169O - Et: a Randomized, Multicenter, Phase III Trial of Platinum Versus Nonplatinum Chemotherapy, After Ercc1 Stratification, in Patients with Advanced/Metastatic Non-Small Cell Lung Cancer (Nsclc)

Abstract

ABSTRACT Aim: Increased expression of excision repair cross-complementing group 1 (ERCC1) protein might be associated with platinum resistance in NSCLC, based on retrospective and meta-analyses findings. We conducted the first ever trial to prospectively evaluate ERCC1 as a predictive marker: to assess whether non-platinum therapy is superior to platinum for ERCC1 + ve, and non-inferior for ERCC1-ve tumors. Methods: Pts with stage IIIB/IV NSCLC (chemo-naive, tissue biopsy available, ECOG PS 0-1) were randomised to receive either platinum-based or non-platinum doublet chemotherapy, after ERCC1 stratification using a recommended monoclonal antibody (clone 8F1) assessed centrally. Pts with squamous (sq) histology had cisplatin/gemcitabine (CG) or paclitaxel/gemcitabine (PG); non-squamous (non-sq) pts had cisplatin/pemetrexed (CP) or paclitaxel/pemetrexed (PP), every 3 wks for up to 6 cycles. Primary endpoint was overall survival (OS). From 2012, we concurrently used another recommended antibody (clone 3F2) specific for XPF/ERCC1 protein complex. Results: 648 pts were recruited from 85 UK centres. Baseline characteristics were balanced for both sq (n = 177) and non-sq (n = 471) pts. Recruitment stopped in 2012 for sq pts because PG OS was inferior to CG, regardless of ERCC1 status: median OS 7.7 vs 11.2 months, HR = 1.54 (95% CI 1.05-2.26, P = 0.03). We stopped accrual in 2013 when main trial objective could not be met for non-sq pts: preliminary OS HR for ERCC1 + ve tumors 1.08 (95%CI 0.75-1.54, P = 0.68), median OS 9.7 (PP) vs 10.9 (CP) months. For ERCC1-ve tumors, HR 0.94 (0.62-1.43, P = 0.79), median OS 9.5 (PP) vs 8.4 (CP) months. HRs using XPF antibody were ERCC1 + ve tumors 1.10 (0.76-1.61, p = 0.61), and ERCC1-ve tumors 1.21 (0.65-2.24, p = 0.54). Findings for progression-free survival were similar. ERCC1 positive rate in non-sq pts was 54% (8F1) or 71% (XPF); 28% of pts had discordant ERCC1 status. Grade 3/4 hematological toxicities were less common with non-platinum therapy: 31% (CG) vs 17% (PG), and 22% (CP) vs 17% (PP). Conclusions: Selecting platinum or non-platinum chemotherapy prospectively based on either of two recommended ERCC1 antibodies in advanced NSCLC did not influence survival. Our prospective data support recent concerns over the reliability of current ERCC1 antibody performance as a predictive biomarker of resistance to platinum-based therapy. Disclosure: All authors have declared no conflicts of interest.