Phase II clinical and immune correlate study of adjuvant nivolumab plus ipilimumab for high-risk resected melanoma

• Authors: Nikhil Khushalani, Moffitt Cancer Center, Tampa; Melinda Vassallo, NYU Langone Health; Judith D Goldberg, NYU Langone Health; Zeynep Eroglu, Moffitt Cancer Center, Tampa; Younchul Kim, Moffitt Cancer Center, Tampa; Biwei Cao, Moffitt Cancer Center, Tampa; Robert Ferguson, NYU Langone Health; Kelsey R Monson, NYU Langone Health; Tomas Kirchhoff, NYU Langone Health; Carol M Amato, University of Colorado, Aurora; Paulo Burke, University of Colorado, Aurora; Ann Strange, University of Colorado, Aurora; Emily Monk, University of Colorado, Aurora; Geoffrey Thomas Gibney, MedStar Georgetown University Hospital; Ragini Kudchadkar, Emory University; Joseph Markowitz, Moffitt Cancer Center, Tampa; Andrew S Brohl, Moffitt Cancer Center, Tampa; Anna Pavlick, NYU Langone Health; Alison Richards, Moffitt Cancer Center, Tampa; David M Woods, University of Colorado; Jeffrey Weber, NYU Langone Health
• Journal Title: JOURNAL FOR IMMUNOTHERAPY OF CANCER
• Volume: Volume 10, Number 11
• Publisher: BMJ PUBLISHING GROUP | 2022-11-01
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1136/jitc-2022-005684
• Subjects: Health Sciences, Oncology; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; Immunology; STAGE IV MELANOMA; DOUBLE-BLIND; SURVIVAL; PLACEBO

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.