Phase I/II study of ipilimumab plus nivolumab combined with sacituzumab govitecan in patients with metastatic cisplatin-ineligible urothelial carcinoma

BackgroundSacituzumab govitecan (SG) demonstrated an objective response rate (ORR) of 28% and median overall survival (OS) of 10.5 months (mo) in metastatic urothelial carcinoma (mUC) patients (pts) after platinum-based chemotherapy (PBC) and PD1/L1 inhibitor. SG and pembrolizumab is safe and active following PBC. Ipilimumab (IPI) 3mg/kg plus Nivolumab (NIVO) 1mg/kg has shown activity after PBC. In this non-randomized, open-label, multicenter trial (NCT04863885), we evaluated combination IPI-NIVO plus SG as frontline treatment for cisplatin ineligible mUC.MethodsStandard 3 + 3 design was used for phase I and in phase II, the recommended phase 2 dose (RP2D) was assessed in an additional 34 pts. Two dose levels (DL) of SG at 8 mg/kg (DL1) and 10 mg/kg (DL2) intravenously (IV) were combined with IPI 3mg/kg and NIVO 1mg/kg (I3+N1) IV every 3 weeks x 4 cycles followed by NIVO 360 mg IV day 1 every 3 weeks. The primary endpoint was ORR; OS, progression-free survival (PFS), duration of response (DOR) and safety were the secondary endpoints.ResultsBetween May 2021- April 2023, total 25 pts were enrolled including 9 pts in phase I. The RP2D of SG was determined to be 8 mg/kg with I3+N1. In phase II,16 pts were enrolled. Two pts (12%), in phase II, developed grade 5 myocarditis due to IPI-NIVO, which led to a decision to terminate the trial early. The most common treatment related adverse events (TRAE) included diarrhea (72%), fatigue (56%), nausea (52%), rash (52%), neutropenia (44%), hypokalemia (44%) and hypophosphatemia (40%). TRAE grade ≥ 3 included neutropenia (36%), anemia (16%), hypokalemia (16%), rash (16%), diarrhea (12%) and colitis (12%). Of the 25 pts, 17 who received the RP2D were considered evaluable for response. ORR was 88.2% (95% CI: 63.56 – 98.5%), mOS has not been reached and mPFS is 31.99 mo (95% CI: 10.78-N.E.). The mDOR was 6.64 mo with a median follow-up of 16.67 mo.ConclusionsThe combination of IPI-NIVO with SG at 8mg/kg is active in cisplatin-ineligible mUC. However, the trial was terminated early due to higher than anticipated grade 5 toxicities. Correlative studies are underway to determine biomarkers for activity and severe myocarditis.Clinical trial identificationNCT04863885.Legal entity responsible for the studyThe authors.FundingBMS and Gilead.DisclosureR.K. Jain: Financial Interests, Personal, Advisory Board: BMS, Gilead, Seattle Genetics, Aveo, EMD Serono, Sanofi, Janssen; Financial Interests, Personal, Invited Speaker: Seattle Genetics, Dava Oncology, FLASCO, Curio Science, Ideology Health; Financial Interests, Institutional, Research Grant: BMS, Gilead, CTEP. J. Zhang: Financial Interests, Personal, Advisory Board, I was also on speaker program before 2023: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer, Dendroen, Sanofi. G.P. Sonpavde: Financial Interests, Personal, Advisory Board: EMD Serono, Bristol Myers Squibb, Genentech, Merck, Seattle Genetics, Exelixis, Janssen, Bicycle Therapeutics, Gilead, Scholar Rock, G1 Therapeutics, Loxo Oncology, Lucence, Tempus, Syapse, Astellas, Pfizer, Atkis, Kura, Syncorp, Vial, PrecisCa; Financial Interests, Personal, Advisory Board, Editor of Bladder cancer virtual center of excellence for Practice Update: Elsevier; Financial Interests, Personal, Other, Member of data safety monitoring board: Mereo; Financial Interests, Personal, Other, Author of chapter: Uptodate; Financial Interests, Personal, Invited Speaker: Research to practice, Seattle Genetics, Gilead, Exelixis, Janssen, Astellas, Merck, Aveo, Pfizer, Natera, Bayer, PeerView, Ideology Health, Grand Rounds in Urology, Onviv; Financial Interests, Personal, Advisory Board, to develop a trial in bladder cancer: Servier Pharmaceuticals; Financial Interests, Personal, Advisory Board, Investigational drug development for HER2+ cancers: Daiichi Sankyo/AstraZeneca; Financial Interests, Institutional, Research Grant: Gilead, EMD Serono, Jazz Pharma; Financial Interests, Institutional, Local PI: BMS; Non-Financial Interests, Principal Investigator, Steering committee of trial: Bristol Myers Squibb; Non-Financial Interests, Other, steering committee of trial: Merck; Other, Spouse employment: Myriad Genetics; Other, Travel: BMS, Astellas. All other authors have declared no conflicts of interest.