ASCO GU 2018: Nivolumab Plus Ipilimumab Versus Standard of Care with Previously Untreated Unresectable or Metastatic Urothelial Carcinoma

San Francisco, CA ( Dr. Matt Galsky discussed the CheckMate 901 phase III randomized trial assessing nivolumab plus ipilimumab or standard of care vs standard of care alone in patients with previously treated metastatic urothelial carcinoma. Cisplatin-containing regimens have been standard of care for metastatic urothelial carcinoma for nearly 40 years, however durable responses are rare with these regimens. Furthermore, a large proportion of patients with unresectable/ metastatic urothelial carcinoma are ineligible for cisplatin therapy. Treatment approaches conferring longer-term disease control and extending to broader metastatic urothelial carcinoma patient populations are urgently needed. Recently, the programmed death-1 (PD-1) inhibitor, nivolumab, induced durable responses in patients with unresectable/ metastatic urothelial carcinoma progressing despite platinum-based chemotherapy [1], and nivolumab combined with ipilimumab (a CTLA-4 inhibitor) demonstrated acceptable safety and clinical activity [2]. This phase III study will evaluate nivolumab + ipilimumab and nivolumab + standard of care vs standard of care in previously untreated patients with unresectable/ metastatic urothelial carcinoma.

Trial Design: The key inclusion criteria for this phase III study include: (i) cisplatin-eligible and -ineligible patients with measurable disease, (ii) no prior systemic chemotherapy for unresectable/metastatic urothelial carcinoma, and (iii) evaluable tumor biopsy. Key exclusion criteria include: (i) active brain metastases, (ii) autoimmune disease, and (iii) prior treatment with drugs specifically targeting T-cell co-stimulation or checkpoint pathways. Cisplatin-eligible and -ineligible patients will be randomized 1:1 to arm A (nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks up to 4 doses, followed by nivolumab 480 mg every 4 weeks until disease progression or unacceptable toxicity) or arm B (gemcitabine-cisplatin or gemcitabine-carboplatin for up to 6 cycles). Additional cisplatin-eligible patients will be randomized to arm C (nivolumab 360 mg + gemcitabine-cisplatin every 3 weeks for up to 6 cycles, followed by nivolumab 480 mg) or arm D (gemcitabine-cisplatin for up to 6 cycles). Patients will be stratified by PD-1 ligand 1 status, cisplatin eligibility, and liver metastasis. The co-primary endpoints for this trial include overall and progression-free survival (OS and PFS) by blinded independent review committee in cisplatin-ineligible patients receiving nivolumab + ipilimumab vs standard of care, and PFS by blinded independent review committee in cisplatin-eligible patients receiving nivolumab + standard of care vs standard of care. Enrollment for CheckMate 901 began March 2017 in 30 countries worldwide, with a target of 897 patients.
Clinical trial information: NCT03036098

Speaker: Matt Galsky, Icahn School of Medicine at Mount Sinai Tisch Cancer Institute, New York, NY

Co-Authors: Thomas Powles, Shengting Li, Delphine Hennicken, Guru Sonpavde

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md, at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA

1. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol 2017;18(3):312-322.

2. Sharma P, Callahan MK, Calvo E, et al. Efficacy and safety of nivolumab plus ipilimumab in previously treated metastatic urothelial carcinoma: First results from the phase I/II CheckMate 032 study. 2016 SITC Annual Meeting.