Exploratory biomarker analyses from ECOG 4508: Three-arm randomized phase II study of carboplatin (C) and paclitaxel (P) in combination with cetuximab (CET), IMC-A12, or both for advanced non-small cell lung cancer (NSCLC) patients (pts).

Abstract

8106 Background: ECOG 4508 was a phase II study that randomized advanced NSCLC pts that were not candidates for bevacizumab to receive: C + P iv on day 1 every 3 wks with either CET iv weekly (arm A, n=39), IMC-A12 iv every 2 wks (arm B, n=42), or both (arm C, n=48). The study was closed prematurely due to safety concerns after 129 eligible pts were treated. The study failed to meet its primary objective (Hanna et al ASCO 2012). Methods: Tumor samples were analyzed by immunohistochemistry (IHC; EGFR, IGF-1R and IGF-2R expression), fluorescent in-situ hybridization (FISH; EGFR gene copy number) and DNA sequencing (EGFR, KRAS gene mutations). Time-to-event distributions were estimated using the Kaplan-Meier method, and differences were tested using the logrank test. Cox proportional hazards models were fitted to estimate hazard ratios. Results: Histology: 38% squamous cell, 39% adenocarcinoma, 2% BAC, 5% NOS and 6% other. OS was similar in EGFR FISH+ (Colorado classification system, n=30/70, 43%) vs EGFR FISH- pts (57%), (9.5 mos vs 8.6 mos, HR=0.62, p=0.08). For EGFR FISH+ pts, there was no difference in outcomes with CET (n=19, OS=9.7 mos, PFS=4.1 mos) vs no CET (n=11, OS=9.5 mos, PFS=5.5 mos). EGFR and KRAS mutations were detected in 6% (5/80) and 22% (6/27) of the pts respectively, but sample sizes were not large enough for robust testing. EGFR and IGFR IHC hybrid (H) scores were assessed on 98/102 available samples (Arm A=29, Arm B=34, Arm C=35). Median H scores (and range): IGF-1R: 190 (30-390), IGF-2R: 145 (20-350), EGFR membrane and cytoplasm: 190 (0-380) and EGFR membrane only: 160 (0-390). With IGF-1R and IGF-2R H score > 200, there was no association with OS (HR 1.3, p=0.26; HR 1.4, p=0.28) or PFS (HR=1.1, p=0.67; HR=1.2, p=0.56), adjusted for whether or not IMCA12 was received. Similarly, no associations with OS or PFS were seen with EGFR membrane H score > 200, adjusted for CET administration (OS HR=0.89, p=0.64; PFS HR 1.1, p=0.62). Conclusions: There was no correlation between EGFR FISH or H score and outcomes with CET. IGF-1R and IGF-2R expression was not predictive of favorable outcome with IMC-A12. Clinical trial information: NCI-2011-01976.