title: Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab.
abstract: The checkpoint inhibitor nivolumab is active in patients with metastatic melanoma who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab-refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug-related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. The response rate for ipilimumab-refractory patients was 30% (95% CI, 21%-41%). The median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when patients were followed up for a median of 16 months. One- and 2-year survival rates were 68.4% and 31.2%, respectively. Ipilimumab-naïve and ipilimumab-refractory patients showed no significant difference in survival. The 21 patients with prior grade 3-4 toxicity to ipilimumab that was managed with steroids tolerated nivolumab well, with 62% (95% CI, 38%-82%) having complete or partial responses or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSC) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab.
authors.affiliation: Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida. Jeffrey.weber2@nyumc.org.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Weber
authors.affiliation: Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Gibney
authors.affiliation: Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Ragini
authors.initials: R
authors.lastname: Kudchadkar
authors.affiliation: Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.affiliation: Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Pingyan
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Martinez
authors.affiliation: Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Jodie
authors.initials: J
authors.lastname: Kroeger
authors.affiliation: Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Allison
authors.initials: A
authors.lastname: Richards
authors.affiliation: Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Lori
authors.initials: L
authors.lastname: McCormick
authors.affiliation: Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Valerie
authors.initials: V
authors.lastname: Moberg
authors.affiliation: Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Heather
authors.initials: H
authors.lastname: Cronin
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Michael
authors.initials: M
authors.lastname: Schell
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Yian Ann
authors.initials: YA
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D015331:Cohort Studies; D003131:Combined Modality Therapy; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D000077594:Nivolumab; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015415:Biomarkers; D000074324:Ipilimumab; D000077594:Nivolumab