A phase Ib single-arm study of bintrafusp alfa for the treatment of pretreated, locally advanced/unresectable or metastatic urothelial cancer.
Authors: Grivas Petros , Morales-Barrera Rafael , Sridhar Srikala S. , Loriot Yohann , Van Der Heijden Michiel Simon , Galsky Matt D. , Baxter Dawn , Khaled Ahmed Hussein , Hug Bruce A. 
Published: March 2021

TPS501 Background: Urothelial cancer (UC) is the most common histological subtype of bladder cancer. For patients with metastatic UC, platinum-containing chemotherapy (CT) is the first-line standard of care. With 5 PD-(L)1 inhibitors approved for second-line treatment of platinum-refractory advanced UC, objective response rates (ORRs) in this setting (15% to 21%) and in first-line cisplatin-ineligible patients (23% to 31%) suggest that there remains a significant unmet need for improved outcomes. TGF-β signaling has been associated with resistance to PD-(L)1 inhibitors in patients with UC. Bintrafusp alfa (BA) is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In murine models, BA resulted in improved antitumor activity vs TGF-β or PD-L1 monotherapies alone or in combination. In 2 phase I trials (NCT02517398 and NCT02699515), BA demonstrated a manageable safety profile and encouraging clinical efficacy in >670 patients with advanced solid tumors. Here we describe a phase Ib study (NCT04349280) that will assess the clinical activity and safety profile of BA in platinum-experienced patients with locally advanced/unresectable or metastatic UC. Colocalized, simultaneous inhibition of the TGF-β and PD-L1 pathways by BA is hypothesized to elicit greater antitumor activity than anti–PD-(L)1 therapies in patients with UC. Methods: This open-label, multicenter, single-arm trial is accruing patients with histologically confirmed locally advanced/unresectable or metastatic UC (ECOG PS ≤1) with disease progression or recurrence after platinum-based CT. Patients must not have received >2 lines of systemic therapy for metastatic disease or prior therapy targeting T-cell costimulation, or checkpoint or TGF-β pathways. Patients with pneumonitis or a history of noninfectious pneumonitis that required systemic immunosuppression are ineligible. Patients will receive BA 1200 mg every 2 weeks until progression, unacceptable toxicity, death, or study withdrawal, or for up to 2 years. The primary endpoint is investigator-assessed confirmed ORR per RECIST 1.1; key secondary endpoints include duration of response and progression-free survival per the investigator and IRC, overall survival, safety, immunogenicity, and pharmacokinetics. Exploratory biomarker analyses will be conducted using patient samples collected during screening and prior to administration of BA. The base ORR used for the null hypothesis is 21%, and the target ORR is 40%. Using a predictive probability design and an estimated enrollment of 40 patients, the type I error rate is 5.70% and the power is 85.39%. As of September 2020, 3 sites in 2 countries have been activated and no patients have been enrolled. Clinical trial information: NCT04349280.