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.

Abstract

5509 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.

The Changing Landscape of Systemic Treatment for Cervical Cancer: Rationale for Inhibition of the TGF-β and PD-L1 Pathways

“…In contrast, anti-PD-(L)1 therapies tend to be less effective in patients with adenocarcinoma (93,102,115) and those who have been exposed to bevacizumab (37,102). Additionally, the safety profile of bintrafusp alfa in patients with heavily pretreated recurrent or metastatic cervical cancer who had disease progression with platinum-containing chemotherapy was consistent with that of anti-PD-(L)1 therapies, except for treatment-related AEs known to be associated with TGF-b inhibitors (e.g., localized skin lesions including keratoacanthomas) (94,109).…”

“…One patient had a delayed partial response after initial disease progression ( 127 ). In a post hoc pooled analysis of patients with recurrent or metastatic cervical cancer from the INTR@PID 001 study and a phase 2 single-center study (NCI 012), the ORR was 28.2% (95% CI, 15.0%-44.9%) ( 94 ). Responses to bintrafusp alfa were long-lasting, with a median DOR of 11.7 months (range, 1.4-41.2 months), and were observed irrespective of tumor histology or prior bevacizumab treatment.…”

“…Treatment responses occurred irrespective of PD-L1 status. In a pooled analysis of patients from the INTR@PID 001 and NCI 012 trials, responses to bintrafusp alfa were observed irrespective of tumor histology ( 94 ), although a systematic approach in a larger trial might shed additional insights.…”

Recurrent or primary metastatic cervical cancer: current and future treatments

“…Bintrafusp alfa is a first-inclass bifunctional fusion protein composed of the extracellular domain of the TGF-b-RII receptor which functions as a TGF-b 'trap' fused to an PD-L1 inhibitor. 68 Strauss et al 69 reported pooled (phase I and II) safety and efficacy of 39 patients with ICI-naive, recurrent/metastatic CC treated with this drug. The ORR was 28.2% in the all-comer population and responses occurred irrespective of tumor histology or prior bevacizumab or radiation treatment.…”

Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy

“…In an evaluation of bintrafusp alfa from phase I and II trials in cervical cancer, there were single reports of grade 3 treatment-related upper-gastrointestinal hemorrhage as well as hematuria [106]. This cohort was assessed in a larger data set of HPV-related malignancies, and across 59 patients, 38 patients (64.4%) experienced treatment-emergent bleeding, with nine patients (15.3%) experiencing grade 3 bleeding events [93].…”