GSK, Merck KGaA Partner to Develop M7824

GlaxoSmithKline (GSK) and Merck KGaA (Darmstadt, Germany) inked a multibillion- dollar deal on February 5 to develop an immunotherapeutic that blocks two independent, but complementary, pathways linked to immune evasion.

The strategic alliance—coming 2 months after GSK reached a $5.1 billion agreement to acquire Tesaro, maker of the PARP inhibitor niraparib (Zejula) and several experimental checkpoint inhibitors—signals the British drug maker's renewed interest in cancer therapeutics, says Wimal Kapadia, an analyst with Sanford C. Bernstein in London, UK. Four years ago, GSK offloaded all its oncology assets to Novartis. Now, he says, “they're trying to step back into the oncology space.”

The pact covers Merck KGaA's M7824 (bintrafusp alfa), a first-in-class bifunctional fusion protein against PD-L1 fused to the extracellular domains of two TGFβ receptor molecules. The first part lifts the brakes off the body's natural anticancer T-cell response, and the second sequesters TGFβ, thereby preventing the growth factor from restricting T-cell infiltration into the tumor microenvironment.

In phase I testing, James Gulley, MD, PhD, and his colleagues at the NCI showed that patients tolerated M7824, with a side-effect profile comparable to approved checkpoint inhibitors; the only new toxicity was a benign skin growth seen in prior trials of TGFβ-depleting therapies. Immunoassays showed that “we were getting good sequestration of activated TGFβ,” Gulley says. Moreover, clinicians saw signs of tumor reduction in heavily pretreated patients, including several with human papillomavirus (HPV)–associated cancers of the cervix and anus.

“That piqued our curiosity,” says Gulley, whose team then launched a phase II trial for patients with HPV-positive malignancies; early results showed an overall response rate of about 35% to 40%, double that historically seen with other checkpoint inhibitors. Gulley and his colleagues are also recruiting for studies looking at M7824′s activity against HPV-associated benign growths in the respiratory tract, small cell lung cancer, and prostate cancer, the latter involving combinations with immune cell–mobilizing vaccines.

Meanwhile, clinicians at The University of Texas MD Anderson Cancer Center in Houston are evaluating M7824 in two populations of women with breast cancer, and in three patient groups thought to be candidates for M7824 treatment: patients with microsatellite instability–high tumors who didn't respond to prior checkpoint therapy, those with a subtype of colorectal cancer linked to high TGFβ expression, and those with resectable metastatic colorectal cancer who test positive for circulating tumor DNA.

The biggest test for M7824 remains a global, 300-person, head-to-head trial of M7824 and the PD-1 inhibitor pembrolizumab (Keytruda; Merck & Co.) as a first-line treatment for PD-L1–expressing non–small cell lung cancer. “That will determine whether the asset is going to create a new platform in immuno-oncology,” says Kapadia.

Under the terms of the deal, Merck KGaA will receive about $342 million up front from GSK, plus up to $3.9 billion for meeting development and commercial milestones. That's “a big number to pay for one asset,” Kapadia says.

However, if M7824 proves superior to pembrolizumab for treating lung cancer and shows similar advantages in other patient populations, it could be a bargain for GSK, he notes, as M7824 would then “become a widespread program, much like Keytruda or Opdivo [nivolumab; Bristol-Myers Squibb] is today.” Each of those immunotherapeutics tallied around $7 billion in sales last year. –Elie Dolgin