Pharmacogenomic analysis from a phase III study of pemetrexed plus carboplatin (PC) versus etoposide plus carboplatin (EC) in chemonaive patients (pts) with extensive-stage disease small cell lung cancer (ED-SCLC)

Abstract

8030 Background: We have reported results of a randomized phase III trial in chemonaive patients with ED-SCLC comparing PC to EC. Study enrollment was closed for futility but pharmacogenomic endpoints were not reported. Here we report the results of immunohistochemistry (IHC) analysis from tumor tissues and single nucleotide polymorphism (SNP) analysis of selected genes implicated in pemetrexed, carboplatin, or etoposide activity. Methods: Proteins studied by validated IHC on Benchmark XT were thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyl transferase (GARFT), and folylpolyglutamate synthetase (FPGS). SNP data from whole blood were genotyped by massArray mass spectrometry from 611 samples. One hundred fifty-eight SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylene tetrahydrofolate reductase (MTHFR), folate receptor- α (FR-α), solute carrier 19A1 (SLC19A1) and adjacent regions. Allele frequency and Hardy-Weinberg equilibrium were calculated for each SNP. Results: Of 408 tissue samples (from 908 enrolled pts) available for IHC, 336 samples were assayed for > 1 assay target. The IHC analyses showed improved OS in the EC arm relative to the PC arm for patients with low TSnuclear (12.9 vs 7.5 month, p < 0.001, interaction p value = 0.017). There was no differential treatment effect within the PC arm for low vs. high TS. High vs low ERCC1 levels did not predict outcome following C exposure. GARFT was not associated with outcome by treatment. SNP rs2838952 (adjacent to SLC19A1) was significant for improved OS (HR = 0.590, p = 0.01) in both study arms. SNP rs12379987 (FPGS) was significantly associated with treatment for OS (interaction p value = 0.036). Exploratory analyses found associations between additional SNPs and PFS within and across treatments. Conclusions: Pharmacogenomic analyses of tumor samples show that low TSnuclear expression correlates with OS in the EC arm. Two germline SNPs in regions including FPGS and SLC19A1 were associated with better OS. Further analysis of these pharmacogenomic results is ongoing. [Table: see text]