MSK NSCLC Anti-PD-1 Prospective Cohort (2018)

Overview

Retrospective cohort of 240 patients with advanced non-small-cell lung cancer (NSCLC) treated with anti-PD-(L)1 therapy at Memorial Sloan Kettering Cancer Center between April 2011 and January 2017, all profiled by MSK-IMPACT targeted next-generation sequencing. The primary scientific contribution of this cohort was establishing that tumor mutation burden (TMB) measured on a targeted panel correlates with whole-exome estimates and predicts durable clinical benefit from immunotherapy in NSCLC. A separate comparison cohort of 1,836 non-ICI-treated NSCLC patients sequenced on MSK-IMPACT 2014–2017 was included for prognostic vs. predictive discrimination. PMID:29337640

Composition

  • 240 advanced NSCLC patients treated with anti-PD-1 or anti-PD-L1 therapy (alone or with anti-CTLA-4) at MSKCC. PMID:29337640
  • Histology: 78% adenocarcinoma (LUAD), 14% squamous (LUSC), 8% other. PMID:29337640
  • Treatment: 86% PD-(L)1 monotherapy (nivolumab, pembrolizumab, atezolizumab, durvalumab); 14% PD-(L)1 + CTLA-4 combination (ipilimumab). PMID:29337640
  • Endpoints: RECIST 1.1; durable clinical benefit (DCB) = CR/PR/SD lasting >6 months; no durable benefit (NDB) = PD or SD ≤6 months. 49 (20%) had CR/PR; 69 (29%) had DCB; 158 (66%) NDB. PMID:29337640
  • Validation subset: 49 patients had paired whole-exome sequencing for TMB correlation. PMID:29337640
  • PD-L1 IHC: Available for 84 patients (22C3, 28-8, E1L3N antibodies). PMID:29337640
  • Comparison cohort: 1,836 non-ICI-treated NSCLC patients sequenced on MSK-IMPACT 2014–2017 (to assess prognostic vs. predictive nature of TMB). PMID:29337640

Assays / panels (linked)

Papers using this cohort

  • PMID:29337640 — Rizvi et al. 2018, Journal of Clinical Oncology — “Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing”

Notable findings derived from this cohort

  • TMB by MSK-IMPACT correlated with TMB by whole-exome sequencing (Spearman r=0.86, P<0.001), validating targeted panel as a practical TMB surrogate. PMID:29337640
  • Median TMB was significantly higher in DCB vs. NDB patients (8.5 vs. 6.6 SNVs/Mb, P=0.006); DCB rate above the 50th TMB percentile was 38.6% vs. 25.1% below (P=0.009). PMID:29337640
  • TMB is predictive, not prognostic: in the non-ICI comparison cohort, higher TMB was associated with worse survival, ruling out a generic favorable prognosis effect. PMID:29337640
  • TMB and PD-L1 are independent predictors (r=0.19, P=0.08); combining TMB-high + PD-L1 ≥1% gave 50% DCB rate vs. 18% when both low. PMID:29337640
  • EGFR-mutant tumors were underrepresented in DCB (7% of EGFR-mutant patients achieved DCB; FDR-adjusted P=0.013). PMID:29337640
  • STK11 mutations were enriched in NDB (FDR-adjusted P=0.007 vs. non-ICI cohort), consistent with LKB1-loss driving low tumor inflammation. PMID:29337640
  • High fraction of copy-number-altered genome (FGA) was enriched in NDB patients (median 0.16 vs. 0.11, P=0.007). PMID:29337640
  • MDM2/MDM4 amplification (n=8) did not show hyperprogression in this series (HR 1.4, P=0.44), in contrast to prior reports. PMID:29337640

Sources

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