Bintrafusp Alfa Shows Efficacy but Does Not Meet Predetermined Threshold in BTC Trial

Milind Javle, MD

Milind Javle, MD

Bintrafusp alfa (M7824) monotherapy demonstrated efficacy, durability, and a manageable safety profile in patients with locally advanced or metastatic biliary tract cancer (BTC) who have progressed or are intolerant to first-line platinum-based chemotherapy in a phase 2 study, according to a press release from Merck KGaA, Darmstadt, Germany.

The multicenter, open-label INTR@PID BTC 047 trial (NCT03833661) looked at second-line bintrafusp alfa at 1200 mg once every 2 weeks until disease progression, death, unacceptable toxicity, or study withdrawal. The primary end point was objective response rate (ORR) according to RECIST v1.1 criteria by Independent Review Committee (IRC). The ORR of the 159 patients enrolled in the trial was 10.1% (95% CI, 5.9%-15.8%).

“Given the high unmet treatment need in BTC, where single agent immunotherapy in PD-L1 all comers has shown an ORR of 5.8%, we are encouraged by the single agent clinical activity of bintrafusp alfa in this study as a second-line treatment,” Milind Javle, MD, professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, and an investigator for this study, said in a statement. “The bintrafusp alfa 047 study is one of the most important clinical investigations conducted for chemo-refractory biliary cancers, and I would like to thank the patients, families, and study team for their valuable participation.”

Although there was single-agent activity in these patients, the trial did not meet the prespecified threshold that would allow for regulatory filing for the second-line treatment of patients with BTC. The entirety of the data will be submitted for publication or presentation at an upcoming medical meeting. Secondary end points included duration of response, durable response of at least 6 months, occurrence of treatment-emergent adverse events, progression-free survival, and overall survival.

Patients enrolled on the study had to have histologically or cytologically confirmed locally advanced or metastatic BTC, available tumor archival material or fresh biopsies, progression or intolerance to 1 prior systemic platinum-base chemotherapy, measurable disease, and an ECOG performance status of 0 or 1. Specific laboratory results were also required, such as adequate hematologic, hepatic, renal, and coagulation function. Those with ampullary cancer, significant acute or chronic infections, active autoimmune disease, or past or current interstitial lung disease were excluded on the trial.

“This study demonstrates single-agent activity with bintrafusp alfa in locally advanced or metastatic BTC, a disease that has been historically difficult to treat,” Danny Bar-Zohar, MD, global head of development for the healthcare business sector of Merck KGaA, Darmstadt, Germany, said in a press release. “The data will contribute to our understanding of addressing both TGF-β and PD-L1 inhibition in the tumor microenvironment.”

Bintrafusp alfa is a potential first-in-class investigational bifunctional fusion protein designed to block the TGF-β and PD-L1 immunosuppressive pathways simultaneously within the tumor microenvironment. This approach is believed to control tumor growth by restoring and enhancing anti-tumor response in patients. Preclinical studies showed this drug has antitumor activity alone and as combination treatment with chemotherapy. Investigators hope to potentially use it as a targeted approach to tackling the underlying pathophysiology of patients with cancers that are more difficult to treat.

Currently, the phase 2/3 INTR@PID BTC 055 trial (NCT04066491) is combining bintrafusp alfa with chemotherapy in patients with BTC as first-line therapy. The phase 2 portion of the trial has completed enrollment. Patients will be treated with either bintrafusp alfa, gemcitabine, and cisplatin or placebo, gemcitabine, and cisplatin. The primary end point of the safety run-in is the number of participants with dose-limiting toxicities during the evaluation period; for the double-blind portion of the trial, the end point is overall survival.


Merck KGaA, Darmstadt, Germany, reports topline data for bintrafusp alfa as second-line monotherapy treatment in biliary tract cancer. News release. Merck KGaA. Published March 16, 2021. Accessed March 17, 2021.

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