Belani CP et al. ASCO 2009; Abstract CRA8000. (Oral Presentation)

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Belani CP et al. ASCO 2009; Abstract CRA8000. (Oral Presentation) Maintenance Pemetrexed Plus Best Supportive Care (BSC) versus Placebo Plus BSC: A Phase III Study in NSCLC Belani CP et al. ASCO 2009; Abstract CRA8000. (Oral Presentation)

Introduction Optimal duration of treatment with 1st-line platinum-doublet is 4-6 cycles Treatment guidelines recommend waiting until disease progression to administer 2nd- and 3rd-line regimens Recent studies of maintenance therapy (sequential, consolidation, “switch” to a new agent), following 1st-line therapy, have not demonstrated a survival benefit Current study objectives: Evaluate pemetrexed, a multitargeted antifolate, as maintenance therapy in patients with advanced NSCLC who have not progressed on 4 cycles of first-line platinum-based chemotherapy Source: Belani CP et al. ASCO 2009; Abstract CRA8000.

Phase III Randomized, Double-Blind Placebo-Controlled Trial Pemetrexed 500 mg/m2 (d1 q3wks) + best supportive care (BSC) (N = 441)* Eligibility Stage IIIB/IV NSCLC 4 prior cycles of platinum + taxane or gemcitabine, with complete or partial response (CR or PR) or stable disease (SD) 2 R Placebo (d1 q3wks) + BSC (N = 222)* 1 *B12, folate, and dexamethasone administered in both arms Source: Belani CP et al. ASCO 2009; Abstract CRA8000.

Efficacy: Progression-Free and Overall Survival (N = 663) Placebo Pemetrexed Hazard ratio P value Progression-free survival 2.0 mos 4.0 mos 0.60 <0.00001 Non-squamous (n = 481) Squamous (n = 182) 1.8 mos 2.5 mos 4.4 mos 2.4 mos 0.47 1.03 0.896 Overall survival (ITT) 10.6 mos 13.4 mos 0.79 0.012 10.3 mos 10.8 mos 15.5 mos 9.9 mos 0.70 1.07 0.002 0.678 Source: Belani CP et al. ASCO 2009; Abstract CRA8000.

Efficacy: Response Rate and Disease Control Rate* Placebo Pemetrexed P value Response rate (CR + PR)* 0.5% 3.4% 0.042 Disease control rate (CR + PR + SD)* 28.9% 49.1% <0.001 *Tumor response based on independently reviewed population (N = 581) Source: Belani CP et al. ASCO 2009; Abstract CRA8000.

Post-Study Systemic Therapy Placebo (n = 222) Pemetrexed (n = 441) Patients with post-study therapy 67% 52% EGFR TKI (erlotinib or gefitinib) 31% 35% Taxane (docetaxel or paclitaxel) 26% Vinorelbine 17% 13% Platinum agent (cis- or carboplatin) 16% 12% Gemcitabine 14% 9% 19% 1% Source: Belani CP et al. ASCO 2009; Abstract CRA8000.

Summary and Conclusions The use of pemetrexed in this study is the first randomized, double-blind, placebo-controlled study demonstrating a significant OS benefit with maintenance therapy in advanced NSCLC (13.4 mos vs 10.6 mos, HR = 0.79, p = 0.012) Non-squamous histology predictive of improved efficacy with pemetrexed (OS of 15.5 mos vs 10.3 mos, HR = 0.70, p = 0.002) No OS benefit for patients with squamous histology Pemetrexed is well tolerated and devoid of cumulative toxicity Grade III/IV AEs in ≤ 5% of patients with pemetrexed Increased Grade III/IV fatigue (5% vs 1%) and neutropenia (3% vs 0%) with pemetrexed Source: Belani CP et al. ASCO 2009; Abstract CRA8000.

Implications for Pemetrexed Trial Only 19% of patients on the placebo arm received pemetrexed Would survival benefit be preserved if more patients received pemetrexed after progression, as delayed 2nd-line therapy? The current study does not definitively prove that a maintenance strategy improves survival Do any patients need maintenance treatment prior to disease progression? Yes, some would benefit Do all patients require it? Definitely not. Many patients will be unnecessarily overtreated ~30% of patients can still enjoy a treatment holiday for 3-6 months Frequent, close follow-up is necessary to avoid losing the opportunity to treat patients Source: Hanna NJ. ASCO 2009; Lung Oral Metastatic Discussion.