Chandra P Belani, MD Deputy Director Penn State Cancer Institute

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

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. Maintenance Therapy: Strategies • 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

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. Phase III Trial of Maintenance Pemetrexed in Advanced NSCLC Double-blind, Placebo-controlled, Multicenter, Phase III Trial Pemetrexed 500 mg/m2 (d1, q21d) + BSC (N = 441)* 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 2:1Randomization Primary Endpoint = PFS Placebo (d1, q21d) + BSC (N = 222)* *B12, folate, and dexamethasone given in both arms 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)

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)

10. IFCT-GFPC 0502: Study Design • 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)

11. Patients who received 2nd-line pemetrexed: 73% (Obs), 55% (Gem), and 60% (Erl) Grade 3-4 treatment-related AEs were more common in Gem (27%) andErl (14%) than in Obs (2%) IFCT-GFPC 0502: Results PFS by independent review, gemcitabine versus observation PFS by independent review, erlotinib versus observation HR = 0.55 (0.43-0.70)Log-rank test, p < 0.0001 HR = 0.82 (0.73-0.93)Log-rank test, p = 0.002 Perol et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7507)

12. SATURN Study Design Erlotinib 150 mg/day PD Chemonaïve advanced NSCLC n = 1,949 4 cycles of first-line platinum doublet chemotherapy* • 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 Non-PD n = 889 (46%) 1:1 Placebo PD Mandatory tumor sampling • 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 Cappuzzo et al, Lancet Oncol, 11(6):521-9, 2010

13. SATURN Survival* All Patients (ITT) • 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 *OS is measured from time of randomization into the maintenance phase;ITT = intent-to-treat population Cappuzzo et al, Lancet Oncol, 11(6):521-9, 2010

14. Brugger et al. J Clin Oncol 2009; 27(suppl):411s (abstract 8020). Biomarker Analyses of the Phase III SATURN Trial: Progression-Free Survival Benefit a Median PFS was 44.6 weeks in the erlotinib arm and 13.0 weeks in the placebo arm.

15. Fidias JCO 27:591 Ciuleanu, Belani Lancet 374:1432 Cappuzzo Lancet Oncol 11:521 Belani ASCO 2010 #7506 Perol ASCO 2010 #7507 *n = 884 for PFS; n = 889 for OS †12.3 weeks vs 11.1 weeks Recent Trials of Maintenance Therapy: Efficacy

16. CONTINUATION Maintenance Therapy • 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? Is this definitive evidence of maintenance? NO

17. PARAMOUNT: Study Design Study Treatment Period Induction Therapy (4 cycles) 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/m2 Pemetrexed + BSC, d1, q21d CR, PR, SD 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) 500 mg/m2 Pemetrexed +75 mg/m2 Cisplatin, d1, q21d PD Randomized, placebo-controlled, double-blind, phase III study Folic acid and vitamin B12 administered to both arms Primary objective: Progression Free Survival (PFS) Paz Ares, ASCO 2011, #7510

18. PARAMOUNT: Independently Reviewed PFS *88% of patients were independently reviewed (472/539). Paz-Ares et al, J Clin Oncol 29:15s, 2011 (suppl; abstr CRA7510)

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

20. ECOG 5508 Phase III Study Design Maintenance Bev vs Pem vs Bev + Pem Primary Endpoint = OS • 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 RANDOMIZE Pemetrexed 500 mg/m2 (q21d) 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)

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