Molecular determinants of response and resistance to anti-PD-(L)1 blockade in patients with NSCLC profiled with targeted next-generation sequencing (NGS).

Abstract

9015 Background: Anti-PD-(L)1 therapy has revolutionized treatment for patients (pts) with NSCLC. We previously reported that non-synonymous tumor mutation burden (TMB) by whole exome sequencing associates with immunotherapy benefit. Targeted NGS is increasingly routine in clinical practice and may be a useful tool for predicting benefit to anti-PD-(L)1 blockade. Methods: Pts had advanced NSCLC treated with anti-PD-(L)1 (+/- aCTLA-4) therapy and profiling by hybrid-capture NGS of 341-468 genes (MSK-IMPACT). Efficacy assessed by RECIST v1.1; durable clinical benefit (DCB) defined as PR or SD > 6mo. TMB and copy number alteration burden (“fraction of genome altered”, FGA) were normalized by size of genome covered. Comparisons were also made to a cohort of all NSCLCs profiled by MSK-IMPACT (n = 1679). Results: Of 437 evaluable pts treated with anti-PD-(L)1, 197 (45%) had NGS profiling, of whom 30% had DCB. TMB was higher in those with DCB vs no DCB (mean 10.2 vs 7.1 SNV/MB, p = 0.02) and compared to all NSCLCs ( < 0.0001). DCB was more common and PFS was longer in pts with > vs < 85th percentile TMB of all NSCLCs (Odds ratio 2.3, 95% CI 1.1-4.9, p = 0.03; HR = 0.59, p = 0.004), but were similar when dichotomized at the 50th or 75th percentile. FGA was higher in pts with no DCB compared to all NSCLCs (p = 0.02). Molecular signatures related to deficient homologous-recombination-based DNA repair and smoking were more common in DCB vs no DCB (p = 0.042, p = 0.058) and vs all NSCLCs (p = 0.026, p = 0.01). Compared to all NSCLCs profiled by NGS, alterations in STK11and EGFRwere enriched in no DCB (p = 0.0008, p = 0.02). Alterations in JAK2and CD274(PD-L1) were uncommon (2.1%, 1.6%) but exclusively associated with no DCB. For a subset (n = 52) of these cases also profiled by whole exome sequencing, comparison with targeted NGS will be presented. Conclusions: In pts with NSCLC, targeted NGS profiling is a routinely available tool that can provide insight into predicting benefit with anti-PD-(L)1 therapy. Increased TMB associates with clinical benefit. Increased copy number alterations (FGA) and alterations in genes including STK11, JAK2, and CD274 may associate with resistance to anti-PD-(L)1 therapy.