TY - JOUR
T1 - Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Patients with Esophageal Adenocarcinoma
T2 - Results from a Phase 1 Cohort
AU - Tan, Benjamin
AU - Khattak, Adnan
AU - Felip, Enriqueta
AU - Kelly, Karen
AU - Rich, Patricia
AU - Wang, Ding
AU - Helwig, Christoph
AU - Dussault, Isabelle
AU - Ojalvo, Laureen S.
AU - Isambert, Nicolas
N1 - Funding Information:
This trial was funded by Merck KGaA, Darmstadt, Germany, and is part of an alliance between Merck KGaA and GlaxoSmithKline. Merck KGaA provided the study drug and worked with investigators on the trial design and plan, collection and analysis of data, and interpretation of results. Funding for a professional medical writer with access to the data was provided by Merck KGaA and GlaxoSmithKline.
Funding Information:
The authors thank the patients and their families, investigators, co-investigators, and study teams at each of the participating centers and at Merck KGaA, Darmstadt, Germany, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; an affiliate of Merck KGaA, Darmstadt, Germany. The authors thank Christian Ihling, of Merck KGaA, and George Locke, of EMD Serono Research & Development Institute, Inc., for their substantial contribution to the immune phenotype and biomarker analysis, respectively. Medical writing support was provided by Lauren Rusnak, PhD, of ClinicalThinking Inc, Hamilton, NJ, USA, which was also funded by Merck KGaA and GlaxoSmithKline in accordance with Good Publication Practice (GPP3) guidelines ( http://www.ismpp.org/gpp3 ).
Funding Information:
B. Tan received research grants from EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; an affiliate of Merck KGaA, Darmstadt, Germany. A. Khattak has consulted for Merck Healthcare Pty. Ltd., Australia; an affiliate of Merck KGaA, Darmstadt, Germany; received research grants from Merck Sharp & Dohme; and reports honoraria from Bayer, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Merck Healthcare Pty. Ltd., and Novartis. E. Felip has consulted for AbbVie, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Guardant Health, Janssen, Merck KGaA, Darmstadt, Germany, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Samsung, Takeda, and GlaxoSmithKline; has received research grants from Fundación Merck Salud; reports honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, prIME Oncology, Medscape, and touchIME; and is an independent member of the Grifols board. K. Kelly has consulted for AbbVie, AstraZeneca, Bristol Myers Squibb, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; an affiliate of Merck KGaA, Darmstadt, Germany, Eli Lilly, Inviata, Novartis, Regeneron, and Takeda; received research grants and other research support from AbbVie, Bristol Myers Squibb, Celgene, EMD Serono Research & Development Institute, Inc., Five Prime, Genentech, Eli Lilly, Lycera, Merck, Novartis, Regeneron, Tizona, and Transgene; reports honoraria from Merck; and reports royalties from UpToDate. P. Rich is an employee of Cancer Treatment Centers of America. D. Wang declares no competing interests. 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. L.S. Ojalvo is an employee of and reports intellectual property interests with EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; an affiliate of Merck KGaA, Darmstadt, Germany. N. Isambert has consulted for Ipsen and Transgene.
Funding Information:
The authors thank the patients and their families, investigators, co-investigators, and study teams at each of the participating centers and at Merck KGaA, Darmstadt, Germany, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; an affiliate of Merck KGaA, Darmstadt, Germany. The authors thank Christian Ihling, of Merck KGaA, and George Locke, of EMD Serono Research & Development Institute, Inc., for their substantial contribution to the immune phenotype and biomarker analysis, respectively. Medical writing support was provided by Lauren Rusnak, PhD, of ClinicalThinking Inc, Hamilton, NJ, USA, which was also funded by Merck KGaA and GlaxoSmithKline in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3 ).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/7
Y1 - 2021/7
N2 - 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 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. 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 Methods: In 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.
AB - 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 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. 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 Methods: In 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.
UR - http://www.scopus.com/inward/record.url?scp=85104127652&partnerID=8YFLogxK
U2 - 10.1007/s11523-021-00809-2
DO - 10.1007/s11523-021-00809-2
M3 - Article
C2 - 34009501
AN - SCOPUS:85104127652
SN - 1776-2596
VL - 16
SP - 435
EP - 446
JO - Targeted Oncology
JF - Targeted Oncology
IS - 4
ER -