Evaluation of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in cervical cancer: Data from phase 1 and phase 2 studies.
Authors: Strauss Julius , Braiteh Fadi S. , Calvo Emiliano , De Miguel Maria , Cervantes Andres , Edenfield William Jeffery , Li Tianhong , Rasschaert Marika Anna , Park-Simon Tjoung-Won , Longo Federico , Paz-Ares Luis G. , Spira Alexander I. , Jehl Genevieve , Dussault Isabelle , Ojalvo Laureen S. , Gulley James L. , Allan Suzanne Wendy 
Published: June 2021

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Background: The accelerated FDA approval of pembrolizumab validated the efficacy of anti–PD-(L)1 therapy for pts with recurrent/metastatic cervical cancer; however, the objective response rate (ORR) with pembrolizumab was 14.3% in pts with PD-L1 expressing tumors. HPV infection is implicated in > 95% of cervical cancers and is linked to upregulation of TGF-β signaling. Bintrafusp alfa 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. We report pooled safety and efficacy in pts with immune checkpoint inhibitor–naive, recurrent/metastatic cervical cancer treated with bintrafusp alfa in phase 1 (INTR@PID 001; NCT02517398) and phase 2 (study 012; NCT03427411) studies. Methods: Pts with pretreated, immune checkpoint inhibitor–naive, recurrent/metastatic cervical cancer received bintrafusp alfa 0.3-30 mg/kg (phase 1 dose escalation) or 1200 mg Q2W (phase 1 expansion/phase 2) until progressive disease, unacceptable toxicity, or withdrawal. Treatment past progression was allowed. Primary endpoints were safety for the dose-escalation part of the phase 1 study and best overall response per RECIST 1.1 for the expansion part of phase 1 and phase 2 studies. Secondary endpoints for the expansion part of the phase 1 and 2 studies included safety. Results: As of May 15, 2020 (phase 1) and December 22, 2020 (phase 2), 39 pts had received bintrafusp alfa for a median duration of 2.8 months (range, 0.5-19.3). The median follow-up to data cutoff was 35.0 months and 24.1 months for the phase 1 and phase 2 studies, respectively. All pts had received prior anticancer therapy; 16 pts (41.0%) had received ≥3 prior anticancer regimens. There were 2 complete responses and 9 partial responses (PRs; ORR per RECIST 1.1, 28.2%). Median duration of response was 11.7 months (range, 1.4-41.2), and 5 pts (45.5%) had ongoing responses (duration 1.5-41.2 months). An additional delayed PR was observed (duration 23.7 months). Reponses occurred irrespective of tumor histology or prior bevacizumab or radiation treatment. Median overall survival (mOS) was 13.4 months (95% CI, 5.5 to not reached); 24-month OS rate was 33.2%. Any-grade treatment-related adverse events (TRAEs) occurred in 33 pts (84.6%). Grade 3 TRAEs occurred in 8 pts (20.5%; anemia, colitis, gastroparesis, upper gastrointestinal hemorrhage, keratoacanthoma, cystitis noninfective, hematuria, pneumonitis, rash macular [n = 1 each]); 1 patient (2.6%) had a grade 4 TRAE (asymptomatic hypokalemia related to the above grade 3 gastroparesis). No treatment-related deaths occurred. Conclusions: Bintrafusp alfa had a manageable safety profile and demonstrated clinical activity in pts with heavily pretreated, immune checkpoint inhibitor–naive recurrent/metastatic cervical cancer. Clinical trial information: NCT02517398 , NCT03427411.