On September 18, 2020 Merck reported that phase 2 data for a kidney cancer drug picked up in its $1.05 billion Peloton buyout, showing it shrank tumors in 28% of patients (Press release, Merck & Co, SEP 18, 2020, View Source [SID1234565373]). Now, that number has jumped to 36%, and the drug is showing promise at shrinking tumors outside of the kidney.

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The new data show the drug, a HIF-2α inhibitor dubbed MK-6482, reduced tumor size enough in 36% of patients for them to be considered responders. But that’s not all—another 38% of patients had stable disease, meaning their tumors had stopped growing, and 92% of patients saw at least some tumor shrinkage.

These numbers are in line with Merck’s expectations that the drug would work in more patients over time. The data, presented Friday at this year’s virtual annual meeting of the European Society for Medical Oncology, show that it takes at least three months for patients to see results, with some patients taking the drug for more than a year (62 weeks) before they start responding. The median time to response was nearly seven months. After one year, MK-6482 staved off cancer progression in virtually all 61 patients (98%).

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And when the treatment works, it continues to work. "I think it’s quite reassuring that these responses are durable. Sometimes, with new drugs, even though they might get an initial response, the tumors find a way to become resistant relatively quickly. What this says is that is just not true here," Eric Rubin, senior vice president of global clinical oncology at Merck Research Laboratories, said.

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The data are good news for patients with kidney cancer linked to Von Hippel-Lindau (VHL) disease, a genetic condition that causes tumors and cysts to grow throughout the body. Patients with VHL disease do not make a protein that binds to HIF-2α, (hypoxia-inducible factor-2 alpha), which plays a role in regulating tissue oxygen levels.

As a result, the HIF-2α is always on, which ramps up the production of red blood cells, stimulates formation of new blood vessels and causes certain cells to proliferate. This leads to the development of growths in places as diverse as the brain, retina, liver, pancreas and lungs.

Despite developing tumors in many organs, it’s usually kidney cancer that kills these patients. They undergo surgery to remove kidney tumors, but those often return, or new ones appear. At some point, those tumors get too big to remove without losing the whole kidney, Roy Baynes, Merck senior vice president and global head of clinical development, said in a previous interview.

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In addition to tackling dangerous kidney tumors, MK-6482 moved the needle in other areas. It shrank pancreatic tumors in 64% of patients, completely banishing them in 7% of them, and shrank a type of benign tumor in the brain or spinal cord in 30% of patients. Of the 16 patients who had retinal growths, none saw them get worse, with 69% of them logging improvement and 25% staying stable.

All 61 patients experienced side effects, but in most patients—75%—they were mild. The most common side effect was anemia, affecting 90% of patients, but that wasn’t a surprise considering HIF-2α’s role in forming new red blood cells.

"Patients are generally responsive to erythropoietin," a hormone involved in making red blood cells, Baynes said, adding that "it can be managed quite readily."

Eight patients (13%) had severe treatment-related side effects, including one patient who developed hypoxia, or low levels of oxygen. One patient died from "toxicity of various agents," but the investigator deemed the death unrelated to treatment.

Although VHL is a relatively uncommon disease, blocking HIF-2α could be useful more broadly. 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 nine out of 10 kidney cancer patients," he noted. "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 Exelixis’ Cabometyx in a phase 2 study in clear cell kidney cancer.