Phase II clinical and immune correlate study of adjuvant nivolumab plus ipilimumab for high-risk resected melanoma. Issue 11 (30th November 2022)

• Record Type: Journal Article
• Authors: Khushalani, Nikhil I; Vassallo, Melinda; Goldberg, Judith D; Eroglu, Zeynep; Kim, Younchul; Cao, Biwei; Ferguson, Robert; Monson, Kelsey R; Kirchhoff, Tomas; Amato, Carol M; Burke, Paulo; Strange, Ann; Monk, Emily; Gibney, Geoffrey Thomas; Kudchadkar, Ragini; Markowitz, Joseph; Brohl, Andrew S; Pavlick, Anna; Richards, Alison; Woods, David M; Weber, Jeffrey
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 11(2022)
• Publication Date: 2022-11-30
• Subjects: Immunotherapy -- Biomarkers, Tumor -- CTLA-4 Antigen -- Clinical Trials, Phase II as Topic -- Programmed Cell Death 1 Receptor; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2022-005684
• Languages: English
• ISSNs: 2051-1426

Abstract

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 .