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 methods: In 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.

Conflict of interest statement

C.-C. Lin reports honoraria from Eli Lilly, Novartis, and Roche; has consulted for Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, and Novartis; and received travel grants from BeiGene and Eli Lilly. T. Doi has consulted for Taiho, Merck Sharp & Dohme, Amgen, Sumitomo Dainippon Pharma, Rakuten Medical, Daiichi Sankyo, Takeda, Bayer, Novartis, Boehringer Ingelheim, AbbVie, and Janssen Pharma; has received research grants from Bristol Myers Squibb, Taiho, Merck Sharp & Dohme, Novartis, Merck Biopharma Co., Ltd., Japan—an affiliate of Merck KGaA, Darmstadt, Germany—Lilly, AbbVie, Boehringer Ingelheim, Eisai, Kyowa Hakko Kirin, IQVIA, Pfizer, Sumitomo Dainippon Pharma, and Daiichi Sankyo; and reports honoraria from Bristol Myers Squibb, Astellas, AbbVie, Ono Pharmaceutical, Oncolys BioPharma, and Taiho. K. Muro has consulted for Ono Pharmaceutical, Amgen, and Solasia Pharma; has received research grants from Parexel International, Merck Biopharma Co., Ltd., Japan—an affiliate of Merck KGaA, Darmstadt, Germany—Merck Sharp & Dohme, Daiichi Sankyo, Sanofi, Sumitomo Dainippon Pharma, Shionogi, Pfizer, Mediscience Planning, and Solasia Pharma; and reports honoraria from Eli Lilly, Chugai, Takeda, Ono Pharmaceutical, Taiho, Sanofi, Bristol Myers Squibb, and Bayer. T. Esaki received research grants from Merck Sharp & Dohme, Novartis, Sumitomo Dainippon Pharma, Ono Pharmaceutical, Daiichi Sankyo, Astellas, Amgen, BeiGene, Pierre Fabre Medicament, Ignyta, Array BioPharma, Bayer, Taiho, and Lilly; and reports honoraria from Chugai, Taiho, Merck Sharp & Dohme, Eli Lilly, Daiichi Sankyo, Nihon Kayaku, Sanofi, Ono Pharmaceutical, Takeda, Bayer, Merck Biopharma Co., Ltd., Japan—an affiliate of Merck KGaA, Darmstadt, Germany—Bristol Myers Squibb, and Eisai. H. Hara has consulted for Lilly, Merck Sharp & Dohme, and Ono Pharmaceutical; received research grants from Astellas, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Sumitomo Dainippon Pharma, Eisai, Incyte, LSK BioPharma, Merck Biopharma Co., Ltd., Japan—an affiliate of Merck KGaA, Darmstadt, Germany—Merck Sharp & Dohme, Ono Pharmaceutical, Pfizer, and Taiho; and reports honoraria from Bayer, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, Merck Biopharma Co., Ltd., Japan—an affiliate of Merck KGaA, Darmstadt, Germany—Merck Sharp & Dohme, Ono Pharmaceutical, Sanofi, Taiho, Takeda, and Yakult. C. Helwig is an employee of and has ownership interest in Merck KGaA, Darmstadt, Germany. I. Dussault is an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA—an affiliate of Merck KGaA, Darmstadt, Germany—and has ownership interest in EMD Serono Research & Development Institute, Inc., and Amgen. M. Osada is an employee of Merck Biopharma Co., Ltd., Japan—an affiliate of Merck KGaA, Darmstadt, Germany. S. Kondo has received research funding from ASLAN Pharmaceuticals, AstraZeneca, Bayer, Eli Lilly, Merck Sharp & Dohme, and Pfizer. The remaining authors declare no competing interests.

Figures

Fig. 1

Tumor response to bintrafusp alfa assessed by independent review. a Best change in sum of diameters and tumor mutation count. A threshold of 1% was used to characterize tumors as either PD-L1 positive (≥ 1%) or negative (< 1%) using an anti–PD-L1 antibody clone 73-10. Three patients had non-evaluable PD-L1 expression. b Time to and duration of response. The upper dashed line represents progression at 20% increase in size of target lesions, and the lower dashed line represents the RECIST boundary for PR at 30% decrease in size of target lesions. Ten patients are not shown due to having either no target lesions identified by independent review committee prior to the first dose (n = 6), no post-baseline assessment (n = 2), or other reasons (n = 2). NE not evaluable, PD progressive disease, PD-1 programmed cell death protein 1, PD-L1 programmed death-ligand 1, PR partial response, RECIST Response Evaluation Criteria in Solid Tumors, SD stable disease. aTumor mutation count unavailable. bPatient had a best change in sum of diameters of > 30% that did not meet the criteria for a PR at the next tumor assessment

Fig. 2

Survival outcomes. Kaplan–Meier survival curves for a independent review committee-assessed PFS and b OS. CI confidence interval, NR not reached, OS overall survival, PFS progression-free survival

Fig. 3

Exploratory biomarker analysis by confirmed best overall response to bintrafusp alfa per independent review committee assessment. a Immune phenotype analysis. b Gene expression analysis; 2 patients with confirmed best overall responses of PD were not included in the RNAseq analysis due to failing QC. CR complete response, IFNG interferon gamma, NE not evaluable, PD progressive disease, PR partial response, QC Quality control, RNAseq RNA sequencing, SD stable disease, TGFB1 transforming growth factor-β 1, TPM transcript per million, TWIST1 twist family bHLH transcription factor 1, VIM vimentin