Excision repair cross complementation group 1 (ERCC-1) gene polymorphisms and response to nivolumab in advanced non-small cell lung cancer (NSCLC).

Abstract

3032 Background: Anti PD1 antibodies showed significant clinical activity in different cancer types. Recently, it was observed that cancers with higher somatic mutation burden, as tumors with genome instability due to DNA repair defects, develop more elevated anti PD1 induced neoantigen specific T cell reactivity which results into increased susceptibility to PD1 blockade. We hypothesize that NSCLC pts with single nucleotide polymorphisms (SNPs) of the ERCC-1 gene, a key enzyme of DNA nucleotide excision repair pathway, may be more responsive to PD-1 blockade due to their genetic instability. Methods: We evaluated the rs11615 and rs3212986 ERCC1 SNPs by pyrosequencing analysis on tumor DNA of stage IIIb-IV previously treated NSCLC patients receiving Nivolumab (Nivo) 3 mg/kg q2w. To be eligible for this study, pts had to have a complete record of clinical and radiological parameters. Objective tumour response was assessed according to RECIST 1.1 criteria. Results: Between Jul 2015 and Jan 2016, 45 NSCLC pts received Nivo. Pts characteristics were as follows: M/F = 37/8; median age (range) = 64 (38-80); ECOG PS, 0/1/2 = 33/9/3; Stage IIIb/IV = 8/37; sqNSCLC/non sq NSCLC = 11/34; current-former smokers/non-smokers = 40/5; EGFR status, mutant/wildtype/unknown = 4/35/6; median cycles (range) = 12 (1-28). Only two pts presented the rs11615 SNP. 16 pts were positive for the rs3212986 SNP. ORR for all pts was 26.6% (95% CI, 10 to 47). The ORR was significantly higher in NSCLC pts positive for the rs3212986 SNP than for wild-type NSCLC patients (62.5% vs. 6.9%. p = 0.0001). For all pts median PFS was 4.3 mos (95% CI, 1.2 to 7.4)and median OS not-reached. Among pts positive for the rs3212986 SNP, median PFS and OS were 8.2 mos and not-reached respectively. In contrast wild-type patients presented a median PFS of 3.1 mos (HR = 0.21 95% CI, 0.07 to 0.57; p = 0.02) and a median OS of 6.5 mos (HR = 0,403 95% CI = 0,131-1,237 p = 0.11). Multivariate analyses confirmed the effect of rs3212986 SNP after adjustment for age, PS, sex and disease stage for PFS. Conclusions: This study suggests that genetic instability due to tumor ERCC1 SNPs in advanced NSCLC pts may be of value to predict clinical benefit from Nivo.