Bintrafusp Alfa Monotherapy Showcases Efficacy, Durability in Second-Line Biliary Tract Cancer

Milind Javle, MD

Single-agent bintrafusp alfa (M7824) demonstrated efficacy, durability, and an acceptable toxicity profile when used in patients with locally advanced or metastatic biliary tract cancer (BTC) who have progressed on or are intolerant of frontline platinum-based chemotherapy, according to data from the phase 2 INTR@PID BTC 047 trial (NCT03833661).¹

After more than 9 months of follow-up, the independent review committee (IRC)–adjudicated objective response rate of 10.1% (95% CI, 5.9%-15.8%) per RECIST v1.1 criteria. Despite the benefit showcased, the trial did not meet the predefined threshold that would have allowed for regulatory filing for the agent’s use in the second-line treatment of BTC.

The data from the trial will be submitted for presentation at a future medical meeting or publication, according to Merck KGaA, Darmstadt, Germany.

“Given the high unmet 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, a professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, stated in a press release. “The bintrafusp alfa 047 study is one of the most important clinical investigations conducted for chemorefractory biliary cancers, and I would like to thank the patients, families, and study team for their valuable participation.”

The potential first-in-class investigational bifunctional fusion protein was developed to simultaneously inhibit 2 immunosuppressive pathways in the tumor microenvironment: TGF-β and PD-L1. The approach is hypothesized to control the growth of the tumor by restoring and strengthening antitumor responses.

In the phase 2 trial, investigators set out to evaluate bintrafusp alfa monotherapy in patients with advanced or metastatic BTC who failed or were intolerant to frontline chemotherapy.² To be eligible for enrollment, patients had to have histologically or cytologically confirmed locally advanced or metastatic BTC, have measurable disease, an ECOG performance status of 0 to 1, a life expectancy of at least 12 weeks, as well as acceptable hematologic, hepatic, and coagulation function.

If patients had ampullary cancer, significant acute or chronic infections, active autoimmune disease that could deteriorate by receiving an immunostimulatory agent, or interstitial lung disease or a history of the disease, they were excluded from the analysis.

The primary outcome measure of the trial was confirmed ORR per RECIST v1.1 criteria, as evaluated by an IRC, while key secondary outcome measures included duration of response per IRC, durable response of at least 6 months per RECIST v1.1 criteria and IRC, treatment-emergent adverse effects, progression-free survival per RECIST v1.1 criteria and IRC, and more.

In the trial, patients were administered an intravenous (IV) infusion of bintrafusp alfa at 1200 mg once every 2 weeks until progressive disease, intolerable toxicity, or withdrawal from the study.

“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, added in the release. “The data will contribute to our understanding of addressing both TGF-β and PD-L1 inhibition in the tumor microenvironment.”

Bintrafusp alfa is also under investigation in combination with gemcitabine and cisplatin in the frontline treatment of patients with BTC as part of the phase 2/3 INTR@PID BTC 055 trial (NCT04066491).³

The trial will comprise an open-label, safety run-in portion, as well as a randomized, double-blind, placebo-controlled portion. In the phase 2/3 portion, investigators are evaluating bintrafusp alfa in combination with the current standard of care to see whether the combination will improve overall survival in both chemotherapy- and immunotherapy-naïve patients with locally advanced or metastatic BTC vs placebo, gemcitabine, and cisplatin.

In the trial, patients will receive IV bintrafusp alfa at a dose of 2400 mg once every 3 weeks until progressive disease, death, intolerable toxicity, withdrawal from the study, or 2 years after the first onset of complete response. Those in the experimental arm will also receive 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.

References

1. 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 March 16, 2021. http://bit.ly/3tvm2wT
2. M7824 monotherapy in locally advanced or metastatic second line (2L) biliary tract cancer (cholangiocarcinoma and gallbladder cancer). ClinicalTrials.gov. Updated February 18, 2021. Accessed March 16, 2021. https://clinicaltrials.gov/ct2/show/NCT03833661
3. Gemcitabine plus cisplatin with or without bintrafusp alfa (M7824) in participants with 1L biliary tract cancer (BTC). ClinicalTrials.gov. Updated February 1, 2021. Accessed March 16, 2021. https://clinicaltrials.gov/ct2/show/NCT04066491