Safety and efficacy of first-line nivolumab plus ipilimumab alternating with nivolumab monotherapy in patients with advanced renal cell carcinoma: the non-randomised, open-label, phase IIIb/IV CheckMate 920 trial

Abstract

Objectives: The non-randomised, open-label, phase IIIb/IV multicohort CheckMate 920 trial explored the safety and efficacy with a less frequent, but continual nivolumab plus ipilimumab (NIVO+IPI) dosing regimen (cohort 1) to determine whether this modification could potentially retain efficacy benefits while improving on the manageable safety profile previously observed with this combination in patients with advanced renal cell carcinoma (aRCC).

Setting: Patients were enrolled from 48 largely community-based sites in the USA.

Participants: 106 patients with previously untreated, predominantly clear cell aRCC received treatment.

Interventions: Patients received NIVO 6 mg/kg plus IPI 1 mg/kg on day 1 of the first week of each 8-week cycle; the combination alternated with NIVO 480 mg monotherapy on day 1 of the fifth week of each 8-week cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or study end. The maximum treatment duration was 2 years. The primary endpoint was the incidence of high-grade (grade 3/4 and grade 5) immune-mediated adverse events (IMAEs) within 100 days of the last dose. Select secondary endpoints included time to onset and resolution of high-grade IMAEs, progression-free survival (PFS) and objective response rate (ORR). The incidence of treatment-related adverse events and the overall survival (OS) were the exploratory endpoints.

Results: The most common grade 3/4 IMAEs were diarrhoea/colitis (7.5%) and rash (6.6%) and no grade 5 IMAEs occurred, with a minimum follow-up of 28.5 months. The median PFS was 4.8 (95% CI 3.0 to 8.3) months, the ORR in evaluable patients (n=96) was 34.4% (95% CI 25.0 to 44.8), and the median OS was not reached (95% CI 24.8 months to not estimable).

Conclusions: While no new safety signals were reported with less frequent, but continual NIVO+IPI dosing in CheckMate 920, the modified regimen was not associated with clinical benefits relative to the approved NIVO+IPI dose. These results support the continued use of the currently approved NIVO+IPI combination dosing schedule for patients with aRCC.

Trial registration number: NCT02982954.

Keywords: clinical trials; immunology; kidney tumours; oncology.

Conflict of interest statement

Competing interests: DJG reports consulting or advisory roles from Bayer, Exelixis, Pfizer, Sanofi, Astellas Pharma, Innocrin Pharma, Bristol Myers Squibb (BMS), Genentech, Janssen, Merck Sharp & Dohme, Myovant Sciences, AstraZeneca, Michael J Hennessy Associates, Vizuri and Constellation Pharmaceuticals; leadership from Capio Biosciences; speakers bureau from Sanofi, Bayer and Exelixis; travel, accommodations and expenses from Bayer, Exelixis, Merck, Pfizer, Sanofi, Janssen Oncology and UroToday; honoraria from Sanofi, Bayer, Exelixis, EMD Serono, OncLive, Pfizer, UroToday, Acceleron Pharma, American Association for Cancer Research, Axess Oncology, Janssen Oncology and Millennium Medical Publishing; and research funding (all institution) from Exelixis, Janssen Oncology, Novartis, Pfizer, Astellas Pharma, BMS, Acerta Pharma, Bayer, Dendreon, Innocrin Pharma, Calithera Biosciences and Sanofi/Aventis. DRS reports consulting or advisory roles (all institution) from Amgen, AstraZeneca, BMS, Curio Science, EMD Serono, Evidera, Exelixis, GlaxoSmithKline, Intellisphere, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Mirati Therapeutics, Molecular Templates, Novartis, Novocure, Pfizer, Puma Biotechnology, Regeneron Pharmaceuticals, Roche/Genentech and Sanofi/Aventis; and research funding (all institution) from Aeglea BioTherapeutics, Agios, Apollomics, Arcus, Arrys Therapeutics, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, BioNTech RNA Pharmaceuticals, Blueprint Medicine, Boehringer Ingelheim, BMS, Calithera, Celgene, Celldex, Clovis, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, EMD Serono, Evelo Biosciences, G1 Therapeutics, Roche/Genentech, GlaxoSmithKline, GRAIL, Hutchison MediPharma, ImClone Systems, Incyte, ImmunoGen, Ipsen, Janssen, Kronos Bio, Lilly, Loxo Oncology, MacroGenics, MedImmune, Merck, Molecular Partners, Molecular Template, Nektar, Neon Therapeutics, Novartis, Novocure, Oncologie, Pfizer, PTC Therapeutics, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, Takeda, Tesaro, Tizona Therapeutics, Transgene, UT Southwestern and Verastem. LNG reports employment from Florida Medical Clinic; leadership from Florida Cancer Specialists; honoraria from Ameris Pharma; consulting or advisory role from Janssen Oncology; and speakers bureau from Myriad Genetics. STK has no conflicts of interests to disclose. AMM reports consulting or advisory roles from Exelixis, Janssen and Eisai; and honoraria from the American Society of Clinical Oncology. JY reports consulting or advisory roles from BMS, Janssen and Lantheus. ARK reports remuneration for a consulting or advisory roles from Exelixis, AstraZeneca, Bayer, Pfizer, Novartis, Genentech, BMS and EMD Serono; speakers bureau from Janssen, Astellas Medivation, Pfizer, Novartis, Sanofi, Genentech/Roche, Eisai, AstraZeneca, BMS, Amgen, Exelixis, EMD Serono, Merck and Seattle Genetics/Astellas; travel, accommodations and expenses from Genentech, Prometheus, Astellas Medivation, Janssen, Eisai, Bayer, Pfizer, Novartis, Exelixis and AstraZeneca; stock ownership from ECOM Medical; and research funding (all institution) from Genentech, Exelixis, Janssen, AstraZeneca, Bayer, BMS, Eisai, MacroGenics, Astellas Pharma, BeyondSpring Pharmaceuticals, BioClin Therapeutics, Clovis Oncology, Bavarian Nordic, Seattle Genetics, Immunomedics and Epizyme. HM has no conflicts of interests to disclose. NT reports consulting or advisory roles from Amgen, IntrinsiQ and Foundation Medicine. SST reports consulting or advisory roles from Merck, Intellisphere, Natera, BMS and Exelixis; patent pending (institution); and research funding (all institution) from Genentech, BMS, Merck, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis and Clinigen Group. JZ reports employment and stock ownership from BMS. MA reports employment from BMS. JLJ reports employment and stock ownership from BMS. TEH reports employment from Texas Oncology; consulting or advisory roles from Bayer/Onyx, Pfizer, Novartis, Astellas Pharma, Johnson & Johnson, BMS, Eisai and Exelixis; speakers bureau from Pfizer, Johnson & Johnson, Eisai, Exelixis, Astellas Pharma and BMS; honoraria from Pfizer, Astellas Pharma, BMS, Exelixis, Eisai, Novartis, Johnson & Johnson and Bayer/Onyx; and research funding (all institution) from Pfizer, Johnson & Johnson, Exelixis, Eisai and BMS.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

CheckMate 920 study design. aOne prior adjuvant or neoadjuvant therapy for completely resectable RCC was allowed if it did not include checkpoint inhibitors and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy. ccRCC, clear cell renal cell carcinoma; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IPI, ipilimumab; KPS, Karnofsky performance status; nccRCC, non-clear cell carcinoma; NIVO, nivolumab; OS, overall survival; Q3W, every 3 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 2

Progression-free survival per investigator (A), investigator-assessed objective response per RECIST V.1.1 (B) and overall survival (C). CR, complete response; NE, not estimable; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; UTD, unable to determine.