New Targeted Drug Yields Promising Activity in Advanced Kidney Cancer

By Megan Brooks

February 20, 2020

NEW YORK (Reuters Health) - A new targeted drug has shown encouraging results in patients with heavily pretreated metastatic clear-cell kidney cancer.

The drug, now known as MK-6482, is an oral, first-in-class agent that specifically targets the master transcription factor, hypoxia-inducible factor (HIF)-2a, a key oncogenic driver of clear-cell renal-cell carcinoma (RCC).

HIF-2 is "an important target" in clear-cell RCC "and was thought to be undruggable," lead investigator Dr. Toni Choueiri, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, explained in a phone interview with Reuters Health.

In the new research, a phase-1/2 study, single-agent treatment with MK-6482 showed an overall response rate of 24% across all risk categories of patients with advanced clear-cell RCC (poor, intermediate, good, and in a heavily refractory population), which is "very promising," Dr. Choueiri said.

He presented the results February 15 during the American Society of Clinical Oncology (ASCO) 2020 Genitourinary Cancers Symposium in San Francisco.

In an email to Reuters Health, Dr. Richard L. Schilsky, ASCO chief medical officer and executive vice president, said, "This work is a direct outgrowth of the Nobel Prize winning research of William Kaelin and colleagues who demonstrated the key role of Hypoxia Inducible Factor as an oxygen sensor in cells. Mutations in the HIF family genes play a key role in driving the development and progression of clear-cell kidney cancer."

"This is one of the rare times that science and chemistry converge on the care of patients. I am excited about the potential for it to help our patients," Dr. Choueiri told Reuters Health.

The study included 55 patients with advanced clear-cell RCC who had an average of three prior lines of treatment.

After a median follow-up period of 13 months, 41 patients had stable disease with a disease-control rate of 80%. Partial responses were seen in two of five favorable-risk patients, in 10 of 40 intermediate-risk patients, and in one of 10 poor-risk patients.

At the time of data presentation, the median duration of response had not been reached: 81% of patients had a response of six months or more. The median progression-free response rate was 11 months.

MK-6482 was well-tolerated with a favorable safety profile. The most common all-grade, all-cause adverse events were anemia (75%), fatigue (67%), dyspnea (47%), nausea (33%), and cough (31%).

"The best thing, I think, in addition to the proof of concept, is that the side effects are tolerated. With VEGF-targeted agents, you see cardiovascular events and hypertension; here you do not see that," Dr. Choueiri said.

A phase-3 trial of MK-6482 monotherapy in previously treated patients with advanced clear-cell RCC is in progress.

This drug "seems to have remarkable anti-tumor activity (80% disease control rate and 24% objective-response rate) in heavily pre-treated patients with ccRCC who have few other treatment options," Dr. Schilsky told Reuters Health.

"If confirmed in larger studies, these results will lead to many new treatment options for these patients. Most importantly, the results underscore the importance of basic research as the fuel that drives the development of new treatments for patients," he added.

Funding for this research was provided by Peloton Therapeutics Inc, a subsidiary of Merck and Co. Dr. Choueiri has financial relationships with the companies.

SOURCE: ASCO 2020 Genitourinary Cancers Symposium, presented February 15, 2020.