paclitaxel 4 6 Pemetrexed 1 19 Vinorelbine Total Validated 2 nd Line Tx Higher rate of follow-up treatment on the placebo arm Balanced selection of therapies between arms and low rate of crossover

25 Phase 3 Study of Immediate vs. Delayed Docetaxel After First Line Gemcitabine/Carboplatin in Advanced NSCLC Fidias et al. J Clin Oncol; 27: Median Survival Number Randomized Pts Pts Who Actually Received docetaxel Delayed Docetaxel 91 (59%) 9.7 mo 12.5 mo Immediate Docetaxel 142 (93%) 12.3 mo NA Fidias trial suggests that ~ 40% will not cross over due to co-morbidities or rapid PD. Analysis of those who went onto Docetaxel as salvage therapy suggests no compromise in longterm survival

26 Potential Criticisms Significant percentage of pts will not get to enjoy the fruits of maintenance pemetrexed Benefits confined to <50% of those who start first-line therapy, maybe < 40% Early 2 nd line vs 2 nd line at progression, ie. mandatory crossover at time of progression not instituted Would have inoculated this study from critique if the OS advantage had been maintained Toxicity of pemetrexed, though mild, is not entirely trivial Early institution of 2 nd line Tx unnecessary in sizable proportion of pts Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. Cost?!

27 Maintenance Pemetrexed: Tx-related Toxicities* Pemetrexed (N = 441) % Placebo (N = 222) % Grade 3/4 All grades Grade 3/4 All grades Neutropenia Anemia Leukopenia Fatigue Anorexia Infection Diarrhea Nausea Vomiting < Sensory neuropathy Mucositis/Stomatitis Early Discontinuation for Toxicity 5 1 *NCI CTC version 3.0 P <0.05 for grade 3/4 rates of neutropenia and fatigue Ciuleanu et al. Lancet 374: (2009)

28 Maintenance Pemetrexed: Tx-related Toxicities* Pemetrexed (N = 441) % Placebo (N = 222) % Grade 3/4 All grades Grade 3/4 All grades Neutropenia Anemia Leukopenia Fatigue Anorexia Infection Diarrhea Nausea Vomiting < Sensory neuropathy Mucositis/Stomatitis Early Discontinuation for Toxicity 5 1 *NCI CTC version 3.0 P <0.05 for grade 3/4 rates of neutropenia and fatigue Ciuleanu et al. Lancet 374: (2009)

29 Perspectives on Toxicity Maintenance Pemetrexed Incidence of grade 3+4 toxicity was low Only 5% dropped out b/o side effects But the cumulative effect of grade 1 and 2 toxicity, especially fatigue and aesthenia, cannot be discounted

30 Perspectives on Toxicity Maintenance Pemetrexed Incidence of grade 3+4 toxicity was low Only 5% dropped out b/o side effects But the cumulative effect of grade 1 and 2 toxicity, especially fatigue and aesthenia, cannot be discounted Particularly in the Palliative Care Setting Many pts will stay on maintenance Tx far longer than their original induction regimens

31 Potential Criticisms Significant percentage of pts will not get to enjoy the fruits of maintenance pemetrexed Benefits confined to <50% of those who start first-line therapy, maybe < 40% Early 2 nd line vs 2 nd line at progression, ie. mandatory crossover at time of progression not instituted Would have inoculated this study from critique if the OS advantage had been maintained Toxicity of pemetrexed, though mild, is not entirely trivial Cumulative effects of fatigue and aesthenia Early institution of 2 nd line Tx unnecessary in sizable proportion of pts Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. Cost?!

32 Progression-free Probability Progression-free Survival HR=0.60 (95% CI: ) P < Pemetrexed 4.0 mos Placebo 2.0 mos Time (months)

33 Benefits of Therapeutic Holiday Recovery from platinum-based toxicities 50% or more will have at least a two month window Time to travel, participate in family events Reconstitute the immune system Many will remain asymptomatic at the time of PD Sufficient time to judiciously implement second line Tx Unethical if 2 nd line Tx is not available

34 Potential Criticisms Significant percentage of pts will not get to enjoy the fruits of maintenance pemetrexed Benefits confined to <50% of those who start first-line therapy, maybe < 40% Early 2 nd line vs 2 nd line at progression, ie. mandatory crossover at time of progression not instituted Would have inoculated this study from critique if the OS advantage had been maintained Toxicity of pemetrexed, though mild, is not entirely trivial Cumulative effects of fatigue and aesthenia Early institution of 2 nd line Tx unnecessary in sizable proportion of pts Therapeutic holiday will do the pt (and the clinician) good Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. Cost?!

35 Relevance in the setting of First-line Therapy with Bevacizumab and Pemetrexed 25 to 40% of US pts with newly diagnosed Non- Sq NSCLC are treated with Bevacizumab upfront An increasing percentage of chemo-naïve pts (~20 to 30%) receive pemetrexed as part of their first-line therapy Neither of these two groups were included in this trial (possibly >50% of potentially eligible pts) Pem maintenance, arguably, is irrelevant to these two groups

36 Are non-cross resistant regimens superior to continuing the original Tx? Delivery of non-cross-resistant regimens? PFS* N HR Interaction p Maintenance w/ same chemo Maintenance w/ different chemo ( ) ( ) *Soon, et al JCO 09: Effects of third generation regimens on PFS

37 Potential Criticisms Significant percentage of pts will not get to enjoy the fruits of maintenance pemetrexed Benefits confined to <50% of those who start first-line therapy, maybe < 40% Early 2 nd line vs 2 nd line at progression, ie. mandatory crossover at time of progression not instituted Would have inoculated this study from critique if the OS advantage had been maintained Toxicity of pemetrexed, though mild, is not entirely trivial Cumulative effects of fatigue and aesthenia Early institution of 2 nd line Tx unnecessary in sizable proportion of pts Therapeutic holiday will do the pt (and the clinician) good Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. This trial may be irrelevant to these two cohorts and the robust PFS and OS advantage might be diluted Cost?!

38 Why this Approach will Never Occur in the UK (or much of the ROW) Cost $5400/cycle/3wks for pemetrexed $27,000/ maintenance pt for a median of 5 cycles With a median improvement of 5.3 mos/pt, then cost per life year gained = $ 61,132 1 Klein R, et al. J Thorac Oncol. 2010;5:

39 Why this Approach will Never Occur in the UK (or much of the ROW) Cost $5400/cycle/3wks for pemetrexed $27,000/ maintenance pt for a median of 5 cycles With a median improvement of 5.3 mos/pt, then cost per life year gained = $ 61,132 Klein cost-analysis: ~ $122,371 per life year gained in the non-squamous population 1 Can we afford to spend this much $$$$ on the palliative therapy of end-stage pts? Of course, the CEO of Lilly can change this endpoint with a keystroke on his laptop 1 Klein R, et al. J Thorac Oncol. 2010;5:

40 Why this Approach will Never Occur in the UK (or much of the ROW) Cost $5400/cycle/3wks for pemetrexed $27,000/ maintenance pt for a median of 5 cycles With a median improvement of 5.3 mos/pt, then cost per life year gained = $ 61,132 Klein cost-analysis: ~ $122,371 per life year gained in the non-squamous population 1 Can we afford to spend this much $$$$ on the palliative therapy of end-stage pts? 1 Klein R, et al. J Thorac Oncol. 2010;5:

41 Potential Criticisms Significant percentage of pts will not get to enjoy the fruits of maintenance pemetrexed Benefits confined to <50% of those who start first-line therapy, maybe < 40% Early 2 nd line vs 2 nd line at progression, ie. mandatory crossover at time of progression not instituted Would have inoculated this study from critique if the OS advantage had been maintained Toxicity of pemetrexed, though mild, is not entirely trivial Cumulative effects of fatigue and aesthenia Early institution of 2 nd line Tx unnecessary in sizable proportion of pts Therapeutic holiday will do the pt (and the clinician) good Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. This trial may be irrelevant to these two cohorts and the robust PFS and OS advantage might be diluted Cost?! Fungible endpoint, but highly relevant in these tight financial times

42 Recent and Ongoing Cytotoxic Maintenance Trials CONTINUATION Belani: Gem vs BSC IFCT-GFPC 0502: Gem vs Erl vs Obs [BSC] PARAMOUNT: Cont Pem vs IV Placebo HYBRID POINT-BREAK: E4599 vs Patel/Hensing E5508: Cont Bev vs Switch Pem vs Both

43 Gemcitabine Maintenance + BSC vs BSC Alone Patients without disease progression randomized 1:1 Chemotherapynaive patients with stage IIIB/IV NSCLC (N = 519) Gemcitabine/Carboplatin for 4 cycles Gemcitabine + BSC (n = 128) BSC (n = 127) Patients stratified by PS, stage, best tumor response Primary endpoint: OS Other endpoints: PFS, ORR, safety Belani CP, et al. ASCO Abstract 7506.

44 Gemcitabine + BSC vs BSC: Treatment Outcomes Outcome Gemcitabine + BSC (n = 128) BSC (n = 127) HR (95% CI) P Value Median OS, mo ( ).838 Median PFS, mo ( ).575 ORR, % NR Benefits of gemcitabine maintenance may have been nullified by patient population studied Median patient age: 66.6 years ECOG PS 2: 64% Belani CP, et al. ASCO Abstract 7506.

45 IFCT-GFPC 0502 study design PD: off A Maintenance treatment Observation PD Progression: 2 nd line Pemetrexed Cisplatin gemcitabine x 4 cycles N=834 Objective response or stable disease R* N=464 B N=155 Gemcitabine N=154 PD Pemetrexed NSCLC Stage IIIB wet IV PS 0-1, years Asymptomatic brain mets allowed Tumor tissue EGFR IHC EGFR mutation C N=155 Erlotinib Primary endpoint: PFS PD Pemetrexed Induction chemo: cisplatin 80mg/m 2 d1 + gemcitabine 1,250mg/m 2 d1, d8 Arm B: gemcitabine 1,250mg/m 2 d1, d8 /3 wks Arm C: erlotinib 150mg daily Perol et al ASCO 2010 *Stratification factors: gender histology: adenocarcinoma vs other histology smoking status: non-smokers vs current/former smokers center response vs stabilization to induction chemotherapy EGFR = epidermal growth factor receptor IHC = immunohistochemistry; PD = progressive disease

46 PFS by independent review Gemcitabine versus observation Probability HR=0.55 ( ) Log-rank test, p< Observation N=152 Observation Gemcitabine Gemcitabine N=149 Median PFS, months PFS at 3 months, % PFS at 6 months, % Time (months) PFS is measured from time of randomization into the maintenance phase

47 PFS by independent review Erlotinib versus observation Probability HR=0.82 ( ) Log-rank test, p=0.002 Observation N=152 Observation Erlotinib Erlotinib N=153 Median PFS, months PFS at 3 months, % PFS at 6 months, % Time (months) PFS is measured from time of randomisation into the maintenance phase

48 Preliminary overall survival Probability Observation Gemcitabine Erlotinib Gemcitabine vs observation HR=0.86 ( ) Erlotinib vs observation HR=0.91 ( ) Time (months) Median follow-up: 21.6 months 324 deaths / 464 randomized patients (69.6%)

49 Maintenance Chemotherapy: ASCO 2011 # 7510 Paz-Ares : 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 non-small cell lung cancer (NSCLC) # 7511 Zhang: Efficacy, tolerability, and biomarker analyses from a phase III, randomized, placebo-controlled, parallel group study of gefitinib as maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) in China (INFORM; C-TONG 0804)

50 Maintenance Chemotherapy: ASCO 2011 # 7510 Paz-Ares : 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 non-small cell lung cancer (NSCLC) # 7511 Zhang: Efficacy, tolerability, and biomarker analyses from a phase III, randomized, placebo-controlled, parallel group study of gefitinib as maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) in China (INFORM; C-TONG 0804)

51 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 Non-small Cell Lung Cancer 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 University Hospital - Virgen del Rocio, Seville, Spain; 2 San Camillo - Forlanini Hospital, Rome, Italy; 3 Institute of Oncology, Bucharest, Romania; 4 Clinic for Thoracic Diseases at University Hospital Heidelberg, Heidelberg, Germany; 5 Montpellier Academic Hospital, Montpellier, France; 6 Medical Oncology Unit, S. Gerardo Hospital, Monza, Italy; 7 Le Mans Regional Hospital, Le Mans, France; 8 Jawaharlal Nehru Cancer Hospital and Research Center, Bhopal, India; 9 University Hospital Hamburg-Eppendorf, Germany; 10 Hospital Grosshansdorf, Grosshansdorf, Germany; 11 Eli Lilly and Company, Indianapolis, IN, USA; 12 Eli Lilly and Company, Suresnes, Hauts de Seine, France ; 13 Eli Lilly and Company, Houten, The Netherlands; 14 San Giuseppe Moscati Hospital, Avellino, Italy

52 #7511 Paz-Ares: PARAMOUNT: Phase III Study of Maintenance Pem vs. Placebo Immediately Following Induction Pem + Cisplatin for Nonsquamous NSCLC Induction Therapy (4 cycles) Study Treatment Period 21 to 42 Days Maintenance Therapy (Until PD) Progression Patients enrolled if: Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0/1 500 mg/m 2 Pemetrexed + 75 mg/m 2 Cisplatin, d1, q21d CR, PR, SD PD 500 mg/m 2 Pemetrexed + BSC, d1, q21d 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)

53 PARAMOUNT: Investigator Assessed PFS (from Maintenance) Survival Probability Pemetrexed: median =4.1 mos ( ) Placebo: median =2.8 mos ( ) Log-rank P= Unadjusted HR: 0.62 ( ) Time (Months) Pem + BSC Placebo + BSC

54 PARAMOUNT: Subgroup PFS Hazard Ratios All Randomized Patients (N=539) Stage IV (n=489) Stage IIIB (n=50) Induction Response CR/PR (n=242) Induction Response SD (n=280) Pre-randomization PS 1 (n=366) Pre-randomization PS 0 (n=170) Non-smoker (n=116) Smoker (n=419) Male (n=313) Female (n=226) Age <70 (n=447) Age 70 (n=92) Age <65 (n=350) Age > 65 (n=189) Other Histologic Diagnosis (n=32) Large Cell Carcinoma (n=36) Adenocarcinoma (n=471) Treatment Hazard Ratio (95% CI) Favors Pemetrexed Favors Placebo PFS results were internally consistent; benefit was seen across all subgroups

55 PARAMOUNT: Drug-related Safety Events Maintenance Phase Pemetrexed (N=359) (%) Placebo (N=180) (%) Drug-related deaths* Drug-related SAEs Discontinuation due to AE grade 3/4 drug-related CTCAE laboratory toxicities grade 3/4/5* drug-related CTCAE non-laboratory toxicities No statistical differences in Health-related Quality of Life Assessments were observed between treatment arms (D1, before each cycle and 30 day discontinuation visit) * On-study deaths: one on pemetrexed (pneumonia); one on placebo (NOS); one death within 30 days (endocarditis on pemetrexed) Statistically significant between arms (Fisher s exact test P 0.05)

56 Study (n) Brodowicz (206) Continuation Maintenance Yr Induction Therapy Maintenance Therapy Median PFS 2006 Gemcitabine 1250 mg/m 2 d 1, 8 + cisplatin 80 mg/m 2 d 1 x 4 Gemcitabine 1250 mg/m 2 d 1,8 BSC 6.6 months 5.0 months (p<.001) Median OS 13.0 months 11.0 months Main grade 3/4 toxicities Maintenance Gem: ANC14.9%, Plts 1.7%; blood transfusion 20% gemcitabine vs. 6.3% BSC Belani (255) 2010 Gemcitabine 1000 mg/m2 d 1,8 + carboplatin AUC 5 d1 x 4 Gemcitabine 1000 mg/m 2 d 1,8 BSC 7.4 months 7.7 months (p=.575) 8.0 months 9.3 months (p=.838) ANC 15% chemo, 2% BSC; Plts 9% chemo, 4% BSC; fatigue: 5% chemo, 2% BSC Perol (309) 2010 Gemcitabine 1250 mg/m 2 d 1, 8 + cisplatin 80 mg/m 2 d 1 x 4 Gemcitabine 1000 mg/m 2 d 1,8 BSC 3.3 months 1.9 months (p<.001) NR NR At least 1 grade 3/4 AE: chemotherapy 27.9%, observation 2.6% Paz Ares (539) 2011 Pemetrexed 500 mg/m 2 d 1 + cisplatin 75 mg/m 2 d 1 x 4 Pemetrexed 500 mg/m 2 d 1 BSC 4.1 months 2.8 months (p=.0006) NR NR Fatigue:4.2% pem, 0.6% BSC, Anemia: 4.5%, 0.6% BSC, ANC: 3.6% pem, 0 BSC Brodowicz et al, Lung Cancer 2006; 52: Belani et al ASCO 2010 Perol et al ASCO 2010 Paz Ares et al ASCO 2011

57 Phase II study of Carboplatin + Pemetrexed + Bevacizumab Patel et al, ASCO 2008, Abst 8044, JCO 2009 Carboplatin AUC 6 i.v. day 1 Chemotherapy-naïve Stage IIIB/IV ECOG PS 0-1 Non-squamous histology No CNS mets Pemetrexed 500 mg/m2 i.v. day 1 Bevacizumab 15 mg/kg i.v. day 1 Cycles q3 weeks X 6 PD Non-PD Off Study Pemetrexed 500 mg/m2 Bevacizumab 15 mg/kg Cycles q3 weeks until PD

58 Phase II study of Carboplatin + Pemetrexed + Bevacizumab Patel et al, ASCO 2008, Abst 8044, JCO patients with stage IIIB/IV nonsquamous NSCLC enrolled ORR 55% (95% CI: 41-69%) Median PFS: 7.8 mos (95% CI: ) Median OS: 14.1 mos (95% CI: ) 0% inc. of FN; 2% inc of TRDs

59 Phase III First-Line Pem/Carbo/ Bevacizumab in Advanced Non-Sq NSCLC POINT-BREAK

60 ECOG 4599: Phase III Trial of Bevacizumab in Non-Squamous NSCLC Eligibility Non-squamous NSCLC No Hx of hemoptysis No CNS metastases Stratification variables RT vs no RT Stage IIIB or IV vs recurrent Wt loss <5% vs 5% Measurable vs nonmeasurable Parameter PC PCB P value RR (%) <0.001 PFS (mo) <0.001 Median survival (months) P = year survival (%) year survival (%) RT = radiotherapy; PD = progressive disease. Sandler A et al. N Engl J Med. 2006;355: PC Paclitaxel 200 mg/m 2 Carboplatin AUC 6 mg/m 2 q3wk PCB Paclitaxel x 6 cycles + bevacizumab (15 mg/kg q3wk) to PD No crossover to bevacizumab permitted

61 ECOG 5508 Phase III Study Design Conti Bev. vs Switch Pem. vs Hybrid Bev.+Pem. Primary Endpoint = OS Eligibility Stage IIIB/IV Bev eligible NSCLC PS 0-1 Tx Brain mets OK 4 prior cycles of CarbTax +Bev (1236), with CR, PR, SD (864) Randomization factors: gender PS stage best tumor response to induction R A N D O M I Z E Pemetrexed 500 mg/m 2 (q21d) Bevacizumab 15mg/kg (q21d) Pemetrexed 500 mg/m 2 (q21d) Bevacizumab 15mg/kg (q21d) *B 12, folate, and dexamethasone given in Pem. arms Total 1236 patients with 864 randomized (288/arm)

62 Switch Maintenance Fidias Ciuleanu Capuzzo Miller Perol Zhang Agent/Control Arm N PFS Docetaxel Delayed Docetaxel Pemetrexed Placebo Erlotinib Placebo Erlotinib + Bevacizumab Placebo + Bevacizumab Erlotinib Observation Gefitinib Placebo m HR m p< m HR m p< w HR w p< m HR m p m HR m p m HR m p< Salvage treatment % OS HR p HR p HR p HR p NA HR.91 NA HR p Fidias, J Clinc Oncol 28:

63 Switch Maintenance Fidias Ciuleanu Capuzzo Miller Perol Zhang Agent/Control Arm N PFS Docetaxel Delayed Docetaxel Pemetrexed Placebo Erlotinib Placebo Erlotinib + Bevacizumab Placebo + Bevacizumab Erlotinib Observation Gefitinib Placebo m HR m p< m HR m p< w HR w p< m HR m p m HR m p m HR m p< Salvage treatment % OS HR p HR p HR p HR p NA HR.91 NA HR p Fidias, J Clinc Oncol 28:

64 Maintenance Tx: Conclusions (1) Reasonable option in fit, motivated pts who are highly symptomatic at the time of initial presentation Bevacizumab maintenance is part of the E4599 paradigm, though not proven vs observation in randomized phase III trials Pemetrexed is well tolerated and convenient Survival benefits confined to non-squamous histology, and are unproven in pts who receive pemetrexed and/or bevacizumab as part of their first line Tx Striking survival advantage seen with pemetrexed in this setting would have been more credible had it been observed in the context of mandatory crossover in the control group at the time of PD Cost may ultimately constitute the 800lb gorilla

65 Mr Debonnair strikes out