Phase 2 Trial of Bintrafusp Alfa in Frontline Biliary Tract Cancer Discontinued

Merck KGaA, Darmstadt, Germany has decided to discontinue the phase 2 INTR@PID BTC 055 trial (NCT04066491) examining bintrafusp alfa (M7824) plus gemcitabine and cisplatin in the frontline treatment of patients with locally advanced or metastatic biliary tract cancer.¹

The decision follows a recommendation from the independent data monitoring committee who concluded that the trial is not likely to meet the primary end point of improving overall survival (OS) in this population. Notably, no new safety signals with the agent were reported.

The company is working on notifying health authorities and study investigators about the decision. Patients who are currently receiving the agent on the trial will be advised on next steps.

“Merck KGaA, Darmstadt, Germany thanks the investigators and the patients and their families who participated in this clinical trial,” the company statement read. “We will share the data and analyses from the study with the scientific community in the future.”

The study was comprised of an open-label, safety run-in portion and a randomized, double-blind, placebo-controlled phase 2/3 portion. In the phase 2/3 portion of the research, investigators set out to evaluate whether bintrafusp alfa plus the current standard of care would improve OS in patients with locally advanced or metastatic biliary tract cancer who were chemotherapy and immunotherapy naïve compared with gemcitabine/cisplatin.

To be eligible for inclusion, patients needed to have histologically or cytologically confirmed locally advanced or metastatic biliary tract cancer, available tumor tissue prior to first treatment administration, at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and a life expectancy of at least 12 weeks.² Moreover, patients needed to have acceptable hematologic, hepatic, renal, and coagulation function.

Patients could not have prior and/or intercurrent cancers, could not have undergone any organ transplantation, and could not have symptomatic central nervous system metastases. Moreover, patients were excluded if they had significant acute or chronic infection, active autoimmune disease that could deteriorate if given an immunostimulatory drug, a history of or current interstitial lung disease, or a history of hypersensitivity reactions to bintrafusp alfa, anaphylaxis, or recent uncontrolled asthma, cardiovascular or cerebrovascular disease.

The primary objective of the safety run-in portion of the trial was to identify the number of patients with dose-limiting toxicities, and the primary objective for the double-blind portion was OS. Secondary objectives in the safety run-in part included treatment-emergent adverse effects (TEAEs), and the number of patients with abnormal laboratory tests. Secondary objectives in the double-blinded portion comprised duration of response, durability of response of at least 6 months per RECIST v1.1 criteria, and TEAEs, among others.

In the trial, patients received intravenous (IV) bintrafusp alfa at a dose of 2400 mg once every 3 weeks until progressive disease, death, unacceptable toxicity, withdrawal from the study, or 2 years after the first onset of a complete response. Those in the investigational arm also received IV gemcitabine at 100 mg/m² on days 1 and 8 of a 21-day treatment cycle for 8 cycles every 3 weeks, along with IV cisplatin at 25 mg/m² on the same schedule as gemcitabine.

Previously, the agent was evaluated as a monotherapy in patients with locally advanced or metastatic biliary tract cancer who had progressed on or were intolerant to frontline platinum-based chemotherapy as part of the phase 2 INTR@PID BTC 047 trial (NCT03833661).³

Patients on the trial were given an IV infusion of bintrafusp alfa at 1200 mg once every 2 weeks. Treatment was administered until disease progression, unacceptable toxicity, or withdrawal from the study.

Results showed that the agent had efficacy, durability, and an acceptable safety profile when used in this population. Specifically, after more than 9 months of follow-up, the agent resulted in an independent review committee–adjudicated objective response rate of 10.1% (95% CI, 5.9%-15.8%) per RECIST v1.1 criteria. However, despite this benefit, this trial did not meet the predefined threshold that would have allowed for regulatory filing for the use of the agent in the second-line setting of this disease.

References

1. Merck KGaA, Darmstadt, Germany statement on phase 2 study of bintrafusp alfa in first-line treatment of biliary tract cancer. News release. Merck KGaA, Darmstadt, Germany. August 23, 2021. Accessed August 24, 2021. https://bit.ly/3y9dBch
2. Gemcitabine plus cisplatin with or without bintrafusp alfa (M7824) in participants with 1L biliary tract cancer (BTC). ClinicalTrials.gov. Updated April 27, 2021. Accessed August 24, 2021. https://clinicaltrials.gov/ct2/show/NCT04066491
3. Merck KGaA, Darmstadt, Germany, reports topline data for bintrafusp alfa as second-line monotherapy treatment in biliary tract cancer. News release. Merck KGaA, Darmstadt, Germany. March 16, 2021. Accessed August 24, 2021. http://bit.ly/3tvm2wT