M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with post-platinum esophageal adenocarcinoma (EAC): Preliminary results from a phase I cohort

Tan, Benjamin; Khattak, Adnan; Felip, Enriqueta; Kelly, Karen; Rich, Patricia; Wang, D.; Helwig, Christoph; Dussault, Isabelle; Ojalvo, L.; Isambert, Nicolás

doi:10.1093/annonc/mdy282.027

Cited by 4 publications

(7 citation statements)

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“…In this study, potentially TGFβ-related skin lesions were well managed and led to discontinuation of bintrafusp alfa in one patient. Overall, the safety profile observed for bintrafusp alfa in patients with esophageal SCC was consistent with results from an esophageal AC cohort in a separate study and other solid tumor types [38,39,54].…”

Section: Discussionsupporting

confidence: 81%

“…However, response to bintrafusp alfa was observed independently of tumor , 3b-g). The average tumor TGFB1 expression level in this esophageal SCC cohort was 71.9% higher (false discovery rate-adjusted p < 0.002) than in an esophageal AC cohort from a separate phase 1 study of bintrafusp alfa [54]. The same trend was also observed for TGFB3; however, the difference was not significant (false discovery rate-adjusted p = 0.426).…”

Section: Biomarker Analysessupporting

confidence: 48%

“…Results of the exploratory analyses showed that response to bintrafusp alfa was independent of tumor mutation count. However, a higher mutation count was observed in this esophageal SCC cohort than in patients with esophageal AC from a separate phase 1 study (NCT02517398) [54]. Analysis of archival tumor samples showed significant differences in the average expression levels of TGFB1 (higher) and TGFB2 (lower) in this cohort compared with other tumor cohorts from phase 1 studies of bintrafusp alfa, including esophageal AC.…”

Section: Discussionmentioning

confidence: 62%

“…In this study, responses to bintrafusp alfa were only seen in tumors with an immune-excluded phenotype. Interestingly, in an esophageal AC cohort from the other phase 1 study, all but one response to bintrafusp alfa also occurred in patients with immune-excluded tumors [54]. Taken together, the results of the exploratory analyses did not identify predictive biomarkers of response to bintrafusp alfa in this small cohort.…”

Section: Discussionmentioning

confidence: 71%

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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

et al. 2021

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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.

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Section: Discussionsupporting

confidence: 81%

Section: Biomarker Analysessupporting

confidence: 48%

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 71%

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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

et al. 2021

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“…in patients with heavily pretreated advanced solid tumors [23][24][25]. Here we report results from an expansion cohort of the phase 1 study, which investigated the efficacy and safety of bintrafusp alfa in patients with advanced, post-platinum esophageal AC, unselected for PD-L1 expression.…”

Section: Key Pointsmentioning

confidence: 99%

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

et al. 2021

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Background Esophageal adenocarcinoma patients have limited treatment options. TGF-β can be upregulated in esophageal adenocarcinoma, and blocking this pathway may enhance clinical response to PD-(L)1 inhibitors. Bintrafusp alfa is a firstin-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. Objective The objective of this study was to investigate the efficacy and safety of bintrafusp alfa in patients with advanced, post-platinum esophageal adenocarcinoma, unselected for PD-L1 expression. Patients and MethodsIn this phase 1 study, patients with post-platinum, PD-L1-unselected esophageal adenocarcinoma received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was confirmed best overall response per RECIST 1.1 by independent review committee (IRC). Results By the database cutoff of 24 August 2018, 30 patients (80.0% had two or more prior anticancer regimens) received bintrafusp alfa for a median of 6.1 weeks. The confirmed objective response rate (ORR) per IRC was 20.0% (95% CI 7.7-38.6); responses lasted 1.3-8.3 months. Most responses (83.3%) occurred in tumors with an immune-excluded phenotype. Investigator-assessed confirmed ORR was 13.3% (95% CI 3.8-30.7). Nineteen patients (63.3%) had treatment-related adverse events: seven patients (23.3%) had grade 3 events; no grade 4 events or treatment-related deaths occurred. Conclusions Bintrafusp alfa showed signs of clinical efficacy with a manageable safety profile in patients with heavily pretreated, advanced esophageal adenocarcinoma. Clinical Trials Registration NCT02517398.

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Population Pharmacokinetic Analysis of Bintrafusp Alfa in Different Cancer Types

Wilkins¹,

Vugmeyster

Dussault

et al. 2019

Adv Ther

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M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with post-platinum esophageal adenocarcinoma (EAC): Preliminary results from a phase I cohort

Cited by 4 publications

References 0 publications

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

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

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

Population Pharmacokinetic Analysis of Bintrafusp Alfa in Different Cancer Types

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