A phase II second-line study of pemetrexed (pem) in combination with bevacizumab (bev) in patients with advanced non-small cell lung cancer (NSCLC): An NCCTG and SWOG study.

8080 Background: This phase II study was performed to evaluate the clinical efficacy and toxicity of pem (500 mg/m2 iv) combined with bev (15mg/kg iv) given every 3 weeks in the 2nd-line therapy of patients (pts) with stage IV/IIIB (pleural effusion) NSCLC. Allelic variants in pem metabolizing genes were also evaluated and correlated with response and toxicity.,The proportion of progression-free (and still on treatment) pts at 3 months (success) was the primary endpoint. Based on a one-stage Fleming design with an exact significance level of 0.09 and 90% power to detect an effective treatment if the true success rate was at least 70%, this treatment would be promising if at least 26 of the first 42 evaluable patients were successes. Based on FPGS re-sequencing and SNP data mining studies, ht-SNPs in pem metabolizing and transport genes (FPGS, GGH, SLC19A1) were constructed. Germ-line DNA was genotyped for these SNPs Results: 48 pts (14 females; 34 males), all evaluable for adverse events (AEs) were accrued. All except one pt are off active treatment. Grade 3+ and 4+AEs occurred in 32 (67%) and 10 (21%) patients respectively. The most common (occurring in 10% or more of patients) grade 3/4 non-hematologic AEs were fatigue (13%), dyspnea (10%), and thrombosis (10%), and grade 3/4 hematologic AEs were neutropenia (19%), leukopenia (17%), and lymphopenia (13%). 24 of the first 42 pts (57%, Exact CI: 41-72%) met the success criteria. The overall disease control rate was 50% (5 confirmed partial response (CPR), 19 confirmed stable disease). In the 5 pts with a CPR, the median response duration was 133 days (range: 84-213). The median follow-up on alive pts is 9 months (m), with a median survival of 8.6 m and a median PFS of 4.1 m. Haplotype-tagged SNPs in GGH (pem inactivation) and reduced folate carrier, SLC19A1(pem transport) were significantly correlated with overall survival, PFS and AE.,With a median PFS of 4.1 m, this combination represents an improvement on the median PFS of 2.9 months for a number of single second-line agents and needs to be further studied. Pharmacogenetic studies in larger pt cohorts may predict for efficacy and/or toxicity to pem. No significant financial relationships to disclose.