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Chandra P Belani, MD Deputy Director Penn State Cancer Institute Miriam Beckner Distinguished Professor of Medicine Penn State College of Medicine Maintenance Therapy for Advanced NSCLC (SWITCH vs CONTINUATION)

 Use of systemic therapy following first- line treatment before progression  To be considered for patients with CR/PR or stable disease  Also referred to as ‘consolidation’ (but not ‘early second-line’ therapy) What Is Maintenance Therapy?

 Continuing one of the same agents from the original combination (“CONTINUATION”) Cisplatin and pemetrexed followed by pemetrexed as maintenance  Continuation of a targeted agent Carboplatin, paclitaxel and bevacizumab followed by bevacizumab  Initiating a new agent (“SWITCH”) Carboplatin and paclitaxel followed by pemetrexed Maintenance Therapy: Strategies

 Advanced non-squamous cell cancer patients whose disease is stable or responding to first- line chemotherapy should generally be offered maintenance pemetrexed  Absolutely agree, provided they do not have Evidence of EGFR mutation Declining PS Maintenance Therapy

 Is there an improvement in survival?  Is the treatment tolerated well?  Are patient selection methods available? Key Questions

Stage IIIB/IV NSCLC PS prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD Randomization factors: gender PS stage best tumor response to induction non-platinum induction drug brain mets Pemetrexed 500 mg/m 2 (d1, q21d) + BSC (N = 441)* Primary Endpoint = PFS Placebo (d1, q21d) + BSC (N = 222)* *B 12, folate, and dexamethasone given in both arms 2:1 Randomization Double-blind, Placebo-controlled, Multicenter, Phase III Trial Phase III Trial of Maintenance Pemetrexed in Advanced NSCLC Ciuleanu…Belani, Lancet 374(9699): , 2009 Belani et al, J Clin Oncol 28:7s, 2010 (suppl; abstr 7506)

Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in Advanced NSCLC Ciuleanu…Belani, Lancet 374(9699): , 2009 Belani et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7506) Pemetrexed Placebo HR (95% CI)p-value OS, non- squamous (n = 481) 15.5 mo10.3 mo 0.70 ( )0.002 OS, squamous (n = 182) 9.9 mo10.8 mo1.07 ( ) 0.678

Effect of Response to Induction on OS in JMEN Ciuleanu…Belani, Lancet 374(9699): , 2009 Belani et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7506) PemetrexedPlaceboHR (95% CI)p-value OS, nonsquamous pts with CR/PR 14.4 mo11.7 mo0.81 (0.58, 1.12) OS, nonsquamous pts with SD 16.6 mo8.6 mo0.61 (0.45, 0.83)

 Primary endpoint dependent review with 80% power to detect 50% improvement in median PFS: PFS by or each comparison (Gem vs Obs and Erl vs Obs)  Secondary endpoints: OS, safety, symptom control, prognostic and predictive effect of tumor EGFR status (IHC, EGFR mut) Perol et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7507) IFCT-GFPC 0502: Study Design

 Patients who received 2 nd -line pemetrexed: 73% (Obs), 55% (Gem), and 60% (Erl)  Grade 3-4 treatment-related AEs were more common in Gem (27%) and Erl (14%) than in Obs (2%) Perol et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7507) IFCT-GFPC 0502: Results Observation N = 152 Gemcitabine N = 149 Median PFS, mo PFS at 3 mo, % PFS at 6 mo, % PFS by independent review, gemcitabine versus observation HR = 0.55 ( ) Log-rank test, p < Observation N = 152 Erlotinib N = 153 Median PFS, mo PFS at 3 mo, % PFS at 6 mo, % PFS by independent review, erlotinib versus observation HR = 0.82 ( ) Log-rank test, p = 0.002

1:1 Chemonaïve advanced NSCLC n = 1,949 4 cycles of first- line platinum doublet chemotherapy* Placebo PD Erlotinib 150 mg/day PD Mandatory tumor sampling  Stratification Factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region  Co-Primary Endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumors  Secondary Endpoints: OS in all patients and those with EGFR IHC+ tumors, OS and PFS in EGFR IHC– tumors; biomarker analyses; safety; time to symptom progression; QoL *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel SATURN Study Design Cappuzzo et al, Lancet Oncol, 11(6):521-9, 2010 Non-PD n = 889 (46%)

*OS is measured from time of randomization into the maintenance phase; ITT = intent-to-treat population SATURN Survival* All Patients (ITT) Cappuzzo et al, Lancet Oncol, 11(6):521-9, 2010 OS probability Erlotinib (n = 438), 12.0 months Placebo (n = 451), 11.0 months HR = 0.81 ( ) Log-rank p =

Brugger et al. J Clin Oncol 2009; 27(suppl):411s (abstract 8020). Number of Patients Hazard Ratiop-value ErlotinibPlacebo EGFR Mutation +a <.0001 EGFR Wild Type EGFR IHC <.0001 EGFR IHC – EGFR FISH EGFR FISH – KRAS Mutation KRAS Wild Type a Median PFS was 44.6 weeks in the erlotinib arm and 13.0 weeks in the placebo arm. Biomarker Analyses of the Phase III SATURN Trial: Progression-Free Survival Benefit

Fidias JCO 27:591 Ciuleanu, Belani Lancet 374:1432 Cappuzzo Lancet Oncol 11:521 Belani ASCO 2010 #7506 Perol ASCO 2010 #7507 FidiasBelaniCappuzzoBelaniPerol Immed vs Delayed Doc (n = 309) Pem vs Placebo (n = 663) Erlot vs Placebo* Gem vs Placebo (n = 255) Gem vs Placebo (n = 301) Erlot vs Placebo (n = 305) TypeSwitch Cont Switch Median OS, months 12.3 vs 9.7 p = vs 10.6 p = vs 11.0 p = vs 9.3 p =.838 HR 0.86HR 0.91 Median PFS, months 5.7 vs 2.7 p = vs 2.6 p < vs 2.6 † p < vs 7.7 p = vs 1.9 p < vs 1.9 p =.002 *n = 884 for PFS; n = 889 for OS † 12.3 weeks vs 11.1 weeks Recent Trials of Maintenance Therapy: Efficacy

 Bevacizumab –Was administered beyond chemotherapy in ECOG 4599 and AVAiL studies?  Cetuximab –Was given as monotherapy following combination therapy in FLEX and BMS-099 study? CONTINUATION Maintenance Therapy Is this definitive evidence of maintenance? NO

Randomized, placebo-controlled, double-blind, phase III study Folic acid and vitamin B12 administered to both arms Primary objective: Progression Free Survival (PFS) 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, ASCO 2011, #7510 PARAMOUNT: Study Design

Paz-Ares et al, J Clin Oncol 29:15s, 2011 (suppl; abstr CRA7510) PARAMOUNT: Independently Reviewed PFS Pem + BSC (n = 316) Placebo + BSC (n = 156) Median PFS* (months) Hazard ratio: 0.64, p = * 88% of patients were independently reviewed (472/539).

 PFS results were internally consistent; benefit was seen across all subgroups PARAMOUNT: Subgroup PFS Hazard Ratios Paz-Ares et al, J Clin Oncol 29:15s, 2011 (suppl; abstr CRA7510)

 Stage IIIB/IV Bev eligible NSCLC  PS 0-1  4 prior cycles of CarbTax + Bev (1236), with CR, PR, SD (864) Randomization factors:  gender  PS  stage  best tumor response to induction Pemetrexed 500 mg/m 2 (q21d) Primary Endpoint = OS B 12, folate, and dexamethasone given in Pem arms ECOG 5508 Phase III Study Design Maintenance Bev vs Pem vs Bev + Pem RANDOMIZERANDOMIZE Bevacizumab 15mg/kg (q21d) Pemetrexed 500 mg/m 2 (q21d) Bevacizumab 15mg/kg (q21d) Total 1236 patients with 864 randomized (288/arm)

 Approximately 45% of eligible patients are receiving maintenance therapy in the US---# is increasing  Patients with PS ≥2 are not candidates for maintenance  Even on close follow-up on a clinical trial approximately 30-40% of patients are unable to receive second-line therapy, eg, PS 2 patients  Increasing the cycle duration to 4 weeks in certain patients will lead to increased acceptance  The next step is to personalize maintenance therapy Maintenance Therapy US View

Saturday, February 11, 2012 Hollywood, Florida Faculty Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Chandra P Belani, MD John Heymach, MD, PhD Pasi A Jänne, MD, PhD Thomas J Lynch Jr, MD Heather Wakelee, MD