Outcomes with novel combinations in non-clear cell renal cell carcinoma (nccRCC): ORACLE study.

BackgroundThere is a paucity of data to guide management of nccRCC due to the heterogeneity and rarity of these tumors. Limited data exists regarding the clinical activity of combination therapies in subtypes of advanced nccRCC.MethodsIn this multicenter retrospective analysis, we evaluated the efficacy of combination systemic therapy from 2012-2024. in patients(pts) with nccRCC. Eligible pts included those with nccRCC and receipt of any combination regimens including IO-IO, IO-VEGF, mTOR-VEGF during any line of treatment. The primary endpoint was objective response rate (ORR) assessed by investigator review. Secondary endpoints were progression- free survival (PFS), disease control rate (DCR), and overall survival (OS).Results253 pts received combination regimens. The median age was 59 years; 72% were male and 64% white. Histologies included papillary (38%), unclassified (34%), chromophobe (16%), translocation (8%), and other (4%). 23% had sarcomatoid and/or rhabdoid differentiation. 73% had prior nephrectomy, 82% were IMDC intermediate/poor risk. 23% and 28% had liver and bone metastasis respectively. The majority (69%) received combination treatment as first line. Comparison of outcomes based on treatment regimen and subtype is shown in the table. ORR/DCR/PFS was significantly lower when combination regimens were utilized in second or later line compared to front line setting. Table: 1709P First line therapy n Entire cohort Papillary (n=68) Chromophobe (n=23) Unclassified/ other (n=68) ORR (%) DCR (%) Median PFS (mo.) OS (mo.) ORR (%) DCR (%) ORR (%) DCR (%) ORR (%) DCR (%) IO/IO 124 26 44 11 24.7 15 33 50 70 31 48 IO/VEGF 81 31 68 8.9 19.7 28 76 28 63 40 60 VEGF/mTOR 28 20 60 14.7 23.9 0 25 76 100 NA NA IO/VEGF (pembrolizumab + axitinib/lenvatinib; atezolizumab + bevacizumab; avelumab + axitinib/nivolumab+cabozantinib); IO/IO (Ipilimumab and nivolumab); VEGF/mTOR (Lenvatinib plus everolimus; Bevacizumab + Everolimus) NA: not available ConclusionsLimited antitumor activity was observed with novel combinations in nccRCC in both frontline and later line setting. nccRCC subsets appear to respond differentially based on the type of combination regimen. Optimal management of nccRCC remains an unmet need.Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureD. Kilari: Financial Interests, Personal, Invited Speaker: Janssen, Pfizer, Aveo oncology, seagen, MJH - life sciences, Binayatra foundation; Financial Interests, Personal, Advisory Board: Exelixis, Eisai; Financial Interests, Institutional, Coordinating PI: Exelixis, Genentech. M.A. Bilen: Financial Interests, Personal, Advisory Board: Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Nektar, EMD Serono, Seagen, Sanofi; Financial Interests, Institutional, Local PI: Merck, Xencor, Bayer, Bristol Myers Squibb, Genentech/Roche, Seagen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, Pfizer. C. Hwang: Financial Interests, Personal, Other, Consultant: TEMPUS; Financial Interests, Personal, Advisory Board: EMD Sorono, Genzyme (Sanofi), Dendreon; Financial Interests, Personal, Stocks/Shares: Johnson and Johnson; Financial Interests, Institutional, Local PI: Merck, Seagen, AstraZeneca, Bayer, Fujifilm, Taiho, Scholar Rock, Century Therapeutics, Exelixis, Hengrui; Non-Financial Interests, Sponsor/Funding: Henry Ford Health System Government Affairs Services PAC. P.M. Coelho Barata: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Eisai, Exelixis, Janssen, EMD Serono, Pfizer, Seattle Genetics, BMS, Bayer; Financial Interests, Personal, Invited Speaker: Caris Life Sciences, Telix; Financial Interests, Personal, Other, educational videos: UroToday; Financial Interests, Institutional, Steering Committee Member: Exelixis, Telix; Financial Interests, Institutional, Local PI: Merck. Y. Zakharia: Financial Interests, Personal, Advisory Board: Pfizer, Eisai, Exelixis, Myovant, BMS, EMD Serono, Janssen. H. Emamekhoo: Financial Interests, Personal, Advisory Board: Janssen, Aveo, Cardinal Health, Eisai, BMS. E. Heath: Financial Interests, Personal, Other, Consulting/Advisory Role, Paid Travel: Astellas; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Janssen; Financial Interests, Personal, Other, Paid Travel: Caris Life Science; Financial Interests, Personal, Advisory Board, Speaker's Bureau, Paid Travel: Sanofi; Financial Interests, Personal, Advisory Board, Paid Travel: Seattle Genetics; Financial Interests, Institutional, Local PI: Arvinas, Astellas, AstraZeneca, Bayer, BioXcel, Bristol Myers Squibb, Calibr, Calithera, Corcept, Daiichi Sankyo, Eisai, Five Prime, Fortis, Gilead Sciences, GSK, Harpoon, Hoffman-La Roche, Infinity, Janssen, Merck, Merck Sharpe Dohme, Mirati, Modra, Novartis, Peloton, Pfizer, Pharmacyclics, iTeos, Point Biopharma; Financial Interests, Personal, Other, Executive Committee Member Precision Oncology Alliance: Caris Life Science; Financial Interests, Institutional, Coordinating PI: Exelixis, Oncolys; Financial Interests, Personal, Steering Committee Member: Seattle Genetics. B.I. Rini: Financial Interests, Personal, Advisory Board: Merck, BMS, Aveo, Pfizer, Eisai, Eusa, Debiopharm, Genentech/Roche; Financial Interests, Personal, Other, Partnership on podcasts and meeting: MashupMD; Financial Interests, Institutional, Coordinating PI: Merck, Surface Oncology, Daiichi Sankyo, Adela; Financial Interests, Institutional, Other, Research funding to institution: BMS; Financial Interests, Institutional, Steering Committee Member: Pfizer; Financial Interests, Institutional, Local PI: Astra-Zeneca; Financial Interests, Institutional, Funding: Aveo; Financial Interests, Institutional, Other, Study funding: Janssen. R.R. McKay: Financial Interests, Personal, Advisory Board: Aveo, AstraZeneca, Bayer, Calithera, Dendreon, Exelixis, JNJ, Merck, Pfizer, Sanofi, Tempus, BMS, Lilly, Sanofi, Seagen, Telix, Sorrento Therapeutics, Eisai, Blue Earth Diagnostics; Financial Interests, Personal, Other, Molecular tumor board: Caris; Financial Interests, Personal, Other, Consultant: Dendreon, Myovant; Financial Interests, Personal, Invited Speaker: Exelixis, Merck, Novartis, Pfizer; Financial Interests, Steering Committee Member: Aveo, Merck, Eli Lilly; Financial Interests, Local PI: JNJ, Seagen, Calibr, Poseida, Oncternal, Scholar Rock, Merck, Xencor, Genentech, Eli Lilly, BMS; Financial Interests, Trial Chair: Bayer, AstraZeneca; Financial Interests, Institutional, Local PI: Exelixis. All other authors have declared no conflicts of interest.