Maintenance Therapy in Advanced NSCLC:

Maintenance Therapy in Advanced NSCLC:
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 19104

Disclosures: Past 5 yrs Grant/Research Support: Scientific Advisor:
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; Vertex Speakers Bureau: curtailed as of 12/2010 Bristol Myers Squibb, Imclone, Sanofi- Aventis, Lilly, Genentech, OSI

Terminology: Maintenance
Is it maintenance? Is it consolidation? Or is it early salvage? 3

Terminology: Maintenance
Prolonged Therapy: continuing the original regimen indefinitely until PD or toxicity Full dose: Identical regimen (Prolonged Chemo) Attenuated dose: usually to mitigate cumulative toxicity Continuation Maintenance: continuing Rx with the non-platinum component of Tx (single agent instead of combination) Switch Maintenance: alternative cytotoxic or targeted agent AKA: Early Second Line Tx

Phase III: 4 Cycles Chemo vs. Continuous Chemo
Followed by Second Line Therapy in Adv NSCLC R A N D O M I Z E Carboplatin AUC 6 + Paclitaxel 200 mg/m2 every 21 days x 4 cyc Eligibility NSCLC IIIb/IV PS ≥ 70 Chemonaive Treated Brain Mets No neuropathy At Progression: Weekly Paclitaxel 80 mg/m2/wk until PD Carboplatin AUC 6 + Paclitaxel 200 mg/m2 every 21 days until PD Endpoints: Survival and Quality of Life Socinski M, et al. J Clin Onc 2005; 20(5). Hensing TA, et al. Lung Cancer 2005; 47:253.

Paclitaxel Carboplatin x 4 Cycles vs Paclitaxel Carboplatin to Progression
Socinski et al. J Clin Oncol 20: 1335, 2002

Paclitaxel Carboplatin x 4 Cycles vs Paclitaxel Carboplatin to Progression
PC x 4 n=114 PC to PD n=116 P value Number of cycles 4 ( 0-6) 4 (0-19) ORR 22% 24% ns Median survival 6.6 mos 8.5 mos 0.63 1-yr survival 28% 34% 2nd-line therapy 42% 47% 0.42 Grade 2-4 neuro toxicity 14% 27% 0.02 Socinski et al. J Clin Oncol 20: 1335, 2002

Prolonged Chemotherapy
MVP x 3 cycles MVP x 6 cycles Stage IIIB/IV NSCLC PS 0-2 R All patients could receive MVP at progression MVP: mitomycin, vinblastine, cisplatin Smith, JCO 19: 1336, 2001

MVP x 3 Cycles versus MVP x 6 Cycles
MVP x 3 n=155 MVP x 6 n=153 P value Received full treatment 113 (72%) 48 (31%) ORR 31% 38% 0.20 Median survival 6.0 mos 7.0 mos TTP 5.0 mos ns Smith et al. J Clin Oncol 19: 1336, 2001

MVP x 3 Cycles versus MVP x 6 Cycles
Survival, all patients Survival, patients who Survival, PS 0-1 patients received at least 3 cycles Smith et al. J Clin Oncol 19: 1336, 2001

Immediate Versus Delayed Docetaxel After Induction
Eligibility & Treatment Plan CR, PR, SD Immediate Docetaxel 75mg/m2 day 1, every 21 days until PD or maximum of 6 cycles R A N D O MI Z E GC Phase Gemcitabine, 1000 mg/m2, D 1, 8 Carboplatin AUC 5, Day 1 Every 21 d 4 cycles Patient Eligibility NSCLC Stage IIIb/IV Chemonaïve ECOG PS = 0-2 CNS Mets allowed Delayed Docetaxel Best Supportive Care, then start therapy at PD 75mg/m2 on day 1, every 21 days, until PD or maximum of 6 cycles Primary endpoint: Overall Survival, HR: 1.43 Fidias et al, ASCO 2007

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

Fidias et al. J Clin Oncol; 27:591-598 2009
Immediate (n=153) Delayed (n=154) LR p-Value Median PFS (mo) 5.7 2.7 <0.0001 12-month PFS, % 20% 9% Immediate (n=153) Delayed (n=154) LR p-Value Med OS (mo) 12.3 9.7 0.085 12-mo OS 51.1% 43.5% And these are the results. The median PFS was 5.7 months in the immediate arm, and 2.7 months in the delayed arm – a difference that was highly statistically significant. The 12 month PFS was 20% in the immediate arm, and 9% in the delayed arm. Fidias et al. J Clin Oncol; 27:

Is this negative for survival benefit or under-powered??
Immediate (n=153) Delayed (n=154) LR p-Value Median PFS (mo) 5.7 2.7 <0.0001 12-month PFS, % 20% 9% Immediate (n=153) Delayed (n=154) LR p-Value Med OS (mo) 12.3 9.7 0.085 12-mo OS 51.1% 43.5% Is this negative for survival benefit or under-powered?? Fidias et al. J Clin Oncol; 27:

Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus BSC: A Phase III Study in NSCLC C.P. Belani1, T. Brodowicz2, 3, T. Ciuleanu3, 4, J.H. Kim5, M. Krzakowski3, 6*, E. Laack7, Y.L. Wu8, P. Peterson9, K.Krejcy10, C. Zielinski2, 3 1Penn State Hershey Cancer Institute, Hershey, PA, USA; 2Medical University, Vienna, Austria; 3Central European Cooperative Oncology Group (CECOG); 4Institutul Oncologic I Chiricuta, Cluj, Romania; 5Yonsei Cancer Center, Seoul, Korea; 6 Maria Sklodowska-Curie Memorial Cancer Center & Institute Of Oncology, Warsaw, Poland; 7Cancer Center, University Hospital Hamburg-Eppendorf, Germany; 8Guangdong General Hospital, Guangzhou, China; 9Eli Lilly and Co. IN, USA; 10Lilly Regional Operations, Vienna, Austria

Study Design Double-blind, Placebo-controlled, Multicenter, Phase III Trial Stage IIIB/IV NSCLC ECOG PS 0-1 4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD Randomization factors: gender PS stage best tumor response non-platinum drug brain mets Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)* Placebo (d1, q21d) + BSC (N=222)* 2:1 Randomization Primary Endpoint = PFS *B12, folate, and dexamethasone given in both arms

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

Baseline Characteristics
Pemetrexed N=441 % Placebo N=222 Median age, years 60.6 60.4 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 74 70 Adenocarcinoma 50 48 Large cell carcinoma 2 5 Other or indeterminate 21 18 Squamous 26 30

Initial Therapy Pemetrexed N=441 % Placebo N=222 Docetaxel-carboplatin
5 3 Docetaxel-cisplatin 2 Paclitaxel-carboplatin 30 27 Paclitaxel-cisplatin 6 9 Gemcitabine-carboplatin 24 22 Gemcitabine-cisplatin 33 38 Best response to initial therapy CR + PR/SD 48/52 52/48

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

Progression-free Survival by Histology
Non-squamous Squamous HR=0.47 (95% CI: ) P < HR=1.03 (95% CI: ) P =0.896 Progression-free Probability Pemetrexed 4.4 mos Pemetrexed 2.4 mos Placebo 2.5 mos Placebo 1.8 mos Time (months) Time (months)

(Intent-to-treat Population)
Overall Survival (Intent-to-treat Population) Pemetrexed 13.4 mos Placebo 10.6 mos Survival Probability Time (months) HR=0.79 (95% CI: 0.65–0.95) P =0.012

Overall Survival by Histology
Non-squamous (n=481) Squamous (n=182) HR=0.70 (95% CI: ) P =0.002 HR=1.07 (95% CI: 0.49–0.73) P =0.678 Survival Probability Pemetrexed 15.5 mos Pemetrexed 9.9 mos Placebo 10.3 mos Placebo 10.8 mos Time (months) Time (months)

Efficacy by Histologic Groups
Histology Groups Median OS, mos Median PFS, mos Pem Plac P-value (HR) Non-squamous (n=481) 15.5 10.3 0.002 (0.70) 4.4 1.8 < (0.47) Adeno (n=329) 16.8 11.5 0.026 (0.73) 4.6 2.7 (0.51) Large cell (n=20) 8.4 7.9 0.964 (0.98) 4.5 1.5 0.104 (0.40) Other (n=133) 11.3 7.7 0.025 (0.61) 4.1 1.6 0.0002 (0.44) Squamous (n=182) 9.9 10.8 0.678 (1.07) 2.4 2.5 0.896 (1.03) There was a statistically significant treatment-by-histology interaction with both PFS (P=0·036) and OS (P=0·033)

Treatment-related Toxicities*
Pemetrexed (N = 441) % Placebo (N = 222) Grade 3/4 Neutropenia‡ 3 Anemia 1 Leukopenia 2 Fatigue‡ 5 Anorexia Infection Diarrhea Nausea Vomiting <1 Sensory neuropathy Mucositis/Stomatitis *NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue

Treatment HRs for Overall Survival in Subgroups of the ITT Population

Conclusions First randomized, double-blind, placebo-controlled study to demonstrate a significant overall survival benefit for maintenance treatment with in patients with advanced NSCLC Non-squamous histology: predictive of the improved efficacy of pemetrexed in patients with advanced NSCLC Administration of pemetrexed in the maintenance setting is fairly well tolerated and is devoid of any cumulative toxicity

Switch Maintenance Agent/Control Arm N PFS Salvage treatment % OS
Fidias Docetaxel Delayed Docetaxel 309 5.7 m HR 0.63 2.7 m p<.001 63 HR 0.80 p.085 Ciuleanu Pemetrexed Placebo 663 4.0 m HR 0.60 2.0 m p<.001 67 HR 0.79 p .012 Capuzzo Erlotinib 889 12.3 w HR 0.71 11.1 w p<.001 72 HR 0.81 p .0088 Miller Erlotinib + Bevacizumab Placebo + Bevacizumab 768 4.8 m HR 0.72 3.8 m p.0012 55.5 HR 0.9 p .2686 Perol Observation 310 2.9 m HR 0.82 1.9 m p.002 81.9 NA HR .91 NA Zhang Gefitinib 296 4.8 m HR 0.42 2.6 m p<0.0001 58.8 HR .83 p Fidias, J Clinc Oncol 28: Zhang et al [INFORM] ASCO 2011

Switch Maintenance Agent/Control Arm N PFS Salvage treatment % OS
Fidias Docetaxel Delayed Docetaxel 309 5.7 m HR 0.63 2.7 m p<.001 63 HR 0.80 p.085 Ciuleanu Pemetrexed Placebo 663 4.0 m HR 0.60 2.0 m p<.001 67 HR 0.79 p .012 Capuzzo Erlotinib 889 12.3 w HR 0.71 11.1 w p<.001 72 HR 0.81 p .0088 Miller Erlotinib + Bevacizumab Placebo + Bevacizumab 768 4.8 m HR 0.72 3.8 m p.0012 55.5 HR 0.9 p .2686 Perol Observation 310 2.9 m HR 0.82 1.9 m p.002 81.9 NA HR .91 NA Zhang Gefitinib 296 4.8 m HR 0.42 2.6 m p<0.0001 58.8 HR .83 p Fidias, J Clinc Oncol 28:

Potential Criticisms Significant percentage of pts will not get to enjoy the “fruits of maintenance” pemetrexed Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted Toxicity of pemetrexed, though mild, is not entirely trivial Early institution of 2nd 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?!

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

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 non-squamous population, ~ 2/3 of the remainder So the benefits of pemetrexed maintenance apply to only 38% of the entire advanced stage good PS NSCLC population (if we use Fidias as our reference)

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 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted Toxicity of pemetrexed, though mild, is not entirely trivial Early institution of 2nd 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?!

Systemic Post-study Therapy
Pemetrexed (N=441) % Placebo (N=222) % Patients with post-study therapy 52 67 Most common post-study therapies Carboplatin 7 10 Cisplatin 5 6 Docetaxel 22 29 Erlotinib 21 Gefitinib 13 Gemcitabine 9 14 Paclitaxel 4 1 19 Vinorelbine 17 Total Validated 2nd Line Tx 58 79 Higher rate of follow-up treatment on the placebo arm Balanced selection of therapies between arms and low rate of crossover

Pts Who Actually Received docetaxel
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 When one looks at the survival of the patients on the delayed docetaxel arm, one can see the median survival of those who actually received docetaxel was the same as for the patients who were randomized to the immediate arm. Analysis of those who went onto Docetaxel as “salvage” therapy suggests no compromise in longterm survival

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 2nd line vs 2nd 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 2nd 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?!

Maintenance Pemetrexed: Tx-related Toxicities*
Placebo (N = 222) % Grade 3/4 All grades Neutropenia‡ 3 6 Anemia 15 1 5 Leukopenia 2 Fatigue‡ 24 10 Anorexia 19 Infection Diarrhea Nausea Vomiting <1 9 Sensory neuropathy 4 Mucositis/Stomatitis 7 Early Discontinuation for Toxicity *NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue Ciuleanu et al. Lancet 374: (2009)

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

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

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 2nd line vs 2nd 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 2nd 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?!

Progression-free Survival
HR=0.60 (95% CI: 0.49–0.73) P < Progression-free Probability Pemetrexed 4.0 mos Placebo 2.0 mos Time (months)

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 2nd line Tx is not available

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 2nd line vs 2nd 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 2nd 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?!

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 (~30 to 50%) receive pemetrexed as part of their first-line therapy Neither of these two groups were included in this trial (probably >50% of potentially eligible pts) Pem maintenance, arguably, is irrelevant to these two groups, and the robust PFS and OS benefit might have been diluted

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 (~30 to 50%) receive pemetrexed as part of their first-line therapy Neither of these two groups were included in this trial (probably >50% of potentially eligible pts) Pem maintenance, arguably, is irrelevant to these two groups, and the robust PFS and OS benefit might have been diluted Concerns since addressed by Paramount and AvaPERL trials

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 2nd line vs 2nd 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 2nd 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?!

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 1Klein R, et al. J Thorac Oncol. 2010;5:

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 population1 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 1Klein R, et al. J Thorac Oncol. 2010;5:

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 2nd line vs 2nd 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 2nd 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

Stratify by EGFR IHC results
SATURN: phase III trial of sequential Tarceva (Erlotinib) in unresectable NSCLC Tumour samples (mandatory) Stratify by EGFR IHC results Erlotinib 150mg/day PD Chemonaïve advanced NSCLC n~1,700 Non-PD n~850 4 cycles of 1st-line platinum-based doublet 1:1 Placebo Stratifications EGFR protein expression by IHC positive vs negative vs indeterminate Stage at randomisation IIIb vs IV ECOG PS 0 vs 1 CT regimen cisplatin-gemcitabine vs carboplatin-docetaxel vs others Smoking status smoking vs former vs never Region PD Completed: 152 centers participated in 29 countries Primary endpoint: PFS (25% improvment) 55

Stratify by EGFR IHC results
SATURN: phase III trial of sequential Tarceva (Erlotinib) in unresectable NSCLC Tumour samples (mandatory) Stratify by EGFR IHC results Erlotinib 150mg/day PD Chemonaïve advanced NSCLC n~1,700 Non-PD n~850 4 cycles of 1st-line platinum-based doublet 1:1 889 1949 Placebo Stratifications EGFR protein expression by IHC positive vs negative vs indeterminate Stage at randomisation IIIb vs IV ECOG PS 0 vs 1 CT regimen cisplatin-gemcitabine vs carboplatin-docetaxel vs others Smoking status smoking vs former vs never Region PD Completed: 152 centers participated in 29 countries Primary endpoint: PFS (25% improvment) 56

SATURN: PFS* all patients (ITT)
Erlotinib Placebo PFS at 12 wks (%) 53 40 PFS at 24 wks (%) 31 17 1.0 0.8 0.6 0.4 0.2 HR=0.71 (0.62–0.82) Log-rank p<0.0001 PFS probability Erlotinib (n=437) Placebo (n=447) Time (weeks) *investigator results corroborated by independent review

Subgroup analysis of PFS
HR (95% CI) n 0.71 (0.62–0.82) 884 0.78 (0.66–0.92) 654 0.56 (0.42–0.76) 230 0.75 (0.64–0.88) 744 0.58 (0.38–0.87) 128 0.60 (0.48–0.75) 401 0.76 (0.60–0.95) 359 0.56 (0.38–0.81) 152 0.66 (0.50–0.88) 242 0.80 (0.67–0.97) 490 All Male Female Caucasian Asian Adenocarcinoma Squamous-cell Never smoker Former smoker Current smoker 0.4 0.6 0.8 1.0 1.2 Favours erlotinib HR Favours placebo

PFS in EGFR Mutation + Tumors*
SATURN PFS in EGFR Mutation + Tumors* PFS probability 1.0 0.8 0.6 0.4 0.2 Erlotinib (n=22) Placebo (n=27) HR=0.10 (0.04–0.25) Log-rank p<0.0001 Time (weeks) *60% censored Cappuzzo F, et al. J Clin Oncol 27:407s, 2009

SATURN: Summary of QoL Data
HR (95% CI) P value Time to Deterioration in QoL (FACT-L) 0.96 ( ) 0.6530 Time to Pain 0.61 ( ) 0.0080 Time to Cough 0.77 ( ) 0.2546 Time to Dyspnea 0.75 ( ) 0.2054 Time to Analgesic Use 0.66 ( ) 0.0199

OS*: all patients (ITT)
1.0 0.8 0.6 0.4 0.2 HR=0.81 (0.70–0.95) Log-rank p=0.0088 Erlotinib (n=438) Placebo (n=451) OS probability 11.0 12.0 Outcome MS 1 yr OS (%) 2 yr OS (%) Erlotinib 12 mos 50 26 Placebo 11 mos 45 19 *OS is measured from time of randomisation into the maintenance phase; ITT = intent-to-treat population

Criticisms of SATURN Fewer than 50% of those enrolled actually made it to the maintenance randomization Toxicity of longterm erlotinib (diarrhea and skin rash in the majority of pts) is not trivial PFS improvement, while statistically signifiicant, may be clinically irrelevant 1 month advantage Survival improvement, similarly, was “clinically underwhelming: 12 vs 11 mos Mandatory crossover to EGFR TKI at the time of PD was not included

Saturn: Toxicity Erlotinib (N=433) Placebo (N=445) Grade ≥ 3
All grades One or more AE 12% 65% 1% 20% Skin issue 9% 62% 10% Rash 60% 8% Pruritis <1% 6% 2% GI issue 23% Diarrhea 18% 3% General Nutritional 5% Anorexia Infection Cappuzzo et al. Lancet Oncol online as of May 20

Criticisms of SATURN Fewer than 50% of those enrolled actually made it to the maintenance randomization Toxicity of longterm erlotinib (diarrhea and skin rash in the majority of pts) is not trivial PFS improvement, while statistically signifiicant, may be clinically irrelevant 1 month advantage Survival improvement, similarly, was “clinically underwhelming: 12 vs 11 mos Mandatory crossover to EGFR TKI at the time of PD was not included (only 21% in the placebo group received Erl at PD) Erlotinib Placebo PFS at 12 wks (%) 53 40 PFS at 24 wks (%) 31 17

SATURN: Survival Subgroup Analyses
Demographic HR No. All 0.81 ( ) 889 Male 0.88 ( ) 659 Female 0.64 ( ) 230 Caucasian 0.86 ( ) 746 Asian 0.66 ( ) 131 Adenoca 0.77 ( ) 403 Squamous cell 0.86 ( ) 360 Never smoker 0.69 ( ) 152 Former smoker 0.75 ( ) 244 Current smoker 0.88 ( ) 493 Cappuzzo F, et al. J Clin Oncol 27:407s, 2009

Maintenance Trials Recently Reported
ATLAS: Bev/Erl vs Bev Belani: Gem vs BSC IFCT-GFPC 0502: Gem vs Erl vs Obs [BSC] INFORM: Gefitinib vs Placebo PARAMOUNT: Cont Pem vs IV Placebo AVAPERL: Bev vs Bev/PEM [ESMO 2011] POINT-BREAK: E4599 v Patel/Hensing Ongoing E5508: Cont Bev vs Switch Pem vs Both

Randomized, Double Blind, Placebo Controlled, Phase IIIb Trial (ATLAS) Comparing Bevacizumab Therapy with or without Erlotinib, after Completion of Chemotherapy with Bevacizumab for 1st-line Treatment of Locally-advanced, Recurrent, or Metastatic Non-small Cell Lung Cancer (NSCLC) Vincent A. Miller, MD,1 Paula O’Connor, MD,2 Chang-Heok Soh, PhD,2 and Fairooz Kabbinavar, MD,3 for the ATLAS Investigators 1Memorial Sloan-Kettering Cancer Center, New York, NY, 2Genentech, Inc, South San Francisco, CA, 3University of California Los Angeles – Translational Oncology Research International, Los Angeles, CA

Post progression therapy
ATLAS Study Design Bevacizumab (15mg/kg) + erlotinib (150mg) to PD Chemo-naïve advanced NSCLC N=1,160 4 cycles of 1st-line chemotherapy* + bevacizumab Non-PD n=768 (66%) Post progression therapy 1:1 Unblind at PD Bevacizumab + placebo to PD Eligibility Stage IIIB**/IV NSCLC ECOG performance status 0-1 Stratification factors Gender Smoking history (never vs former/current) ECOG performance status (0 v >1) Chemotherapy regimen Primary endpoint PFS in all randomized pts (26% improvement) Secondary endpoints Overall survival Safety Exploratory endpoints Biomarker analyses (IHC, FISH, EGFR & K-Ras mutation) *Carbo/paclitaxel; cis/vinorelbine; carbo or cis/gemcitabine; carbo or cis/docetaxel. **IIIB with pleural effusion 69

Proportion Without Event Progression-Free Survival (months)
ATLAS: Progression-Free Survival (ITT population, investigator assessment) Proportion Without Event 1.0 Bev + Placebo (n=373) 0.8 Bev + Erlotinib (n=370) 0.6 HR=0.722 ( ) Log-rank P=0.0012 0.4 0.2 0.0 3 6 9 12 15 18 21 Progression-Free Survival (months) No. of patients at risk: Bev + Placebo 373 142 58 27 15 6 3 Bev + Erlotinib 370 178 81 43 20 6 3 1

ATLAS: Additional PFS Outcome Measures
Progression Free Survival: HR=0.722 ( ) Log-rank P=0.0012 (ITT population, investigator assessment) Bev + Placebo (n=370) Bev + Erlotinib (n=373) Median PFS, mos (95% CI) 3.75 (2.83, 4.04) 4.76 (4.14, 5.52) PFS rate, % (95% CI) 3 mos 53.4 (47.5, 58.9) 67.7 (61.9, 72.7) 6 mos 28.4 (23.0, 34.1) 40.3 (34.2, 46.3) 71 71

ATLAS: Additional PFS Outcome Measures
Progression Free Survival: HR=0.722 ( ) Log-rank P=0.0012 (ITT population, investigator assessment) Bev + Placebo (n=370) Bev + Erlotinib (n=373) Median PFS, mos (95% CI) 3.75 (2.83, 4.04) 4.76 (4.14, 5.52) PFS rate, % (95% CI) 3 mos 53.4 (47.5, 58.9) 67.7 (61.9, 72.7) 6 mos 28.4 (23.0, 34.1) 40.3 (34.2, 46.3) Overall Survival* 13.93 15.93 *HR = ( ) Log rank p=0.2686 72 72

ATLAS: Grade 3-4 Adverse Events of Special Interest during the Post Chemotherapy Phase (Cont.)
Bev + Placebo, n (%) (n=368) Bev + Erlotinib, n (%) (n=367) Grade 3–4 Rash 2 (0.5%) 38 (10.4%) Diarrhea 3 (0.8%) 34 (9.3%) Infection 17 (4.6%) 15 (4.1%) ILD-like events Renal failure/ deficiency* Hepatic events* 1 (0.3%) Grade 5 events: Bev + Placebo: 1 (0.3%) infection. 73

Is there a role for Continuation Maintenance Tx in NSCLC?
Belani IFCT-GFPC 0502 Paramount Avaperl

Gemcitabine Maintenance + BSC vs BSC Alone
Patients without disease progression randomized 1:1 Gemcitabine + BSC (n = 128) Chemotherapy-naive patients with stage IIIB/IV NSCLC (N = 519) Gemcitabine/Carboplatin for 4 cycles 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.

Gemcitabine + BSC vs BSC: Treatment Outcomes
Benefits of gemcitabine maintenance may have been nullified by patient population studied Median patient age: 66.6 years ECOG PS 2: 64% Outcome Gemcitabine + BSC (n = 128) BSC (n = 127) HR (95% CI) P Value Median OS, mo 8.0 9.3 0.97 ( ) .838 Median PFS, mo 7.4 7.7 1.09 ( ) .575 ORR, % 28 6 -- NR Belani CP, et al. ASCO Abstract 7506.

IFCT-GFPC 0502 study design
PD: off Maintenance treatment Progression: 2nd line A Observation PD Pemetrexed N=155 Cisplatin gemcitabine x 4 cycles N=834 Objective response or stable disease B R* N=464 Gemcitabine PD Pemetrexed N=154 C Erlotinib PD Pemetrexed NSCLC Stage IIIB wet – IV PS 0-1, years Asymptomatic brain mets allowed Tumor tissue EGFR IHC EGFR mutation N=155 Primary endpoint: PFS Induction chemo: cisplatin 80mg/m2 d1 + gemcitabine 1,250mg/m2 d1, d8 Arm B: gemcitabine 1,250mg/m2 d1, d8 /3 wks Arm C: erlotinib 150mg daily *Stratification factors: gender histology: adenocarcinoma vs other histology smoking status: non-smokers vs current/former smokers center response vs stabilization to induction chemotherapy Perol et al ASCO 2010 EGFR = epidermal growth factor receptor IHC = immunohistochemistry; PD = progressive disease

PFS by independent review Gemcitabine versus observation
Probability Observation N=152 Gemcitabine N=149 Median PFS, months 1.9 3.8 PFS at 3 months, % 30.3 55.0 PFS at 6 months, % 8.6 22.1 1.0 0.8 0.6 0.4 0.2 HR=0.55 (0.43–0.70) Log-rank test, p<0.0001 Observation Gemcitabine Time (months) PFS is measured from time of randomization into the maintenance phase

PFS by independent review Erlotinib versus observation
Probability Observation N=152 Erlotinib N=153 Median PFS, months 1.9 2.9 PFS at 3 months, % 30.3 35.3 PFS at 6 months, % 8.6 16.3 1.0 0.8 0.6 0.4 0.2 HR=0.82 (0.73–0.93) Log-rank test, p=0.002 Observation Erlotinib Time (months) PFS is measured from time of randomisation into the maintenance phase

Preliminary overall survival
Probability 1.0 0.8 0.6 0.4 0.2 Observation Gemcitabine Erlotinib Gemcitabine vs observation HR=0.86 (0.66–1.12) Erlotinib vs observation HR=0.91 (0.80–1.04) Time (months) Median follow-up: 21.6 months 324 deaths / 464 randomized patients (69.6%)

PARAMOUNT: Study Design
Study Treatment Period Progression Induction Therapy (4 cycles) Maintenance Therapy (Until PD) 21 to 42 Days 500 mg/m2 Pemetrexed + 75 mg/m2 Cisplatin, d1, q21d CR, PR, SD PD Placebo + BSC, d1, q21d 500 mg/m2 Pemetrexed + BSC, d1, q21d 2:1 Randomization Patients enrolled if: Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0/1 Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD) Primary objective: progression-free survival Secondary objectives: Overall survival, response rate, pt reported outcomes, resource utilization, adverse events

PARAMOUNT: Study Design
Study Treatment Period Progression Induction Therapy (4 cycles) Maintenance Therapy (Until PD) 21 to 42 Days 500 mg/m2 Pemetrexed + 75 mg/m2 Cisplatin, d1, q21d CR, PR, SD PD Placebo + BSC, d1, q21d 500 mg/m2 Pemetrexed + BSC, d1, q21d 2:1 Randomization Patients enrolled if: Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0/1 Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD) N=539 57% N=359 N=180 N=939 Primary objective: progression-free survival Secondary objectives: Overall survival, response rate, pt reported outcomes, resource utilization, adverse events Paz-Ares et al, ASCO 2011, abstract CRA7510

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

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) ─0.62 ─0.55 ─0.48 ─0.74 ─0.67 ─0.53 ─0.41 ─0.70 ─0.49 ─0.69 ─0.34 ─0.64 ─0.39 Treatment Hazard Ratio (95% CI) Favors Pemetrexed Favors Placebo PFS results were internally consistent; benefit was seen across all subgroups

PARAMOUNT: Final OS from Induction
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Pemetrexed Median OS =16.9 mos (95% CI: 15.8–19.0) Placebo Median OS =14.0 mos (95% CI: 12.9–15.5) Log-rank P=0.0191 HR=0.78 (95% CI: 0.64–0.96) Survival Probability Time from Induction (Months) Patients at Risk Pem + BSC Placebo + BSC

PARAMOUNT: Subgroup OS Hazard Ratios
The survival results were internally consistent; benefit was seen across all subgroups

PARAMOUNT: Induction Response Subgroups OS Hazard Ratios
All Randomized Patients (N=539) Stage IV (n=490) Stage IIIB (n=49) Induction Response CR/PR (n=234) Induction Response SD (n=285) Pre-randomization ECOG PS 1 (n=363) Pre-randomization ECOG PS 0 (n=173) Non-smoker (n=117) Smoker )n=418) 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) 0.78 0.79 0.82 0.81 0.76 Hazard Ratio CR/PR HR = 0.81 SD HR = 0.76 Time from Randomization (Months) Survival probability Treatment Hazard Ratio (95%% CI) Favors Pemetrexed Favors Placebo The survival results were consistent across both induction response subgroups

Continuation Maintenance
Study Year Induction Therapy Maintenance Therapy Median PFS Median OS Main grade 3/4 toxicities Brodowicz 2006 Gemcitabine 1250 mg/m2 d 1, 8 + cisplatin 80 mg/m2 d 1 x 4 Gemcitabine 1250 mg/m2 d 1,8 BSC 6.6 months 5.0 months (p<.001) 13.0 months 11.0 months Maintenance Gem: ANC14.9%, Plts 1.7%; blood transfusion 20% gemcitabine vs. 6.3% BSC Belani 2010 Gemcitabine 1000 mg/m2 d 1,8 + carboplatin AUC 5 d1 x 4 Gemcitabine 1000 mg/m2 d 1,8 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 3.3 months 1.9 months NR At least 1 grade 3/4 AE: chemotherapy 27.9%, observation 2.6% Paz Ares 2011 Pemetrexed 500 mg/m2 d 1 + cisplatin 75 mg/m2 d 1 x 4 Pemetrexed 500 mg/m2 d 1 4.1 months 2.8 months (p=.0006) 13.9 months 11.1 months (p=0.034) Fatigue:4.2% pem, 0.6% BSC, Anemia: 4.5%, 0.6% BSC, ANC: 3.6% pem, 0 BSC

How do we Combine Platinum and Pemetrexed with Bevacizumab?
Are there clinical insights? Should both Bevacizumab and Pemetrexed be continued beyond 6 cycles?

AVAPERL: Patient disposition
Arm A: Bevacizumab (n= 125) CR/PR/SD by RECIST Patients screened (n=414) First-line induction with Bev-cis-pem (n=376) Patients randomized to maintenancea (n=253)b 5 patients not treated PD Arm B: bevacizumab + pemetrexed (n=128) Not eligible for randomization (n=123) patients not randomized 50 discontinued due to AEs 49 discontinued due to PD 9 patients died 7 withdrew consent 5 discontinued for other reasons 3 did not start treatment 3 patients not treated Median follow-up time for this analysis: 11 months a RECIST-related end points measured from the preinduction phase. b Intent-to-treat population 91

AVAPERL: Patient characteristics: maintenance population
Bevacizumab (n=125) Bevacizumab + pemetrexed (n=128) Median age, y <65 y, no. (%) 60 88 (70) 88 (69) Male, no. (%) 70 (56) 74(58) ECOG PS, no. (%) 1 52 (43) 67 (55) 66 (52) 59 (46) Current stage IV, no. (%) 110 (88) 121 (94) Histology, no. (%) Adenocarcinoma Large cell Other 115 (92) 9 (7) 1 (1) 110 (86) 12 (9) 6 (5) Smoking status, no. (%) Current smoker Past smoker Never smoker 31 (25) 60 (48) 33 (27) 30 (23) 67 (52) 31 (24)

AVAPERL: PFS from inductiona
100 75 50 25 Bev+pem 10.2 months (81 events) Bev 6.6 months (104 events) HR, 0.50 (0.37–0.69); P <.001 Cont. maintenance bev+pem (n=128) Cont. maintenance bev (n=125) Progression -free survival (%) Time (months) Pts at risk Bev+pem Bev a Randomized pts, Intent-to-treat population 93 Bev, bevacizumab; HR, hazard ratio; Pem, pemetrexed; pts, patients.

AVAPERL: PFS from randomizationa
100 75 50 25 Bev+pem 7.4 months (81 events) Bev 3.7 months (104 events) HR, 0.48 (0.35–0.66); P <.001 Cont. maintenance bev+pem (n=128) Cont. maintenance bev (n=125) from date of randomization(%) Progression -free survival Time (months) Pts at risk Bev+pem Bev a Median follow-up time in ITT population (excluding induction): 8.28 months (bev+pem arm), 7.95 months (bev arm) bev, bevacizumab; cont., continuation; HR, hazard ratio; ITT, intent to treat; pem, pemetrexed; pts, patients. 94

AVAPERL: OS from inductiona
100 75 50 25 Bev+pem NR (34 events) Bev months (42 events) HR: (0.47–1.20); P=0.23 Overall survival (% of patients) Cont. maintenance bev+pem (n=128) Cont. maintenance bev (n=125) Time (months) Pts at risk Bev+pem Bev a Randomized pts, Intent-to-treat population Median follow-up time: 11 months (8 months, excluding induction). 30% of events at the time of analysis for overall survival. bev, bevacizumab; HR, hazard ratio; NR, not reached; pem, pemetrexed; pts, patients. 95

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

Phase II study of Carboplatin + Pemetrexed + Bevacizumab Patel et al, ASCO 2008, Abst 8044
51 patients enrolled ORR 55% (41-69%) MPFS 7.8 months (5.2 – 11.5) MST 14.1 months (10.8 – 19.6) 0% inc. of FN; 2% inc of TRDs Patel JD. Hensing T et al. JCO 2009

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

Two POINT-BREAK Questions:
Would it POINT the way to a new treatment paradigm? If Pemetrexed/Bevacizumab became a new standard during induction and maintenance, would the combination BREAK the bank?

from Randomization (ITT)
PointBreak: KM OS from Randomization (ITT) Pem+Cb+Bev Pac+Cb+Bev OS median (mo) 12.6 13.4 HR (95% CI); P value 1.0 (0.86, 1.16); P=0.949 Censoring (%) 27.8 27.2 Survival rate (%) 1-year 52.7 54.1 2-year 24.4 21.2

PointBreak: Kaplan-Meier (KM) PFS from Randomization (ITT)
Pem+Cb+Bev Pac+Cb+Bev PFS median (mo) 6.0 5.6 HR (95% CI); P value 0.83 (0.71, 0.96); P=0.012 G4 PFS median (mo) 4.3 3.0 0.74 (0.64, 0.86) P<.001 TTPD (mo) 7.0 0.79 (0.67, 0.94); P=0.006 ORR (%) 34.1 33.0 Censoring rate for Pem+Cb+Bev was 26.9; for Pac+Cb+Bev was 23.3

PointBreak: Prespecified Analysis of KM PFS from Randomization for the Maint. Population
Pem+Cb+Bev (n=292) Pac+Cb+Bev (n=298) PFS median (mo) 8.6 6.9 Censoring (%) 24.7 14.1 Pem-Bev Bev Prespecified exploratory non-comparative subgroup analyses

PointBreak: Prespecified Analysis of KM OS from Randomization for the Maintenance Population
Pem+Cb+Bev (n=292) Pac+Cb+Bev (n=298) OS median (mo) 17.7 15.7 Censoring (%) 36.0 30.2 Pem-Bev Bev Prespecified exploratory non-comparative subgroup analyses

ECOG 5508 Phase III Study Design “Cont” Bev. vs “Switch” Pem
ECOG 5508 Phase III Study Design “Cont” Bev. vs “Switch” Pem. vs “Hybrid” Bev.+Pem. Primary Endpoint = OS RANDOMIZE Pemetrexed 500 mg/m2 (q21d) 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 Bevacizumab 15mg/kg (q21d) Pemetrexed 500 mg/m2 (q21d) Bevacizumab 15mg/kg (q21d) *B12, folate, and dexamethasone given in Pem. arms Total 1236 patients with 864 randomized (288/arm) 104

Maintenance Tx: Conclusions (1)
Reasonable option in fit, motivated pts who have stabilized or responded to initial plaintum-based chemotherapy Bevacizumab maintenance is part of the E4599 paradigm, though not proven vs observation in randomized phase III trials Pemetrexed is well tolerated and convenient PFS and Overall Survival benefits seen Both “continuation” and “switch” settings Confined to non-squamous histology 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

Maintenance Tx: Conclusions (2)
Maintenance therapy with erlotinib after cytotoxic chemotherapy offers a clinically modest, but statistically significant advantage wrt PFS and OS Survival benefits are a bit more robust in the phenotypically favored subgroups (Asians, women, adenoca, never smokers), but not secure in the mutation (+) cohorts The (not so) striking survival advantage seen with erlotinib in this setting would have been far more credible had it been observed in the context of mandatory crossover in the control group Inclusion of QoL and TOI enhances the clinical credibility of maintenance trials No survival advantage as yet for Pem-Bev or Erl-Bev combinations over Bev alone

Mr Debonnair strikes out

Maintenance Therapy in Advanced NSCLC:

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