Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC)

Abstract

CRA8000 Background: Pemetrexed's efficacy, favorable tolerability profile, and ease of administration provided a strong rationale for evaluation as maintenance therapy in patients (pts) with advanced NSCLC. We present the final analyses for all outcomes, including overall survival (OS), from a phase III study of Pem vs. Plac (Ciuleanu, J Clin Oncol 26, 2008, A 8011) in pts with stage IIIB/IV NSCLC who had not progressed on four cycles of platinum-based chemotherapy. Methods: In this double-blind trial, pts were randomized 2:1 to receive Pem (500 mg/m2, day 1) plus BSC or Plac plus BSC in 21-day cycles until disease progression. All pts received vitamin B12, folic acid, and dexamethasone. The final OS analysis was performed using an unadjusted Cox model. Overall α = 0.05 for PFS and OS. Results: In the 663 randomized pts (Pem 441: Plac 222), Pem resulted in significantly better OS (13.4 vs. 10.6 mos [HR 0.79, 95% CI: 0.65–0.95, P = 0.012]). As reported earlier, Pem also had better PFS (P <0.00001) and response (P <0.001) (Table). The improvements in PFS and OS were observed primarily in patients with non-squamous histology (PFS HR = 0.47 and OS HR = 0.70). Treatment by histology interaction for OS was significant (P = 0.038). Drug-related grade 3/4 toxicities were higher for Pem (16% vs 4%; P <0.001); specifically, fatigue (5% vs 0.5%) and neutropenia (2.9% vs. 0%). Grade 3/4 toxicities did not increase significantly in pts who received ≥6 and ≥10 cycles of Pem. There were no Pem-related deaths. Fewer pts in the Pem arm (51.5% vs 67.1%; P <0.001) received systemic post-discontinuation therapy. Conclusions: Pem maintenance therapy is well tolerated and offers superior OS and PFS compared with Plac, making it a new treatment paradigm for patients with advanced NSCLC who respond to initial therapy. This trial further validates that Pem has greater efficacy in patients with non-squamous histology. Median OS months p value (HR) Median PFS,* months p value (HR) CR+PR+SD,* % p value Pem Placebo Pem Placebo Pem Placebo Overall population 13.4 10.6 0.012 (0.79) 4.3 2.6 <0.0001 (0.50) 51.7 33.3 <0.001 Nonsquamous (n=482) 15.5 10.3 0.002 (0.70) 4.37 1.84 <0.00001 (0.47) 54.3 26.6 <0.001 Adeno (n=329) 16.8 11.5 0.026 (0.73) 4.60 2.66 <0.00001 (0.51) 58.2 29.6 <0.001 Large Cell (n=20) 8.4 7.9 0.964 (0.98) 4.53 1.45 0.104 (0.40) 30.0 25.0 0.999 Other (n=133) 11.3 7.7 0.025 (0.61) 4.11 1.58 0.0001 (0.44) 47.5 18.9 0.004 Squamous (n=181) 9.9 10.8 0.678 (1.07) 2.43 2.50 0.896 (1.03) 33.3 34.5 1.000 * Independent review data. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company AstraZeneca, Eli Lilly and Company, Pfizer, Roche Eli Lilly and Company