FRACTION-RCC: nivolumab plus ipilimumab for advanced renal cell carcinoma after progression on immuno-oncology therapy

Abstract

Background: The role and sequencing of combination immuno-oncology (IO) therapy following progression on or after first-line IO therapy has not been well-established. The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology (FRACTION) program is an open-label, phase 2 platform trial designed to evaluate multiple IO combinations in patients with advanced renal cell carcinoma (aRCC) who progressed during or after prior IO therapy. Here, we describe the results for patients treated with nivolumab plus ipilimumab. For enrollment in track 2 (reported here), patients with histologically confirmed clear cell aRCC, Karnofsky performance status ≥70%, and life expectancy ≥3 months who had previously progressed after IO (anti-programmed death 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)) therapy were eligible. Previous treatment with anti-CTLA-4 therapy plus anti-PD-1/PD-L1 therapy precluded eligibility for enrollment in the nivolumab plus ipilimumab arm. Patients were treated with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks for up to 2 years or until progression, toxicity, or protocol-specified discontinuation. The primary outcome measures were objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Secondary outcomes were safety and tolerability up to 2 years. Overall survival (OS) was a tertiary/exploratory endpoint. Overall, 46 patients were included with a median follow-up of 33.8 months. The ORR was 17.4% (95% CI, 7.8 to 31.4) with eight (17.4%) patients achieving partial response. Stable disease was achieved in 19 (41.3%) patients, while 14 (30.4%) had progressive disease. Median DOR (range) was 16.4 (2.1+ to 27.0+) months. The PFS rate at 24 weeks was 43.2%, and median OS was 23.8 (95% CI, 13.2 to not reached) months. Grade 3-4 immune-mediated adverse events were reported in seven (15.2%) patients. No treatment-related deaths were reported. Patients with aRCC treated with nivolumab plus ipilimumab may derive durable clinical benefit after progression on previous IO therapies, including heavily pretreated patients, with a manageable safety profile that was consistent with previously published safety outcomes. These outcomes contribute to the knowledge of optimal sequencing of IO therapies for patients with aRCC with high unmet needs.

Trial registration number: NCT02996110.

Keywords: immunotherapy; kidney neoplasms.

Conflict of interest statement

Competing interests: TKC reports consulting or advisory board fees, honoraria, and research grants from AstraZeneca, Aravive, AVEO Pharmaceuticals, Bayer, Bristol Myers Squibb (BMS), Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVIA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, NiKang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH and others), outside the submitted work. Institutional patents filed on molecular mutations and immunotherapy response/toxicity, and circulating tumor DNA. Equity holdings: Tempest, Pionyr, Osel, and Precede Bio. Committees: NCCN, GU Steering Committee, ASCO/ESMO, ACCRU, and KidneyCan. Medical writing and editorial assistance support may have been funded by communications companies in part. Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. Dr Choueiri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan-Mass Challenge, and Loker Pinard Funds for Kidney Cancer Research at DFCI. CV provided upon request for scope of clinical practice and research. HK reports institutional research grant funding from Apexigen, BMS, and Merck; personal fees from Array Biopharma, BMS, Calithera Biosciences, Celldex, ChemoCentryx, Clinigen, Elevate Bio, GI reviewers, GigaGen, Immunocore, Instil Bio, Iovance, Merck, Shionogi, and Signatera. SG reports consulting or advisory role from BMS, Bayer, Pfizer, Exelixis, Corvus Pharmaceuticals, Sanofi/Genzyme, EMD Serono, Seattle Genetics/Astellas, Eisai, Merck, AVEO Pharmaceuticals, and QED Therapeutics; and research funding (institutional) from Pfizer, Merck, Agensys, Novartis, BMS, Bayer, Eisai, Seattle Genetics/Astellas, Calithera Biosciences, Immunomedics, Corvus Pharmaceuticals, and Surface Oncology. SST reports consulting or advisory board fees from Merck, Intellisphere LLC, Natera, BMS, and Exelixis; patent pending (Fred Hutchinson Cancer Center); and research funding (institutional) from Genentech, BMS, Merck Sharp & Dohme, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis, and Clinigen Group. TMK has nothing to disclose. RP reports consulting fees from Karyopharm Therapeutics and BiolineRx. SN has nothing to disclose. GP reports advisory board fees from AstraZeneca, BMS, Ipsen, Janssen, Merck Sharp & Dohme, Novartis, and Pfizer. MAC reports consulting or advisory fees from Astellas Pharma, AbbVie, Roche/Genentech, Pfizer, and Foundation Medicine; and research funding (institutional) from BMS, AstraZeneca, Pfizer, and Gilead Science. VC reports consulting or speakers’ bureau fees from Ipsen, Eisai, Merck, AstraZeneca, Pfizer, Novartis, BMS, Astellas and Janssen. EF has nothing to disclose. C-HL reports research funding (institutional) from BMS, Calithera Biosciences, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer; consulting fees from Amgen, BMS, Exelixis, Eisai, Merck, Pfizer, and EMD Serono; and honoraria from AiCME, Intellisphere, and Research to Practice. SJH reports compensation for advisory boards and speakers’ bureaus from Astellas, AstraZeneca, Bayer, BMS, Eisai, Exelixis, Janssen, Ipsen, Merck, Roche, Sanofi, Seagen, and SignalChem; institutional research or grant funding from Astellas, AstraZeneca, Ayala, Bayer, BMS, Eisai, Exelixis, Janssen, Ipsen, Merck, Roche, Sanofi, Seagen, and SignalChem. WHM reports consulting or advisory board fees from BMS, Merck, Roche, Novartis, GlaxoSmithKline, and Amgen; honoraria from BMS, Roche, Novartis, and GlaxoSmithKline; and research funding (institutional) from Merck, BMS, Novartis, GlaxoSmithKline, Roche, AstraZeneca, MethylGene, and MedIm. SSS, C-WL, HD, and PB are employed by and has stock ownership in BMS. RJM reports advisory board fees from AstraZeneca, AVEO Pharmaceuticals, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer; and research funding (institutional) from BMS, Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer. BE reports research funding (institutional) from BMS; consulting fees from Pfizer, BMS, Ipsen, AVEO Pharmaceuticals, Oncorena, and Eisai; honoraria from Pfizer, BMS, Ipsen, Oncorena, and Eisai; and travel accommodations and expenses from BMS, Ipsen, and Merck Sharp & Dohme.

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Figures

Figure 1

Kaplan-Meier plots of progression-free survival (PFS; A) and overall survival (OS; B). NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab.