Declaration of interests C.L. reports research funding from Genentech/imCORE. W.X. reports performing consulting for Convergent Therapeutics, Inc. R.J.M. reports clinical trial support (institutional) from Bristol Myers Squibb (BMS) for this manuscript; advisory board fees from AstraZeneca, AVEO, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer; and fees (institutional) for coordinating principal investigator from AVEO, BMS, Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer. T.P. reports honoraria and consulting/advisory roles with Roche/Genentech, Bristol-Myers Squibb, and Merck; consulting/advisory role with AstraZeneca and Novartis; research funding from AstraZeneca/MedImmune and Roche/Genentech; and other relationships with Ipsen and Bristol-Myers Squibb. B.I.R reports grants or contracts from Pfizer, Hoffman-LaRoche, Incyte, AstraZeneca, Seattle Genetics, Arrowhead Pharmaceuticals, Immunomedics, BMS, Mirati Therapeutics, Merck, Surface Oncology, Aravive, Exelixis, Jannsen, Pionyr, and AVEO; consulting fees from BMS, Pfizer, GNE/Roche, Aveo, Synthorx, Merck, Corvus, Surface Oncology, Aravive, Alkermes, Arrowhead, Shionogi, Eisai, Nikang Therapeutics, EUSA, Athenex, Allogene Therapeutics, and Debiopharm; support for travel from BMS, Pfizer, and Merck; participation on a data safety monitoring board or advisory board (Astra Zeneca); and stock or stock options (PTC Therapeutics). L.A. reports research grants (institutional) from BMS; consulting fees (institutional) from BMS, Ipsen, Roche, Novartis, Pfizer, Astellas Pharma, Merck, MSD, AstraZeneca, Janssen, and Eisai; and travel support from BMS and MSD. S.K.P. reports their institution received grants from or has contracts with Exelixis, Xencor, Pfizer, Allogene Therapeutics, AstraZeneca, Genentech, and CRISPR Therapeutics; reports payment or honoraria for lectures, presentations, or speakers’ bureaus from EMD Serono and Pfizer; and reports meeting or travel support from CRISPR Therapeutics and Roche. B.Mc.G. reports grants or contracts, paid to their institution, from Exelixis, SeaGen, Pfizer, and Bristol Myers Squibb and consulting fees from Astellas, Bristol-Myers Squibb, Calithera, Eisai, Exelixis, Pfizer, and SeaGen. T.P. reports research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; consulting fees from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and support for attending meetings or travel Astra Zeneca, Ipsen, MSD, Pfizer, and Roche. R.R.McK. reports consulting or advisory roles: Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion Therapeutics, Calithera Biosciences, AstraZeneca, Myovant Sciences, Caris Life Sciences, Sorrento Therapeutics, and AVEO; and research funding from Pfizer (Inst), Bayer (Inst), and Tempus (Inst). S.S. reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis, and Novartis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; receives royalties from Biogenex; and mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. E.M.V. reports advisory or consulting roles for Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Riva Therapeutics, and Serinus Bio; research support from Novartis, BMS, and Sanofi; equity at Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics, and Serinus Bio; institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag; and being on the editorial boards of JCO Precision Oncology and Science Advances. S.A.S. reports nonfinancial support from Bristol-Myers Squibb and equity in Agenus Inc., Agios Pharmaceuticals, Breakbio Corp., Bristol-Myers Squibb, and Lumos Pharma. T.K.C. reports research funding, paid to their institution, from AstraZeneca, Aveo, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, and Takeda; consulting fees from AstraZeneca, Aravive, Aveo, Bayer, Bristol-Myers Squibb, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Nuscan, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events; payment or honoraria for lectures, presentations, manuscript writing, or educational events from AstraZeneca, Aravive, Aveo, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, Takeda, Tempest, Up-To-Date, and CME events; support for attending meetings or travel from Eisai, Merck, Exelixis, and Pfizer; patents planned, issued, or pending related to ctDNA and biomarkers of response to immune checkpoint inhibitors (no royalties as of April 12, 2022); participation on a data safety monitoring board or advisory board for Aravive; a leadership or fiduciary role in other board, society, committee, or advocacy group, for KidneyCan (unpaid), committees for American Society of Clinical Oncology, European Society for Medical Oncology, National Comprehensive Cancer Network®, and Genitourinary Steering Committee of the National Cancer Institute; stock or stock options from Pionyr, Tempest, Precede Bio, and Osel; and salary and research support from Dana-Farber and Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School, and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute. D.A.B. reports honoraria from LM Education/Exchange Services; advisory board fees from Exelixis and AVEO; consulting fees from Merck and Elephas; equity in Elephas, Fortress Biotech (subsidiary), and CurIOS Therapeutics; personal fees from Schlesinger Associates, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, AbbVie, Accolade 2nd.MD, DLA Piper, Merck, Link Cell Therapies, and Compugen; and research support from Exelixis and AstraZeneca, outside of the submitted work.