'Incredible' Results With Kidney Cancer Agent With Nobel Prize Ties

Nick Mulcahy

February 17, 2020

SAN FRANCISCO — For the first time, a clear cell renal cell carcinoma therapy targets a molecular driver of the cancer that was previously believed to be "undruggable," said investigator Toni Choueiri, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, here at the Genitourinary Cancers Symposium (GUCS) 2020.

That driver, hypoxia-inducible factor (HIF) 2α, promotes new blood vessel growth that fuels kidney tumors and is the target of the experimental therapy, a once-a-day pill known as MK-6482 (Merck).

The first-in-class drug, an oral HIF-2α inhibitor, appears to be succeeding in hitting its mark at a high rate in this setting. MK-6482 had an overall response rate of 24% among 55 patients with heavily pretreated advanced clear cell disease, with all responses being partial, reported Choueiri. Median follow-up was 13 months.

The patients in this phase I/II study had a median of three prior lines of therapies (range 1-9), including vascular endothelial growth factor (VEGF) inhibitors and immune checkpoint inhibitors.

Monty Pal, MD, a renal cell carcinoma specialist, City of Hope Comprehensive Cancer Center, Duarte, California, placed the results in the context of both current practice and drug development.

"The response rate is incredible," he told Medscape Medical News, given the previous lines of therapy.

In addition, the clinical benefit rate of 80% (stable disease plus responsive disease) is the "best progression-free survival rate amongst agents in development," he said.

Currently, these advanced cancer patients, having repeatedly failed approved renal cell therapies, "don't do very well," said Pal, adding that there is no standard of care in this setting.

During his oral presentation, Choueiri explained that the "vast majority" (about 90%) of patients with clear cell renal carcinoma have a "defective" protein known as von Hippel-Lindau (VHL).

"We thought for a long time that this [target pVHL] was undruggable," Choueiri told ecancer in a video interview at the meeting.

The result of having this defective VHL protein is activation of HIF proteins, which accumulate inside the tumor cell, falsely signaling a shortage of oxygen and activating the formation of blood vessels, thereby fueling tumor growth, according to Dana-Farber press materials.

The discovery of this sequence "partially led" to the 2019 Nobel Prize in Medicine that Dana-Farber scientist William Kaelin Jr shared with two other Americans, said Choueiri, who collaborates with Kaelin.

"It's a very real connection," said Pal about the discovery of this activation path of HIF-2α, the Nobel Prize, and the development of the first-in-class HIF-2α inhibitor drug, MK-6482.

Activity in Each Risk Category

In the phase I/II study, 55 patients with a median age of 62 years and with previously treated advanced renal cell carcinoma enrolled in the dose-expansion cohort and 39 (71%) eventually discontinued, with the most common reason being disease progression (55%).

The results show partial responses in 2/5 favorable-risk patients; 10/40 intermediate-risk patients; and 1/10 poor-risk patients.

The median duration of response had not been reached: 81% of patients had an estimated response of more than 6 months, and 16 patients (29%) continued treatment beyond 12 months. The median progression-free response rate was 11 months.

In terms of adverse events (AEs), four patients died due to disease-related events (and none from a treatment-related event). A total of 65% had grade 3-5 AEs. Five patients had a dose reduction because of toxicity.

The most common all-grade, all-cause adverse events were anemia (75%), fatigue (67%), dyspnea (47%), nausea (33%), and cough (31%). Anemia (26%) and hypoxia (15%) were the most common grade-3 adverse events.

Both anemia and hypoxia are "on target" toxicities; anemia occurs because the drug lowers the level of erythropoietin, said Choueiri

The new agent now moves to a phase 3 trial that compares MK-6482 to everolimus with the endpoint of progression-free survival.

Eligible patients will have unresectable, locally advanced or metastatic clear cell renal cell carcinoma and received systemic treatment with a programmed cell death 1 ligand 1 (PD-1/L1) checkpoint inhibitor (at least 2 doses) and a VEGF-targeted therapy (including tyrosine kinase inhibitors or monoclonal antibodies) as monotherapy, or in combination.

City of Hope's Pal thinks that the design will allow investigators to expeditiously determine if the new agent is effective in this setting because patients will have already not succeeded on currently approved and commonly used drugs.

The study was funded by Merck. Choueiri has multiple financial ties to pharmaceutical companies, including Merck, and has pending patents for biomarkers of immune checkpoint blockers. Pal has financial ties to multiple pharmaceutical companies, but not to Merck.

Genitourinary Cancers Symposium (GUCS) 2020: Abstract 611. Presented February 15, 2020.

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