MSKCC NSCLC Pembrolizumab Cohort (Rizvi 2015)

Overview

Two independent cohorts of advanced non-small cell lung cancer (NSCLC) patients treated with the anti-PD-1 antibody pembrolizumab at Memorial Sloan Kettering Cancer Center; paired tumor/normal whole-exome sequencing used to characterize somatic mutation burden and its relationship to anti-PD-1 response. The study was published in Science in 2015 by Rizvi et al. (DOI: 10.1126/science.aaa1348). Data are deposited at cBioPortal (study “Rizvi lung cancer”) and dbGaP (phs000980.v1.p1).

Composition

  • Discovery cohort: n=16 advanced NSCLC patients treated with pembrolizumab.
  • Validation cohort: n=18 advanced NSCLC patients treated with pembrolizumab.
  • 34 paired tumor/normal exomes total.
  • PD-L1 expression measured on 30/34 patients; cohort was enriched for PD-L1 expression (24/30 with detectable expression).
  • Cancer type: NSCLC.

Assays / panels (linked)

  • whole-exome-seq — mean target coverage 164×; 94.5% of target covered ≥10×. Orthogonal Ampliseq resequencing of 376 variants confirmed 357 (95%).
  • pd-l1-ihc-22c3 — PD-L1 expression by clone 22C3 (Merck) on 30/34 patients.
  • HLA class I-restricted neoantigen prediction (mutant nonamers ≤500 nM binding) and MHC multimer screening on serially collected peripheral blood lymphocytes.

Papers using this cohort

  • PMID:25765070 — Rizvi et al. (2015). Whole-exome sequencing of 34 pembrolizumab-treated NSCLC tumors; established nonsynonymous mutation burden as a predictive biomarker for durable clinical benefit and demonstrated neoantigen-specific T cell expansion paralleling tumor regression.

Notable findings derived from this cohort

  • Higher nonsynonymous somatic mutation burden significantly associated with durable clinical benefit (DCB), objective response rate, and progression-free survival in both discovery and validation cohorts; pooled analysis (n=34) Mann-Whitney P=0.0008, PFS HR 0.19 (95% CI 0.08–0.47, P=0.0004). PMID:25765070
  • A cutoff of ≥178 nonsynonymous mutations showed discovery sensitivity 100%/specificity 67% and validation sensitivity 86%/specificity 75% for predicting DCB. PMID:25765070
  • A molecular smoking signature (transversion-high classifier) stratified outcomes more powerfully than self-reported smoking history (PFS HR 0.15, P=0.0001 vs P=0.29 for self-reported). PMID:25765070
  • Neoantigen burden (median 112/tumor, range 8–610) strongly correlated with mutation burden (Spearman ρ=0.91) and DCB (median 203 vs 83 neoantigens, P=0.001). PMID:25765070
  • Deleterious mutations in POLD1, POLE, and MSH2 identified a never-smoker subset reaching the high-burden state via DNA repair/replication defects. PMID:25765070
  • In one exceptional responder, anti-PD-1 induced a CD8+ T cell response specific for a HERC1 P3278S neoantigen (HLA-A-restricted; ASNASSAAK) that paralleled radiographic tumor regression, directly linking mutation-derived neoantigen recognition to clinical efficacy. PMID:25765070
  • Mutation burden stratified outcomes within PD-L1-positive tumors, suggesting mutation burden and PD-L1 IHC capture complementary information. PMID:25765070

Sources

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