CA209-038 Melanoma Nivolumab (Riaz et al. 2017)

Overview

Riaz et al. profiled paired pre- and on-therapy biopsies from 68 advanced melanoma patients enrolled on the prospective CA209-038 trial (NCT01621490) of nivolumab (3 mg/kg q2w). Patients were stratified into ipilimumab-progressed (Ipi-P, n=35) and ipilimumab-naive (Ipi-N, n=33) cohorts. Combining whole-exome sequencing, RNA-seq, and TCR beta-chain sequencing on biopsies obtained pre-treatment and at cycle 1 day 29, the study establishes the genomic basis of tumor immunoediting on PD-1 blockade and characterizes the divergent response dynamics by prior immunotherapy exposure. Published in Cell (2017). The dataset is the genomic backbone of the iAtlas resource.

Composition

  • 68 advanced melanoma patients with paired biopsies — 35 previously progressed on ipilimumab (Ipi-P), 33 ipilimumab-naive (Ipi-N).
  • Median age 55 (range 22–89); stage distribution 1 M0 / 13 M1a / 10 M1b / 36 M1c / 8 unknown.
  • Response rates (RECIST v1.1): Ipi-N 21% CR/PR, Ipi-P 22% CR/PR.
  • Biopsies from the same anatomic site — pre-therapy (1–7 days before first dose) and on-therapy (cycle 1 day 29, between days 23–29).
  • Cancer type: Skin Cutaneous Melanoma (SKCM).
  • 85 patients accrued on the trial; 68 had sufficient material for genomic analysis.

Assays / panels (linked)

  • whole-exome sequencing — Agilent SureSelect All Exon V2 with HiSeq 2000/2500, mean depth 168×; somatic variant calling by intersection of MuTect 1.1.4, SomaticSniper, VarScan 2.3.7, and Strelka 1.0.13 (n=68 pre-therapy; n=41 paired pre/on)
  • RNA-seq — aligned with STAR on hg19, DESeq2-normalized FPKM, immune deconvolution by CIBERSORT (n=45 baseline; n=26 paired with WES)
  • TCR beta-chain sequencing — tumor DNA via Adaptive Biotechnologies immunoSEQ (n=34 paired pre/on)
  • FISH / IHC — PD-L1 (clone 28-8), CD3, CD4, CD8, FOXP3
  • FACETS v0.5.0 — allele-specific copy number; GISTIC for recurrent SCNAs; PyClone v0.13.0 — cancer cell fraction
  • NetMHCpan v4.0 — neoantigen prediction (9-mer sliding windows, rank < 2%)
  • GSEA — pathway analysis

Papers using this cohort

  • PMID:29033130 — Riaz et al., Cell (2017): Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.

Notable findings derived from this cohort

  • Pre-therapy tumor mutation burden (TMB) and clonal mutation load predict overall survival in ipilimumab-naive (Ipi-N) but not ipilimumab-progressed (Ipi-P) melanoma patients. Median cohort mutation load 183 (range 1–7360). PMID:29033130
  • Mutation and neoantigen load drop markedly on-therapy in responders (n=41 paired WES): mean 19% of pre-therapy variants retained in CR/PR vs 101% in PD (p=5.87e–5); consistent with active immunoediting. PMID:29033130
  • Net genomic contraction (variants undergoing mutational contraction minus persistence) predicts response and OS better than raw TMB change. PMID:29033130
  • Selective depletion of antigenic mutations on-therapy: neoantigen-to-non-antigenic mutation ratio dropped in CR/PR vs PD (p=0.03); number of expanded T-cell clones scales linearly with neoantigens becoming undetectable in responders (p=0.03). PMID:29033130
  • Focal CDKN2A loss emerged on-therapy in 4 PD patients; 3/4 had co-occurring chromosome-9p deletions encompassing the IFN gene cluster, suggesting acquired immune evasion. PMID:29033130
  • Immune checkpoint genes upregulated on-therapy in all patients regardless of response: PDCD1, CD274, CTLA4, LAG3, TNFRSF9, ICOS; additionally TNFRSF4, TIGIT, HAVCR2, VSIR selectively upregulated in responders. PMID:29033130
  • Diverging TCR-diversity dynamics by prior-therapy status: on-therapy CDR3 richness change associated with benefit in Ipi-P (p=0.016); evenness change associated with benefit in Ipi-N (p=0.036). PMID:29033130
  • Cytolytic activity (GZMA/PRF1 geometric mean) on-therapy associated with benefit in both Ipi-N (p=0.005) and Ipi-P (p=0.043) patients. PMID:29033130
  • Pre-existing immunity distinguishes responders: 189 DEGs between CR/PR vs PD pre-therapy; all Ipi-P responders showed a “hot tumor” phenotype pre-therapy. PMID:29033130
  • TCGA mutational subtypes (BRAF, RAS, NF1, triple-WT) did not stratify response to nivolumab. PMID:29033130

Sources

  • cBioPortal study ID: mel_iatlas_riaz_nivolumab_2017
  • Trial: NCT01621490 (CA209-038)
  • iAtlas resource (TCIA immunotherapy cohorts portal)

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