GSK, Merck KGaA's BTC Drug Fails for Second Time This Year

Cancer Cells

Topline data from Germany’s Merck KGaA’s Phase II INTR@PID BTC 047 study show bintrafusp alfa has single-agent efficacy and safety in the second-line treatment of locally advanced or metastatic biliary tract cancer (BTC) in patients who have either failed or are intolerant to first-line platinum-based chemotherapy.

While the findings were reportedly promising, the company said the study did not meet a pre-defined threshold to support regulatory filing for BTC in the second-line setting.

BTC is a rare, aggressive gastrointestinal (GI) cancer that has limited treatment options. As such, the disease is often associated with poor prognosis. No globally accepted standard of care exists in the second-line setting. Additionally, chemotherapy and immunotherapies have generally been associated with relatively low rates of response in patients with BTC.

Bintrafusp alfa is a first-in-class investigational bifunctional fusion protein that simultaneously blocks TGF-β and PD-L1, two immunosuppressive pathways, within the tumor microenvironment. The drug was discovered by Merck KGaA, Darmstadt, Germany and represents a potentially effective treatment option for BTC. Currently, bintrafusp alfa is under clinical development in a strategic alliance with GlaxoSmithKline (GSK). This partnership saw GSK pay Merck KGaA up to $4.5 billion to develop bintrafusp alfa.

Both Merck KGaA and GSK recently discontinued a trial of bintrafusp alfa after the Phase III study showed the therapy was unlikely to improve progression-free survival in the first-line setting of stage IV non-small cell lung cancer with high PD-L1 expression.

The newer Phase II INTR@PID BTC 047 study enrolled 159 patients with BTC who were treated with bintrafusp alfa monotherapy. Treatment was administered via intravenous infusion at 1200 milligrams once every two weeks until either confirmed disease progression, death, unacceptable toxicity or withdrawal.

After more than nine months of follow up, the researchers found that treatment with the single agent was associated with efficacy and durability and a manageable safety profile. An Independent Review Committee-adjudicated objective response rate (ORR) with the therapy was 10.1% (95% CI: 5.9%-15.8%).

Merck KGaA said in a statement of the study results that INTR@PID BTC 047 did not meet the pre-defined threshold, despite the efficacy and durability findings, which prevents the company from commencing with regulatory filing for the drug as a second-line approach to BTC.

"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," said Milind Javle, MD, investigator for the INTR@PID BTC 047 study and professor of GI medical oncology at the MD Anderson Cancer Center. "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."

"This study demonstrates single-agent activity with bintrafusp alfa in locally advanced or metastatic BTC, a disease that has been historically difficult to treat," added Danny Bar-Zohar, M.D., Merck KGaA’s Global Head of Development for the Healthcare business sector. "The data will contribute to our understanding of addressing both TGF-β and PD-L1 inhibition in the tumor microenvironment."

Another placebo-controlled Phase II/III trial from Merck KGaA is currently enrolling up to 512 participants with BTC to investigate the safety and efficacy of bintrafusp alfa plus chemotherapy as a first-line treatment. Primary endpoints of this study include the number of participants with dose-limiting toxicities and overall survival at up to four years.

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