Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND

The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only.

METHODS

In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or T

FINDINGS

Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related.

INTERPRETATION

Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma.

FUNDING

US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests VM reports support for attending meetings or travel from American College of Surgeons; and participation on the Advisory Board on Diversity, Equity, and Inclusion at Exelixis. VM also reports a leadership role (unpaid) on Society of Urologic Oncology Clinical Trials Consortia. DFM received payment or honoraria from Bristol Myers Squibb, Pfizer, Merck, Eisai, Xilio, Aveo, Genentech, Cullinan, and Exelixis; and support for attending meetings or travel from Bristol Myers Squibb, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes. LCH reports ownership of stock in Coherus and previous employment at Surface Oncology. SS reports grants or contracts from Bristol Myers Squibb and Exelixis to their institution; and royalties or licenses from Biogenex. SS also reports consulting fees from AstraZeneca, Merck, and CRISPR Therapeutics; and a leadership or fiduciary role at American Association for Cancer Research as Senior Editor at Clinical Cancer Research and at the NCI National Cancer Institute as Renal Task Force Co-Chair. HE reports consulting fees for Janssen and Aveo advisory boards. NA reports grants or contracts from Exelixis, Genentech, Merck, and Bristol Myers Squibb; and consulting fees from Exelixis, Bristol Myers Squibb, Aveo, Merck, EMD Serono, and Sanofi. MAB reports institutional grants from Merck, Xencor, Bayer, Bristol Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, and Pfizer; and payment or honoraria for Advisory Board participation from Exelixis, Bayer, Bristol Myers Squibb, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi. TMM reports payment to their institution for clinical trials from Merck, Curium, and ECOG; consulting fees from Impact Network and Aptitude Health; and honoraria from Exelixis and Blue Earth Diagnostics. TC reports support from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH, CCO, and others), outside the submitted work. TC also reports institutional research funding related to clinical trials from AstraZeneca, Aveo, Arcus, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, and Takeda. TC also reports consulting fees from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO, and others), outside the submitted work. TC also reports payment or honoraria from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO, and others), outside the submitted work. TC also reports support for attending meetings or travel in relation to meetings, lectures, and advisory boards; and participates in the Aravive Data and Safety Monitoring Board or advisory board. TC also reports a patent related to ctDNA and biomarkers of response to immune checkpoint inhibitors (no royalties as of current date). TC also reports a leadership or fiduciary role in KidneyCan (unpaid) and committees for American Society of Clinical Oncology, European Society of Medical Oncology, National Comprehensive Cancer Network, and Genitourinary Steering Committee of the NCI. TC also reports stock ownership (for being an advisor) of Pionyr, Tempest, Precede Bio, Osel, Curesponse, Immdura, and Primium. TC also reports no receipt of equipment, materials, drugs, medical writing, gifts, or other services, except for travel and accommodation (flights, hotel, and meals) related to advisory or consulting when travel needed. TC also reports to be supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE(2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan-Mass Challenge, Hinda and Arthur Marcus Fund, and Loker Pinard Funds for Kidney Cancer Research at Dana Farber Cancer Institute. MDD reports participation on the Scientific Advisory Boards (honoraria received) at Merck, Eisai, Exelixis, and Janssen. DYH reports compensation from consulting work from Bristol Myers Squibb, Merck, Ipsen, Exelixis, Pfizer, and Eisai. BS reports consulting fees from Merck, Veracyte, Telix, and Johnson and Johnson; payment or honoraria from Merck; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Telix. BCL reports a leadership or fiduciary role at Kidney Cancer Association as Chair of Board of Directors. JM reports participation on the NCI Central Institutional Review Board and has been recused from all discussions of this study. RU reports participation and financial support on a Data Safety Monitoring Board at Pfizer and other financial support on a steering committee at Merck. RU also reports a leadership or fiduciary role (non-financial support) at Haymarket Media as a board member. GB reports a leadership role during the study as President of the Society of Urologic Oncology–Clinical Trial Consortium. NBH reports participation in the Data and Safety Monitoring Committee atezolizumab at Roche Genentech and advisory boards at Bristol Myers Squibb and Eisai. NBH also reports a non-financial leadership role as ECOG ACRIN Genitourinary Committee Co-Chair. All other authors declare no competing interests.