GSK, German Merck's $4.2B bintrafusp alfa drug flops again, but companies squint to see glimmers of hope

Two months after GlaxoSmithKline and Merck KGaA’s oncology asset bintrafusp alfa failed to beat out King Keytruda in certain lung cancers, it has followed up with another disappointment.

The bifunctional fusion protein immunotherapy, which is the center of the $4.2 billion deal GSK penned with Merck in 2019, flopped a midstage test on its own treating 159 second-line patients with locally advanced or metastatic biliary tract cancer (BTC).

An independent review showed it had an objective response rate (ORR) of just 10.1% , with efficacy hitting below a predefined threshold that would have let it file the drug in that setting.

Merck is not throwing in the towel completely for this target, as an ongoing phase 2/3 study of bintrafusp alfa with chemo as a first-line treatment for BTC “is assessing a different hypothesis than the second-line monotherapy study,” according to a statement.

Despite the second-line flop, Merck still says it saw single-agent activity in a tough area; and, though it had a small ORR, this was better than what others had achieved.

“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, M.D., professor of GI medical oncology at the MD Anderson Cancer Center and an investigator for the INTR@PID BTC 047 study.

“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.”

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“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., global head of development for the healthcare business sector of Merck. “The data will contribute to our understanding of addressing both TGF-β and PD-L1 inhibition in the tumor microenvironment.”

The drug is designed to combine a TGF-β trap with the anti-PD-L1 mechanism in one fusion protein and to combine co-localized blocking of the two immuno-suppressive pathways. Targeting both pathways aims to control tumor growth by potentially restoring and enhancing anti-tumor responses.

This impressed GSK enough two years back to see the U.K. Big Pharma hand German Merck €300 million upfront with development milestone payments of up to €500 million and potential sales-related payments of €2.9 billion, which brought the total to an eye-watering figure of €3.7 billion ($4.16 billion).

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But it’s not had a good run thus far: In January this year, in a late-stage test of the drug in PD-L1-expressing non-small cell lung cancer patients, an independent monitoring committee told the pair the drug will likely not hit its primary endpoint, which was progression-free survival, in the trial known as INTR@PID Lung 037.

The drug was going head-to-head with Merck’s rival U.S. pharma, also called Merck, and its winner-takes-all checkpoint inhibitor Keytruda, in newly diagnosed late-stage lung cancer patients. Beating out Keytruda, which has a strong track record in lung cancer, was always going to be a tough ask, and both companies were given some slack because of this.

Looking past a second failure just two months down the line, even in a tough-to-treat cancer, might be a bigger ask.