(UroToday.com) The 2023 ESMO annual meeting included a session on urothelial carcinoma, featuring a presentation by Dr. Petros Grivas discussing results from a phase 1b single-arm trial of bintrafusp alfa for pretreated, locally advanced/unresectable or metastatic urothelial cancer. Patients with advanced urothelial carcinoma have poor prognosis after progression on platinum-based chemotherapy with the need to develop more safe and effective therapies. Immune checkpoint inhibitors post-platinum-based chemotherapy provide overall response rate (ORR) ≤ 21%.1 Furthermore, TGF-β pathway can mediate resistance to immune checkpoint inhibitors in advanced urothelial carcinoma. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of extracellular domain of TGF-βRII receptor (“trap”) fused to a human IgG1 monoclonal antibody blocking PD-L1. As such, Dr. Grivas and colleagues conducted a phase 1b trial evaluating the safety/efficacy of bintrafusp alfa in platinum-based chemotherapy-refractory advanced urothelial carcinoma.
This open-label multicenter trial enrolled patients with platinum-based chemotherapy-refractory advanced urothelial carcinoma (ECOG PS ≤ 1) with ≤2 lines of systemic therapy for advanced urothelial carcinoma (no prior therapy targeting T-cell co-stimulation, immune checkpoint inhibitors, or TGF-β pathway). Patients received bintrafusp alfa 1200mg every 2 weeks until progression, unacceptable toxicity, death, withdrawal, or for ≤2 years. The primary endpoint was investigator-assessed confirmed ORR (RECIST 1.1), and secondary endpoints included duration of response (DOR), PFS, OS. A Bayesian predictive probability design for the primary endpoint had 5.7% alpha (type I error) and 85.4% power to rule out ORR ≤21% (target ORR ≥ 40% and target accrual 40 patients).
Accrual was stopped for this trial based on available data indicating that bintrafusp alfa was unlikely to show meaningful benefit beyond currently available therapies, also considering the evolving therapy landscape. Between October 15, 2020, and August 26, 2021, 25 patients (21 men, median age 67) were enrolled. The baseline characteristics are as follows:
At data cutoff (August 15, 2022), 24 patients had discontinued treatment and 1 patient was receiving bintrafusp alfa. The confirmed ORR was 20% (5 patients; 95% CI 6.8-40.7; 2 complete responses, 3 partial responses), and an additional 3 patients had stable disease (best response) resulting in a disease control rate of 32%:
The median DOR was not reached, median PFS was 1.8 months (95% CI 1.2-3.4), and median OS was not reached. The median number of bintrafusp alfa doses was 4, and 24 patients discontinued bintrafusp alfa [14 for progression, 8 for treatment-emergent adverse events, one completed therapy, and one death]. The safety population included 25 patients who received ≥ 1 dose of bintrafusp alfa and all patients experienced treatment-emergent adverse events, of which the most common were anemia (44%), constipation (32%), pruritus (28%), and fatigue. Seventeen (68%) patients experienced treatment-related adverse events and 7 patients developed grade ≥3 events, of which the most common were anemia (12%):
Treatment related adverse events led to permanent discontinuation of study treatment in 6 (24%) patients (colitis, acute kidney injury, nephropathy, pneumonitis, keratosis pilaris, and other), and there were no treatment-related deaths. Immune-related adverse events were noted in 8 (32%) of patients, of which 5 (20%) patients experienced grade 3 events. There were no grade 4-5 events:
Limitations include the relatively small size, no randomization, lack of granularity of data regarding ECOG performance status, sites of metastasis, Bellmunt risk factors, histology, tumor location, PDL-1 IHC, and FGFR2/3 genomic status.
Dr. Grimm concluded his presentation by discussing results from a phase 1b single-arm trial of bintrafusp alfa for pretreated, locally advanced/unresectable or metastatic urothelial cancer with the following concluding statements:
- Accrual was feasible but further development of bintrafusp alfa in this therapy setting was halted by the sponsor
- Future studies are needed to further assess the role of TFG-β pathway inhibition in urothelial carcinoma, including in combination with the anti-PD(L)1 inhibition
Presented by: Petros Grivas, MD, PhD, University of Washington, Seattle, WA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.
References:
- Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376(11):1015-1026.