1969P - Phase I/II study of ipilimumab plus nivolumab combined with sacituzumab govitecan in patients with metastatic cisplatin-ineligible urothelial carcinoma

Background

Sacituzumab 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.

Methods

Standard 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.

Results

Between 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.

Conclusions

The 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 identification

NCT04863885.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

BMS and Gilead.

Disclosure

R.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.