Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGFβ and PD-L1, in Patients with Esophageal Squamous Cell Carcinoma: Results from a Phase 1 Cohort in Asia

Abstract

Background Patients with esophageal squamous cell carcinoma (SCC) have limited treatment options. Blocking transforming growth factor-β (TGFβ), which can be overexpressed in these tumors, may enhance responses to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] inhibitors. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGFβ receptor II (TGFβRII) (a TGFβ "trap") fused to a human IgG1 monoclonal antibody blocking PD-L1. Objective The objective of this study was to investigate the safety and efficacy of bintrafusp alfa in Asian patients with pretreated, PD-L1-unselected esophageal SCC. Patients and MethodsIn a phase 1 study, Asian patients with pretreated esophageal SCC received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was safety/tolerability with a goal of exploring clinical activity. Results By the database cutoff of August 24, 2018, 30 patients (76.7% had two or more prior anticancer regimens) received bintrafusp alfa for a median of 6.1 weeks; two remained on treatment. Nineteen patients (63.3%) had treatment-related adverse events, seven (23.3%) with grade 3/4 events, and there were no treatment-related deaths. The confirmed objective response rate (ORR) per independent review was 10.0% (95% confidence interval [CI] 2.1-26.5); responses lasted 2.8-8.3 + months. All responses occurred in immune-excluded tumors. Investigator-assessed confirmed ORR was 20.0% (95% CI 7.7-38.6). Median overall survival was 11.9 months (95% CI 5.7-not reached). Conclusions Bintrafusp alfa demonstrated a manageable safety profile and efficacy in Asian patients with pretreated esophageal SCC. Clinical Trials Registration NCT02699515.

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Patients with Esophageal Adenocarcinoma: Results from a Phase 1 Cohort

“…Importantly, skin lesions, such as keratoacanthomas, are anticipated AEs for TGF-β inhibition [ 49 ]. The overall safety profile reported here for bintrafusp alfa in esophageal AC was consistent with those previously observed with bintrafusp alfa treatment in other solid tumors, including esophageal SCC [ 23 , 24 , 39 ].…”

“…Interestingly, all but one response occurred in immune-excluded tumors in this esophageal AC cohort. Similar results were also observed in patients with esophageal SCC from the other study, in which responses were seen exclusively in immune-excluded tumors [ 39 ]. Taken together, the results of the exploratory analyses did not identify predictive biomarkers of response to bintrafusp alfa in this small cohort.…”

“…3 b–g). Further investigation revealed different average levels of tumor TGFB1 expression between patients with esophageal AC in this study and patients with esophageal SCC in a separate phase 1 study of bintrafusp alfa [ 39 ], with 41.8% lower expression in AC than in SCC (false discovery rate–adjusted p < 0.002). TGFB3 expression was also lower in patients with esophageal AC than in those with esophageal SCC, but the difference was not significant (false discovery rate–adjusted p = 0.426).…”

“…Results of exploratory analyses showed that response to bintrafusp alfa was independent of tumor mutation count. Patients in this esophageal AC cohort had lower mutation counts than patients with esophageal SCC enrolled in a different phase 1 study of bintrafusp alfa (NCT02699515) [ 39 ]. Furthermore, the average expression levels of TGFB1 , TGFB2 , and TGFB3 in tumor samples from patients in this study were similar to those from patients with other tumors across phase 1 studies of bintrafusp alfa; however, the levels of TGFB1 and TGFB2 were significantly different (lower and higher, respectively) than those observed in an esophageal SCC cohort of the separate phase 1 study of bintrafusp alfa.…”

NHS-IL12 and bintrafusp alfa combination therapy enhances antitumor activity in preclinical cancer models

“…In preclinical models, BA was shown to activate both the innate and adaptive immune systems and provide long-term protective antitumor immunity, reduce metastasis and fibrosis, and be an effective combination partner with radiation or chemotherapy [ 33 , 34 ]. In phase I clinical trials in patients with advanced solid tumors, BA showed early evidence of clinical activity [35] , [36] , [37] , [38] , [39] , [40] .…”