One year after betting $1.05 billion on Peloton Therapeutics, Merck is unveiling data from a phase 2 study of a HIF-2α inhibitor picked up in that deal—and it’s promising.
The drug curbed tumor growth in 43% and shrank tumors in 28% of patients with kidney cancer linked to a particular genetic condition, offering hope not only to a patient group that must undergo multiple abdominal surgeries, but also to kidney cancer patients more broadly.
Although the 28% response rate might seem low, Merck expects to see the drug—now dubbed MK-6482—work in more patients as time goes on. Some of the trial patients have been taking the drug for as long as 73 weeks, but others are earlier in their treatment.
“Each time we do a new imaging cut, we find more responses,” Roy Baynes, Merck SVP and global head of clinical development, told FierceBiotech. “Some [responses] come in quite late. It’s not like you know immediately whether someone is going to respond.”
And when the therapy works, it continues to work: “Those who have responses remain in response,” Baynes said.
MK-6482 blocks HIF-2α (hypoxia-inducible factor-2 alpha), a protein that plays a role in regulating tissue oxygen levels. Merck tested it in 61 patients with clear cell kidney cancer linked to von Hippel-Lindau (VHL) disease, a genetic condition that causes tumors and cysts to grow throughout the body. People with VHL disease do not make a protein that binds to HIF-2α, “so the pathway is turned on all the time,” Baynes said.
That ramps up the production of red blood cells, stimulates formation of new blood vessels and causes certain cells to proliferate—good news for cancer, but bad news for patients. Patients with VHL disease can develop growths in places as diverse as the brain, retina, liver and lungs, but it’s usually kidney cancer that kills them. They undergo surgery to remove kidney tumors, but those often return, or new ones appear, Baynes said. At some point, those tumors get too big to remove without losing the whole organ.
“It’s a relatively uncommon genetic abnormality, but it’s one with pretty dire consequences, and a treatment is clearly needed,” Baynes said.
But blocking HIF-2α could come in handy beyond this small population. Patients with kidney cancer that can’t be surgically treated or has metastasized tend to receive an immuno-oncology drug, often alongside a kinase inhibitor. If they relapse, they might try a different kinase inhibitor, Baynes said.
“What we find as we look at clear cell kidney cancer is VHL function is lost or silenced in almost 9 out of 10 kidney cancer patients,” he added. “The majority of patients, once they’ve failed all treatments, actually have a dysregulated VHL pathway.”
Targeting that pathway with a drug like MK-6842 could become an option for those patients. Merck is already testing the drug against standard of care in a phase 3 kidney cancer trial and studying it in combination with Cabometyx in a phase 2 study in clear cell kidney cancer.
The safety data look promising too—while nearly all the patients experienced side effects, most of them were mild, with less than 10% considered severe. Only 2 patients have quit the study. The most common side effect was anemia, which affected 86% of the patients. But that wasn’t a surprise given HIF-2α’s role in forming new red blood cells.
“Patients are generally responsive to erythropoietin [a hormone involved in making red blood cells]. It can be managed quite readily,” Baynes said.