Alliance A031501: Phase III randomized adjuvant study of MK-3475 (pembrolizumab) in muscle-invasive and locally advanced urothelial carcinoma (MIBC) (AMBASSADOR) versus observation

Background:

Patients with high-risk MIBC have a poor prognosis. Radical cystectomy remains the standard treatment. Yet despite substantial improvements in surgical techniques, mortality from metastatic recurrence remains high. A large number of MIBC patients are ineligible for cisplatin-based chemotherapy or have persistent muscle-invasive disease despite neoadjuvant chemotherapy (NAC). Pembrolizumab, a PD-1 inhibitor, has demonstrated significant activity and is FDA-approved for patients with advanced/chemotherapy-refractory metastatic urothelial carcinoma. We hypothesize that pembrolizumab given post-cystectomy will improve overall survival (OS) and disease-free survival (DFS) in patients with high-risk MIBC.

Methods:

Patients must have histologically confirmed muscle-invasive urothelial carcinoma of the bladder or upper tract, have received NAC and have ≥ pT2 and/or pN+ at surgery or be cisplatin-ineligible and have ≥ pT3 and/or pN+ at surgery or have declined adjuvant cisplatin-based therapy and have ≥ pT3 and/or pN+ at surgery. Surgery could be radical cystectomy, nephrectomy, or ureterectomy. Patients are stratified by pathologic stage, central PD-L1 status, and prior NAC. Patients are randomized to receive pembrolizumab 240 mg every 3 weeks for 1 year, or observation. The dual primary objectives are to determine DFS and OS. Secondary objectives are to determine DFS and OS in PD-L1-positive and -negative patients and assess safety. Correlative objectives are to determine whether 12 immune gene signatures, tumor molecular subtypes, diversity of T-cell receptor (TCR) clonotypes, persistence of TCR clonotypes, tumor and neoantigen burden, HLA subtypes, and plasma HGF and VEGF levels with IL-10 and IL-17 are associated with OS and DFS. Quality of Life Correlative objectives are to compare health-related quality of life as assessed by the EORTC QLQ-C30. Clinical trial information: NCT03244384.

Andrea B. Apolo, Jonathan E. Rosenberg, William Y. Kim, Ronald C. Chen, Guru Sonpavde, Sandy Srinivas, Amir Mortazavi, Colleen Watt, Marissa Mallek, Katherine Graap, Carlos Diaz, Meagan Odegaard, Karla V. Ballman, Michael J. Morris

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Memorial Sloan Kettering Cancer Center, New York, NY; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; University of North Carolina at Chapel Hill, Chapel Hill, NC; Department of Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA; Stanford University, Stanford, CA; Arthur G. James Cancer Hospital, Ohio State University Wexner Medical Center, Columbus, OH; University of Chicago, Chicago, IL; National Cancer Institute, Bethesda, MD; Mayo Clinic, Rochester, MN; Weill Cornell Medicine, New York, NY

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