Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma

Nat Med. 2021 Feb;27(2):256-263. doi: 10.1038/s41591-020-01211-7. Epub 2021 Feb 8.

Abstract

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / immunology
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / immunology
  • Disease-Free Survival
  • Female
  • Humans
  • Immunotherapy / adverse effects
  • Interferon-gamma / genetics
  • Ipilimumab / administration & dosage*
  • Ipilimumab / adverse effects
  • Male
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Melanoma / pathology
  • Middle Aged
  • Mutation / genetics
  • Neoadjuvant Therapy / adverse effects
  • Neoplasm Staging
  • Nivolumab / administration & dosage*
  • Nivolumab / adverse effects
  • Recurrence

Substances

  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CTLA-4 Antigen
  • IFNG protein, human
  • Ipilimumab
  • Nivolumab
  • Interferon-gamma

Associated data

  • ClinicalTrials.gov/NCT02977052
  • ClinicalTrials.gov/NCT02437279