Novel Drug Can Target Molecular Driver of Clear Cell Renal Cell Carcinoma

Researchers at the Dana-Farber Cancer Institute have reported promising activity of a novel drug that targets a key molecular driver of clear cell renal cell carcinoma (ccRCC) in patients with metastatic disease. Based on the results of treatment with the drug, MK-6482, a phase 3 trial has been launched.

The response rate was noted as 24% across all risk categories of patients given the oral first-in-class agent that targets hypoxia-inducible factor (HIF) 2-a, key for promoting new blood vessel growth that fuels kidney tumors.

The study included 55 patients with advanced clear cell kidney cancer who had an average of 3 prior lines of therapies. After a median follow-up period of 13 months, the overall response rate was 24%. Forty-one patients had stable disease with disease control rate of 80%. There were partial responses in 2 of 5 favorable-risk patients, 10 of 40 intermediate-risk patients, and 1 of 10 poor-risk patients.

The median duration of response had not been reached, as 81% of patients had an estimated response of more than 6 months and 16 patients continued treatment beyond 12 months. The median progression-free response rate was 11 months.

“A new drug as a single agent showing an overall response rate of 24% across all risk categories—poor, intermediate, and good and in a heavily refractory population—is quite promising,” said Toni Choueiri, MD, first author of the abstract, in a press release.

The drug targets a component of the body’s mechanism for sensing oxygen levels and turning on genes that enable the body to adjust to hypoxia, by making more red blood cells and forming new blood vessels.

In patients with ccRCC, a tumor suppressor protein Von Hippel-Lindau (VHL) is not functional. As a result, HIF proteins accumulate inside the tumor cell, wrongly signaling there is a shortage of oxygen, and activating the formation of blood vessels, thereby fueling tumor growth. Understanding this abnormal process has led to new cancer drugs. MK-6482 is distinct in that it targets HIF-2a directly leading to blocking cancer cell growth, proliferation, and abnormal blood vessel formation.

From the study findings, the researchers concluded that MK-6482 is well-tolerated with a favorable safety profile and it demonstrated promising single-agent activity in heavily pre-treated patients with ccRCC across the various risk groups.

Reference

• Novel Targeted Drug Shows Promise in Advanced Kidney Cancer [news release]. Dana Farber Cancer Institute website. Published February 15, 2020. https://www.dana-farber.org/newsroom/news-releases/2020/novel-targeted-drug-shows-promise-in-advanced-kidney-cancer/. Accessed February 27, 2020.