Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer

Abstract

Purpose: Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody blocking PD-L1, was evaluated as treatment in patients with locally advanced or persistent, recurrent, or metastatic (P/R/M) cervical cancer. Experimental Design: In this multicenter, open-label, phase 1b trial (NCT04551950), patients with P/R/M cervical cancer received bintrafusp alfa 2400 mg once every 3 weeks (Q3W) plus cisplatin or carboplatin plus paclitaxel with (Cohort 1A; n=8) or without (Cohort 1B; n=9) bevacizumab; patients with locally advanced cervical cancer received bintrafusp alfa 2400 mg Q3W plus cisplatin plus radiation, followed by bintrafusp alfa monotherapy maintenance (Cohort 2; n=8). The primary endpoint was safety; secondary endpoints included efficacy (including objective response rate) and pharmacokinetics. Results: At the data cut-off of 27 April 2022, patients in Cohorts 1A, 1B, and 2 had received bintrafusp alfa for a median duration of 37.9, 31.1, and 16.7 weeks, respectively. Two dose-limiting toxicities (grade 4 amylase elevation and grade 3 menorrhagia) unrelated to bintrafusp alfa were observed in Cohort 1B and none in other cohorts. Most treatment-emergent adverse events of special interest were grades 1-2 in severity, most commonly anemia (62.5%-77.8%) and bleeding events (62.5%-77.8%). Objective response rate was 75.0% (95% CI, 34.9-96.8), 44.4% (95% CI, 13.7-78.8) and 62.5% (95% CI, 24.5-91.5) in Cohorts 1A, 1B, and 2, respectively. Conclusions: Bintrafusp alfa had manageable safety and demonstrated clinical activity, further supporting the investigation of TGF-β/PD-L1 inhibition in HPV-associated cancers, including cervical cancer.