Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

Julius Strauss; Margaret E. Gatti-Mays; Byoung Chul Cho; Andrew Hill; Sébastien Salas; Edward McClay; Jason M. Redman; Houssein A. Sater; Renee N. Donahue; Caroline Jochems; Elizabeth Lamping; Andrea Burmeister; Jennifer L. Marté; Lisa M. Cordes; Marijo Bilusic; Fatima Karzai; Laureen S. Ojalvo; Genevieve Jehl; P. Alexander Rolfe; Christian S. Hinrichs; Ravi A. Madan; Jeffrey Schlom; James L. Gulley

doi:10.1136/jitc-2020-001395

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

Julius Strauss, Margaret E. Gatti-Mays, Byoung Chul Cho, Andrew Hill, Sébastien Salas, Edward McClay, Jason M. Redman, Houssein A. Sater, Renee N. Donahue, Caroline Jochems, Elizabeth Lamping, Andrea Burmeister, Jennifer L. Marté, Lisa M. Cordes, Marijo Bilusic, Fatima Karzai, Laureen S. Ojalvo, Genevieve Jehl, P. Alexander Rolfe, Christian S. HinrichsRavi A. Madan, Jeffrey Schlom, James L. Gulley

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

Background Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β 'trap') fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa. Methods In these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety. Results As of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred. Conclusion Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.

Original language	English
Article number	e001395
Journal	Journal for ImmunoTherapy of Cancer
Volume	8
Issue number	2
DOIs	https://doi.org/10.1136/jitc-2020-001395
Publication status	Published - 2020 Dec 15

Bibliographical note

Funding Information:
Twitter Margaret E Gatti-Mays @DrGattiMays, Houssein A Sater @HsaterMD, Marijo Bilusic @mbilusic and James L Gulley @gulleyj1 Acknowledgements We thank the patients involved in this study and their families. We express appreciation to the nurses, medical oncology fellows, and consultation services at the National Institutes of Health Clinical Center for their excellent patient care. We thank the study teams at Merck KGaA, Darmstadt, Germany, and EMD Serono Research & Development Institute, an affiliate of Merck KGaA, as well as Angie Schwab (Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute [NCI]) for technical assistance with immune assays. The authors also thank Christian Ihling, of Merck KGaA, for his substantial contribution to the immune phenotype analysis. This research was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health, and through a Cooperative Research and Development Agreement with EMD Serono Research & Development Institute and GSK. This study was also funded in part by Merck KGaA and is part of an alliance between Merck KGaA and GSK. Medical writing support was provided by Ravi Subramanian, PhD, of ClinicalThinking Inc, which was also funded by Merck KGaA and GSK in accordance with Good Publication Practice guidelines (http://www. ismpp.org/gpp3).

Funding Information:
Competing interests JStrauss, CSH, and JLG disclose inventorship on a National Institutes of Health patent related to the work. JSchlom and JLG disclose that the National Cancer Institute has a Cooperative Research and Development Agreement (CRADA) with EMD Serono Research & Development Institute; an affiliate of Merck KGaA, Darmstadt, Germany. BCC discloses research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, and Merck Sharp & Dohme; discloses consultancy with Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, Bristol Myers Squibb, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and Merck Sharp & Dohme; discloses stock ownership with TheraCanVac; and discloses royalty from Champions Oncology. CSH is an employee of Merck KGaA. LSO and PAR are employees of EMD Serono Research and Development Institute. CSH discloses CRADA with Kite Pharma.

Publisher Copyright:
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology
Molecular Medicine
Oncology
Pharmacology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/jitc-2020-001395

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Strauss, J., Gatti-Mays, M. E., Cho, B. C., Hill, A., Salas, S., McClay, E., Redman, J. M., Sater, H. A., Donahue, R. N., Jochems, C., Lamping, E., Burmeister, A., Marté, J. L., Cordes, L. M., Bilusic, M., Karzai, F., Ojalvo, L. S., Jehl, G., Rolfe, P. A., ... Gulley, J. L. (2020). Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies. Journal for ImmunoTherapy of Cancer, 8(2), [e001395]. https://doi.org/10.1136/jitc-2020-001395

Strauss, Julius ; Gatti-Mays, Margaret E. ; Cho, Byoung Chul ; Hill, Andrew ; Salas, Sébastien ; McClay, Edward ; Redman, Jason M. ; Sater, Houssein A. ; Donahue, Renee N. ; Jochems, Caroline ; Lamping, Elizabeth ; Burmeister, Andrea ; Marté, Jennifer L. ; Cordes, Lisa M. ; Bilusic, Marijo ; Karzai, Fatima ; Ojalvo, Laureen S. ; Jehl, Genevieve ; Rolfe, P. Alexander ; Hinrichs, Christian S. ; Madan, Ravi A. ; Schlom, Jeffrey ; Gulley, James L. / Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies. In: Journal for ImmunoTherapy of Cancer. 2020 ; Vol. 8, No. 2.

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title = "Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies",

abstract = "Background Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β 'trap') fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa. Methods In these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety. Results As of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred. Conclusion Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.",

author = "Julius Strauss and Gatti-Mays, {Margaret E.} and Cho, {Byoung Chul} and Andrew Hill and S{\'e}bastien Salas and Edward McClay and Redman, {Jason M.} and Sater, {Houssein A.} and Donahue, {Renee N.} and Caroline Jochems and Elizabeth Lamping and Andrea Burmeister and Mart{\'e}, {Jennifer L.} and Cordes, {Lisa M.} and Marijo Bilusic and Fatima Karzai and Ojalvo, {Laureen S.} and Genevieve Jehl and Rolfe, {P. Alexander} and Hinrichs, {Christian S.} and Madan, {Ravi A.} and Jeffrey Schlom and Gulley, {James L.}",

note = "Funding Information: Twitter Margaret E Gatti-Mays @DrGattiMays, Houssein A Sater @HsaterMD, Marijo Bilusic @mbilusic and James L Gulley @gulleyj1 Acknowledgements We thank the patients involved in this study and their families. We express appreciation to the nurses, medical oncology fellows, and consultation services at the National Institutes of Health Clinical Center for their excellent patient care. We thank the study teams at Merck KGaA, Darmstadt, Germany, and EMD Serono Research & Development Institute, an affiliate of Merck KGaA, as well as Angie Schwab (Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute [NCI]) for technical assistance with immune assays. The authors also thank Christian Ihling, of Merck KGaA, for his substantial contribution to the immune phenotype analysis. This research was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health, and through a Cooperative Research and Development Agreement with EMD Serono Research & Development Institute and GSK. This study was also funded in part by Merck KGaA and is part of an alliance between Merck KGaA and GSK. Medical writing support was provided by Ravi Subramanian, PhD, of ClinicalThinking Inc, which was also funded by Merck KGaA and GSK in accordance with Good Publication Practice guidelines (http://www. ismpp.org/gpp3). Funding Information: Competing interests JStrauss, CSH, and JLG disclose inventorship on a National Institutes of Health patent related to the work. JSchlom and JLG disclose that the National Cancer Institute has a Cooperative Research and Development Agreement (CRADA) with EMD Serono Research & Development Institute; an affiliate of Merck KGaA, Darmstadt, Germany. BCC discloses research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, and Merck Sharp & Dohme; discloses consultancy with Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, Bristol Myers Squibb, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and Merck Sharp & Dohme; discloses stock ownership with TheraCanVac; and discloses royalty from Champions Oncology. CSH is an employee of Merck KGaA. LSO and PAR are employees of EMD Serono Research and Development Institute. CSH discloses CRADA with Kite Pharma. Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2020",

month = dec,

day = "15",

doi = "10.1136/jitc-2020-001395",

language = "English",

volume = "8",

journal = "Journal for ImmunoTherapy of Cancer",

issn = "2051-1426",

publisher = "BioMed Central",

number = "2",

}

Strauss, J, Gatti-Mays, ME, Cho, BC, Hill, A, Salas, S, McClay, E, Redman, JM, Sater, HA, Donahue, RN, Jochems, C, Lamping, E, Burmeister, A, Marté, JL, Cordes, LM, Bilusic, M, Karzai, F, Ojalvo, LS, Jehl, G, Rolfe, PA, Hinrichs, CS, Madan, RA, Schlom, J & Gulley, JL 2020, 'Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies', Journal for ImmunoTherapy of Cancer, vol. 8, no. 2, e001395. https://doi.org/10.1136/jitc-2020-001395

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies. / Strauss, Julius; Gatti-Mays, Margaret E.; Cho, Byoung Chul; Hill, Andrew; Salas, Sébastien; McClay, Edward; Redman, Jason M.; Sater, Houssein A.; Donahue, Renee N.; Jochems, Caroline; Lamping, Elizabeth; Burmeister, Andrea; Marté, Jennifer L.; Cordes, Lisa M.; Bilusic, Marijo; Karzai, Fatima; Ojalvo, Laureen S.; Jehl, Genevieve; Rolfe, P. Alexander; Hinrichs, Christian S.; Madan, Ravi A.; Schlom, Jeffrey; Gulley, James L.

In: Journal for ImmunoTherapy of Cancer, Vol. 8, No. 2, e001395, 15.12.2020.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

AU - Strauss, Julius

AU - Gatti-Mays, Margaret E.

AU - Cho, Byoung Chul

AU - Hill, Andrew

AU - Salas, Sébastien

AU - McClay, Edward

AU - Redman, Jason M.

AU - Sater, Houssein A.

AU - Donahue, Renee N.

AU - Jochems, Caroline

AU - Lamping, Elizabeth

AU - Burmeister, Andrea

AU - Marté, Jennifer L.

AU - Cordes, Lisa M.

AU - Bilusic, Marijo

AU - Karzai, Fatima

AU - Ojalvo, Laureen S.

AU - Jehl, Genevieve

AU - Rolfe, P. Alexander

AU - Hinrichs, Christian S.

AU - Madan, Ravi A.

AU - Schlom, Jeffrey

AU - Gulley, James L.

N1 - Funding Information: Twitter Margaret E Gatti-Mays @DrGattiMays, Houssein A Sater @HsaterMD, Marijo Bilusic @mbilusic and James L Gulley @gulleyj1 Acknowledgements We thank the patients involved in this study and their families. We express appreciation to the nurses, medical oncology fellows, and consultation services at the National Institutes of Health Clinical Center for their excellent patient care. We thank the study teams at Merck KGaA, Darmstadt, Germany, and EMD Serono Research & Development Institute, an affiliate of Merck KGaA, as well as Angie Schwab (Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute [NCI]) for technical assistance with immune assays. The authors also thank Christian Ihling, of Merck KGaA, for his substantial contribution to the immune phenotype analysis. This research was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health, and through a Cooperative Research and Development Agreement with EMD Serono Research & Development Institute and GSK. This study was also funded in part by Merck KGaA and is part of an alliance between Merck KGaA and GSK. Medical writing support was provided by Ravi Subramanian, PhD, of ClinicalThinking Inc, which was also funded by Merck KGaA and GSK in accordance with Good Publication Practice guidelines (http://www. ismpp.org/gpp3). Funding Information: Competing interests JStrauss, CSH, and JLG disclose inventorship on a National Institutes of Health patent related to the work. JSchlom and JLG disclose that the National Cancer Institute has a Cooperative Research and Development Agreement (CRADA) with EMD Serono Research & Development Institute; an affiliate of Merck KGaA, Darmstadt, Germany. BCC discloses research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, and Merck Sharp & Dohme; discloses consultancy with Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, Bristol Myers Squibb, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and Merck Sharp & Dohme; discloses stock ownership with TheraCanVac; and discloses royalty from Champions Oncology. CSH is an employee of Merck KGaA. LSO and PAR are employees of EMD Serono Research and Development Institute. CSH discloses CRADA with Kite Pharma. Publisher Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2020/12/15

Y1 - 2020/12/15

N2 - Background Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β 'trap') fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa. Methods In these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety. Results As of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred. Conclusion Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.

AB - Background Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β 'trap') fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa. Methods In these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety. Results As of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred. Conclusion Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.

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Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

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