1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

2. 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)

3.  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?

4.  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

5.  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

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

7. Stage IIIB/IV NSCLC 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 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):1432-40, 2009 Belani et al, J Clin Oncol 28:7s, 2010 (suppl; abstr 7506)

8. Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in Advanced NSCLC Ciuleanu…Belani, Lancet 374(9699):1432-40, 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 (0.56-0.88)0.002 OS, squamous (n = 182) 9.9 mo10.8 mo1.07 (0.49-1.73) 0.678

9. Effect of Response to Induction on OS in JMEN Ciuleanu…Belani, Lancet 374(9699):1432-40, 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) 0.19854 OS, nonsquamous pts with SD 16.6 mo8.6 mo0.61 (0.45, 0.83)0.00171

10.  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

11.  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 1.9 3.8 PFS at 3 mo, % 30.3 55.0 PFS at 6 mo, % 8.622.1 PFS by independent review, gemcitabine versus observation HR = 0.55 (0.43-0.70) Log-rank test, p < 0.0001 Observation N = 152 Erlotinib N = 153 Median PFS, mo 1.9 2.9 PFS at 3 mo, % 30.335.3 PFS at 6 mo, % 8.616.3 PFS by independent review, erlotinib versus observation HR = 0.82 (0.73-0.93) Log-rank test, p = 0.002

12. 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%)

13. *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 (0.70-0.95) Log-rank p = 0.0088

14. Brugger et al. J Clin Oncol 2009; 27(suppl):411s (abstract 8020). Number of Patients Hazard Ratiop-value ErlotinibPlacebo EGFR Mutation +a 22270.10<.0001 EGFR Wild Type1991890.78.0185 EGFR IHC + 3073110.69<.0001 EGFR IHC – 62590.77.01768 EGFR FISH + 1211100.68.0068 EGFR FISH – 1281270.81.13 KRAS Mutation + 49410.77.2246 KRAS Wild Type2051980.70.0009 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

15. 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 =.0853 13.4 vs 10.6 p =.012 12.0 vs 11.0 p =.0088 8.0 vs 9.3 p =.838 HR 0.86HR 0.91 Median PFS, months 5.7 vs 2.7 p =.0001 4.3 vs 2.6 p <.0001 2.8 vs 2.6 † p <.0001 7.4 vs 7.7 p =.575 3.8 vs 1.9 p <.0001 2.9 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

16.  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

17. 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

18. 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) 3.92.6 Hazard ratio: 0.64, p = 0.0002 * 88% of patients were independently reviewed (472/539).

19.  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)

20.  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)

21.  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

22. 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