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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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).
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.
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All Science Journal Classification (ASJC) codes
- Immunology and Allergy
- Molecular Medicine
- Cancer Research