Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: A phase III study

Abstract

8011 Background: This multicenter phase III trial compared the efficacy and safety of pemetrexed (Pem) versus placebo (Plac) in pts with stage IIIB/IV NSCLC who had not progressed on four cycles of platinum-based induction chemotherapy. Per protocol, final analyses were completed for all outcomes except overall survival (OS). Sub-group analyses were based on results from prior studies. Methods: In this double-blind trial, pts were randomized (2:1 ratio; balanced for stage, ECOG PS, sex, response to induction therapy, non-platinum component of induction therapy, and brain metastases) 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 primary analysis of progression-free survival (PFS) was based on an unadjusted Cox HR (target n=660; alpha=0.05; power=85% to show HR<1.00 assuming 462 events and HR=0.75). Results: A total of 663 pts were enrolled (Pem=441; Plac=222). Pt characteristics were well balanced between arms: median age=61 years; 27% female; 39% PS 0, 60% PS 1; 19% Stage IIIB; 23% East Asian; 50% adenocarcinoma, 27% squamous cell, 3% large cell, and 20% other/indeterminate histology; 49% induction CR/PR; and 8% with brain metastases. Pem had better efficacy with respect to PFS (4.3 vs 2.6 mos [HR 0.502, 95% CI: 0.42–0.61, p <0.00001]) and tumor response (p <0.001), especially in non-squamous pts. With 55% censoring (all pts), preliminary OS was 13.0 mos with Pem and 10.2 mos with Plac (HR 0.798, 95% CI 0.63–1.01, p = 0.060). There were no significant toxicity differences between arms except for grade 3–4 anemia (Pem 4.5%, Plac 1.4%) and total SAEs due to drug (Pem 4.3%, Plac 0%). Conclusions: Post-induction maintenance therapy with Pem is well tolerated and offers superior PFS compared with Plac in pts with advanced NSCLC. This trial confirms that Pem has greater efficacy in patients with non-squamous histology. Median PFS (mos) HR p-value Objective Tumor Response (CR+PR+SD) p-value Pem Placebo Pem Placebo All patients 4.3 2.6 0.502 <0.00001 51.7 33.3 <0.001 Non-squamous (n=482) 4.5 2.6 0.444 <0.00001 57.7 32.7 <0.001 Adenocarcinoma (n=329) 4.7 2.6 0.452 <0.00001 61.0 33.0 <0.001 Large Cell (n=20) 3.5 2.1 0.400 0.109 45.5 33.3 0.670 Other (n=133) 4.2 2.8 0.433 0.0002 51.1 31.7 0.041 Squamous (n=181) 2.8 2.6 0.692 0.039 34.8 34.8 1.000 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company