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

Abstract

Bintrafusp alfa; Cervical cancer

Bintrafusp alfa; Cáncer de cuello uterino

Bintrafusp alfa; Càncer de coll uterí

Purpose: Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGFβ receptor II (a TGFβ “trap”) fused to a human IgG1 mAb blocking programmed death-ligand 1 (PD-L1), was evaluated as treatment in patients with locally advanced or persistent, recurrent, or metastatic (P/R/M) cervical cancer. Patients and Methods: In this multicenter, open-label, phase Ib trial (NCT04551950), patients with P/R/M cervical cancer received bintrafusp alfa 2,400 mg once every 3 weeks 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 2,400 mg every 3 weeks 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 cutoff of April 27, 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% confidence interval (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 TGFβ/PD-L1 inhibition in human papillomavirus–associated cancers, including cervical cancer.

The authors thank the patients and their families, investigators, coinvestigators, and study teams at each of the participating centers and at the healthcare business of Merck KGaA, Darmstadt, Germany. Medical writing support was provided by Rebecca Yao, PhD, and Joyce Lee, PhD, of MediTech Media Asia Pacific, which was funded by the healthcare business of Merck KGaA (CrossRef Funder ID: 10.13039/100009945) and was previously part of an alliance between the healthcare business of Merck KGaA and GlaxoSmithKline, in accordance with Good Publication Practice (GPP 2022) guidelines (https://www.ismpp.org/gpp-2022). The trial was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) and was previously part of an alliance between the healthcare business of Merck KGaA and GlaxoSmithKline. The healthcare business of Merck KGaA provided the trial drugs. The investigators worked with the healthcare business of Merck KGaA on the trial design, collection and analysis of data, and interpretation of results. The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.