P1.01-09 Randomized Trial Comparing Maintenance Pemetrexed with Observation Followed by Pemetrexed at Progression in Advanced NSCLC

Previous placebo-controlled studies show that maintenance treatment with pemetrexed prolongs progression free survival (PFS) and overall survival (OS) in advanced non-squamous non-small-cell lung cancer (NSCLC) patients who do not progress on induction platinum-doublet chemotherapy. There were, however, a few limitations of these studies: Few on the control arms received pemetrexed at progression, few patients >70 years were enrolled, and patients with performance status 2 (PS2) were ineligible. In this open phase III trial, patients with stage IIIB/IV non-squamous NSCLC ineligible for curative treatment who had PS 0-2, and non-progression after four courses of carboplatin (AUC=5) day 1 + vinorelbine (25 mg/m2 IV day 1 and 25 mg/m2 IV or 60 mg/m2 PO day 8) were randomized to receive immediate pemetrexed maintenance therapy or observation followed by pemetrexed at progression. There was no upper age limit. The primary endpoint was OS, secondary endpoints were PFS and toxicity. To demonstrate an improvement in median OS from 6 to 8 months (from the time of randomization) with an α=0.05 and β=0.20, 198 patients were required on each arm. Accounting for a drop-out of maximum 10%, we aimed to randomize 436 patients. 105 patients were randomized between May 2014 and September 2017 at 19 hospitals in Norway (maintenance: n= 54, observation: n=51). Inclusion was stopped prematurely due to poor recruitment after immunotherapy became available. Median age was 67 years (range 46-83), 34% were >70 years, 14% had PS 2, 93% stage IV, and 54% were women. 75% of the patients received pemetrexed at progression. The median number of pemetrexed courses were 4 (maintenance: 3, observation: 4; p=0.265). Patients in the maintenance-arm had a significantly longer PFS (median 3.1 vs. 1.9 months; p=0.02), and a 2 months longer median OS (12.0 vs. 10.0 months; p=0.10). In a Cox regression analysis adjusting for baseline patient and disease characteristics (gender, stage of disease, PS), there was a trend towards a statistically significant difference in OS (HR 0.67 95% CI 0.436-1.030; p=0.068). There were no significant differences in toxicity between those who received maintenance therapy and those who received pemetrexed at progression. Maintenance pemetrexed therapy prolongs PFS and with a trend towards improved OS in non-squamous NSCLC compared with observation followed by pemetrexed at progression in a cohort including more elderly patients than previous studies of maintenance pemetrexed therapy and when allowing PS2 patients.