Phase II clinical and immune correlate study of adjuvant nivolumab plus ipilimumab for high-risk resected melanoma
Year: 2022
Type: article
Study design: Clinical Trial
Abstract: BACKGROUND: Adjuvant therapy for high-risk resected melanoma with programmed cell-death 1 blockade results in a median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of adjuvant nivolumab (NIVO) in CheckMate-915 did not result in increased RFS. A pilot phase II adjuvant study of either standard dose or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative biomarker studies. METHODS: Patients with resected stages IIIB/IIIC/IV melanoma received either IPI 3 mg/kg and NIVO 1 mg/kg (cohort 4) or IPI 1 mg/kg and NIVO 3 mg/kg (cohorts 5 and 6) induction therapy every 3 weeks for 12 weeks, followed by maintenance NIVO. In an amalgamated subset of patients across cohorts, peripheral T cells at baseline and on-treatment were assessed by flow cytometry and RNA sequencing for exploratory biomarkers. RESULTS: High rates of grade 3-4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of the patients in cohorts 4, 5 and 6, respectively. At a median of 63.9 months of follow-up, 16/56 patients (29%) relapsed. For all patients, at 5 years, RFS was 71% (95% CI: 60 to 84), and overall survival was 94% (95% CI: 88 to 100). Expansion of CD3+CD4+CD38+CD127-GARP- T cells, an on-treatment increase in CD39 expression in CD8+ T cells, and T-cell expression of phosphorylated signal-transducer-and-activator-of-transcription (STAT)2 and STAT5 were associated with relapse. CONCLUSIONS: Adjuvant IPI/NIVO at the induction doses used resulted in promising relapse-free and overall survival, although with a high rate of grade 3-4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T cells and STAT signaling pathways with relapse, warranting future validation. TRIAL REGISTRATION NUMBER: NCT01176474 and NCT02970981.
Authors: Nikhil I Khushalani, Melinda Vassallo, Judith D Goldberg, Zeynep Eroglu, Younchul Kim, Biwei Cao, Robert Ferguson, Kelsey R Monson, Tomas Kirchhoff, Carol M Amato, Paulo Burke, Ann Strange, Emily Monk, Geoffrey Thomas Gibney, Ragini Kudchadkar, Joseph Markowitz, Andrew S Brohl, Anna Pavlick, Alison Richards, David M Woods, Jeffrey Weber
Institutions: Moffitt Cancer Center, NYU Langone Health, NYU Langone’s Laura and Isaac Perlmutter Cancer Center, New York University, University of Colorado Anschutz, University of Colorado Denver, MedStar Georgetown University Hospital, Georgetown Lombardi Comprehensive Cancer Center, Emory University, Winship Cancer Institute
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
Awards: G1046846124, G547246955
OpenAlex ID: W4310580589