Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Second-Line Treatment of Patients With NSCLC: Results From an Expansion Cohort of a Phase 1 Trial

Luis Paz-Ares, Tae Min Kim, David Vicente, Enriqueta Felip, Dae Ho Lee, Ki Hyeong Lee, Chia Chi Lin, Maria Jose Flor, Massimo Di Nicola, Rosa Maria Alvarez, Isabelle Dussault, Christoph Helwig, Laureen S. Ojalvo, James L. Gulley, Byoung Chul Cho

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11 Citations (Scopus)

Abstract

Introduction: The safety and efficacy of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β (TGF-β) receptor II (a TGF-β “trap“) fused to a human immunoglobulin G1 antibody blocking programmed death-ligand 1 (PD-L1), was evaluated in patients with advanced NSCLC. Methods: This expansion cohort of NCT02517398, an ongoing, phase 1, open-label trial, includes 80 patients with advanced NSCLC that progressed after platinum doublet therapy or after platinum-based adjuvant or neoadjuvant treatment and those who also have not received previous immunotherapy. Patients were randomized at a one-to-one ratio to receive either bintrafusp alfa 500 mg or the recommended phase 2 dosage of 1200 mg every 2 weeks. The primary end point was the best overall response (by Response Evaluation Criteria in Solid Tumors 1.1 as adjudicated by independent review committee) and was assessed by the objective response rate (ORR). Results: A total of 80 patients were randomized to receive bintrafusp alfa 500 or 1200 mg (n = 40 each). Median follow-up was 51.9 weeks (IQR, 19.6–74.0). The ORR in all patients was 21.3% (17 of 80). The ORR was 17.5% (seven of 40) and 25.0% (10 of 40) for the 500 mg dose and the 1200 mg dose (recommended phase 2 dose), respectively. At the 1200 mg dose, patients with PD-L1–positive and PD-L1–high (≥80% expression on tumor cells) had ORRs of 36.0% (10 of 27) and 85.7% (six of seven), respectively. Treatment-related adverse events occurred in 55 of the 80 patients (69%) and were graded as greater than or equal to 3 in 23 of the 80 patients (29%). Of the 80 patients, eight (10%) had a treatment-related adverse event that led to treatment discontinuation; no treatment-related deaths occurred. Conclusions: Bintrafusp alfa had encouraging efficacy and manageable tolerability in patients with NSCLC previously treated with platinum.

Original languageEnglish
Pages (from-to)1210-1222
Number of pages13
JournalJournal of Thoracic Oncology
Volume15
Issue number7
DOIs
Publication statusPublished - 2020 Jul

Bibliographical note

Funding Information:
LP-A was funded by ISCIII ( PI14/01964 , PIE15/00076 , PI17/00778 , and DTS17/00089 ) and CIBERONC ( CD16/12/00442 ) and cofunded by Fonds européen de développement régional from Regional Development European Funds (European Union). Medical writing support was provided by Abhijith Thippeswamy, of ClinicalThinking, which was also funded by Merck KGaA and GlaxoSmithKline in accordance with Good Publication Practice guidelines ( http://www.ismpp.org/gpp3 ). Merck KGaA, Darmstadt, Germany, provided the study drug and worked with investigators on the trial design and plan, collection and analysis of data, and interpretation of results. The authors thank Christian Ihling, of Merck KGaA, for his substantial contribution to the immune phenotype analysis.

Funding Information:
Disclosure: Dr. Paz-Ares is an external member on the board of Genomica; has received honoraria from Adacap, Amgen, AstraZeneca, Bayer, Blueprint, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Incyte, Ipsen, Lilly, Merck KGaA (Darmstadt, Germany), Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, and Sysmex; is cofounder and board member of Altum Sequencing; and has served in nonfinancial senior leadership roles in other medical societies, research groups, foundations, and political pressure groups. Dr. Kim has received research funding from AstraZeneca -KHIDI. Dr. Felip has served as a speaker for AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Prime Oncology, Roche, and Takeda, and has served in advisory roles for all of the aforementioned companies in addition to BerGenBio, Blueprint Medicines, Guardant Health, Janssen, Samsung, and Touch Time. Dr. D.H. Lee has received honoraria from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ChongKeunDang, CJ Healthcare, Eli Lilly, Genexine, Janssen, Merck KGaA, Merck Sharp & Dohme, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Bio-Pharm, ST Cube, and Takeda. Dr. K.H. Lee has served in advisory roles for AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme. Dr. Lin has received honoraria from BeiGene, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Roche, and Takeda. Alvarez has received honoraria from Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Novartis, PharmaMar, and Roche/Genentech. Drs. Dussault and Ojalvo are employees of EMD Serono Research and Development Institute, Inc. (a business of Merck KGaA). Mr. Helwig is an employee of Merck KGaA, Darmstadt, Germany. Dr. Gulley reports that his institute has a Cooperative Research and Development Agreement with EMD Serono Research and Development Institute, Inc.; is a coprimary investigator on the Cooperative Research and Development Agreement but with no personal financial interests; and is an unpaid member of the expert oncology faculty that advises EMD Serono Research and Development Institute, Inc. Dr. Cho has received research funding from AstraZeneca , Bayer , Champions Oncology , Dizal Pharma , Dong-A ST , Janssen , Merck Sharp & Dohme , MOGAM Institute , Novartis , Ono, and Yuhan; has provided consultancy to AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Ono, Pfizer, Roche, Takeda, and Yuhan; has stock in TheraCanVac Inc., Gencurix Inc., and Bridgebio therapeutics; and receives royalties from Champions Oncology. The remaining authors declare no conflict of interest.

Funding Information:
Disclosure: Dr. Paz-Ares is an external member on the board of Genomica; has received honoraria from Adacap, Amgen, AstraZeneca, Bayer, Blueprint, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Incyte, Ipsen, Lilly, Merck KGaA (Darmstadt, Germany), Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, and Sysmex; is cofounder and board member of Altum Sequencing; and has served in nonfinancial senior leadership roles in other medical societies, research groups, foundations, and political pressure groups. Dr. Kim has received research funding from AstraZeneca-KHIDI. Dr. Felip has served as a speaker for AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Prime Oncology, Roche, and Takeda, and has served in advisory roles for all of the aforementioned companies in addition to BerGenBio, Blueprint Medicines, Guardant Health, Janssen, Samsung, and Touch Time. Dr. D.H. Lee has received honoraria from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ChongKeunDang, CJ Healthcare, Eli Lilly, Genexine, Janssen, Merck KGaA, Merck Sharp & Dohme, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Bio-Pharm, ST Cube, and Takeda. Dr. K.H. Lee has served in advisory roles for AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme. Dr. Lin has received honoraria from BeiGene, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Roche, and Takeda. Alvarez has received honoraria from Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Novartis, PharmaMar, and Roche/Genentech. Drs. Dussault and Ojalvo are employees of EMD Serono Research and Development Institute, Inc. (a business of Merck KGaA). Mr. Helwig is an employee of Merck KGaA, Darmstadt, Germany. Dr. Gulley reports that his institute has a Cooperative Research and Development Agreement with EMD Serono Research and Development Institute, Inc.; is a coprimary investigator on the Cooperative Research and Development Agreement but with no personal financial interests; and is an unpaid member of the expert oncology faculty that advises EMD Serono Research and Development Institute, Inc. Dr. Cho has received research funding from AstraZeneca, Bayer, Champions Oncology, Dizal Pharma, Dong-A ST, Janssen, Merck Sharp & Dohme, MOGAM Institute, Novartis, Ono, and Yuhan; has provided consultancy to AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Ono, Pfizer, Roche, Takeda, and Yuhan; has stock in TheraCanVac Inc., Gencurix Inc., and Bridgebio therapeutics; and receives royalties from Champions Oncology. The remaining authors declare no conflict of interest.LP-A was funded by ISCIII (PI14/01964, PIE15/00076, PI17/00778, and DTS17/00089) and CIBERONC (CD16/12/00442) and cofunded by Fonds europ?en de d?veloppement r?gional from Regional Development European Funds (European Union). Medical writing support was provided by Abhijith Thippeswamy, of ClinicalThinking, which was also funded by Merck KGaA and GlaxoSmithKline in accordance with Good Publication Practice guidelines (http://www.ismpp.org/gpp3). Merck KGaA, Darmstadt, Germany, provided the study drug and worked with investigators on the trial design and plan, collection and analysis of data, and interpretation of results. The authors thank Christian Ihling, of Merck KGaA, for his substantial contribution to the immune phenotype analysis. For all new products or new indications approved in both the European Union and the US after January 1, 2014, Merck KGaA, Darmstadt, Germany, will share patient-level and study-level data after deidentification and redacted study protocols and clinical study reports from clinical trials in patients. These data will be shared with qualified scientific and medical researchers, on the researcher's request, as necessary, for conducting legitimate research. Such requests must be submitted in writing to the company's data sharing portal. More information can be found at https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html. Where Merck KGaA has a coresearch, codevelopment, comarketing, or copromotion agreement or where the product has been out-licensed, it is recognized that the responsibility for disclosure may be dependent on the agreement between parties. Under these circumstances, Merck KGaA will endeavor to gain agreement to share data in response to requests.

Publisher Copyright:
© 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

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