A randomized phase II study of pemetrexed (PEM) with or without sorafenib (S) as second-line therapy in advanced non-small cell lung cancer (NSCLC) of nonsquamous histology: NCCTG N0626 study.

Abstract

7513 Background: Based on preclinical data of additive cytotoxicity with sorafenib (S) and pemetrexed (PEM), this randomized phase II study was done to evaluate the safety and efficacy of the combination of S plus PEM vs PEM alone, as second line treatment of non-squamous NSCLC (determined by central pathology review). Methods: A lead-in phase to determine the tolerability of S plus PEM was followed by a 1:1 randomization of either PEM 500 mg/m2 q21 days plus S 400 mg p.o. BID for 21 days (arm A) or PEM 500 mg/m2 q21 days (arm B). The primary endpoint was progression-free survival (PFS). 47 patients (pts) per arm provided 82% power to detect an increase in the median PFS from 3.0 to 5.5 months (mos), with a 1-sided alpha of 0.05. Polymorphisms in VEGFA, VEGFR1-3, FPGS, GGH, SLC19A1 and TYMS were evaluated in germline DNA and correlated with outcomes. Results: One-hundred evaluable pts were randomized (49-A, 51-B). Baseline age, gender, and ECOG performance status were balanced between arms (p > 0.24). Prior exposure to bevacizumab (BEV) was 43% in A and 59% in B. Median number of cycles was 2 (1-31) on A and 4 (1-22) on B. A had a significantly increased rate of grade 3 non-hematologic (NH) adverse events (AE) (76% vs. 39%, p < 0.001). Grade 4/5 NH AE rates were similar for A and B (14% vs. 16%, p=1.00). No significant difference in grade 4 hematologic AE (20% vs 10.0%, p = 0.17). The overall median follow-up was 13.6 mos (1.6-27.8). PFS and OS was similar (PFS: A=3.4 mos vs B=4.1 mos, p = 0.22; OS: A=9.4 mos, B=9.7 mos, p=0.49). In arm A, the median PFS for patients with no prior BEV exposure was 2.8 mos compared to 5.0 mos in those with prior BEV exposure (p=0.06). In arm B, the median PFS was 3.5 vs 4.2 mos (p=0.91). The CT+TT genotypes of VEGFA rs3025039 was associated with worse PFS in A than in B (interaction p=0.03). Conclusions: Although the trial did not meet the protocol specified success criteria, post-hoc sub group analyses suggests a marginal improvement in PFS for patients on S plus PEM with prior exposure to BEV. Polymorphisms in VEGFA appear to predict for a worse outcome in patients receiving S. These preliminary findings warrant further investigation.