Expanding “Practice-Changing” Belzutifan's Reach in RCC

Findings from two trials of belzutifan (Welireg; Merck) strongly support making this drug more widely available to patients with clear-cell renal cell carcinoma (ccRCC), beyond the limited subset of those for whom it's currently indicated. The data were presented during the 2023 ESMO Congress in Madrid, Spain, October 20–24.

Belzutifan targets a member of the hypoxia-inducible factor (HIF) family of oxygen-sensing proteins, HIF-2α, preventing its interaction with HIF-1β and thereby keeping downstream tumorigenic effects, including cell proliferation and angiogenesis, at bay.

In 2021, the FDA greenlighted this first-in-class agent for cancers associated with the rare hereditary von Hippel-Lindau (VHL) disease—RCCs, central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors, which arise from a germline VHL mutation leading to overexpressed, constitutively active HIF-2α. However, ccRCC not linked with this condition often features somatic mutations in VHL; as such, belzutifan's clinical potential is of considerable interest to the broader kidney cancer community.

Laurence Albiges, MD, PhD, of Institut Gustave Roussy in Villejuif, France, reported interim results from phase III LITESPARK-005, a comparison of belzutifan with the mTOR inhibitor everolimus as later-line treatments for advanced ccRCC. Among 746 patients randomly assigned to receive belzutifan or everolimus, the 12-month progression-free survival was 33.7% versus 17.6%, respectively, and at 18 months, 22.5% versus 9%, respectively. Overall survival (OS) appears to favor the HIF-2α inhibitor but hasn't yet reached statistical significance.

Belzutifan was active in patients considered to be at high or intermediate risk of disease progression, Albiges noted, “with complete responses [CR] seen even in a population where most [87.2%] were treated in the third or fourth line.” The drug was highly tolerable, with anemia, hypoxia, and fatigue being the main side effects.

The fact that toxicity-driven treatment discontinuation rates were higher with everolimus (14.7%) than with belzutifan (5.9%) “was interesting to me,” Albiges observed, considering that “everolimus is known to be a well-tolerated agent.”

Discussant Lisa Pickering, PhD, of The Royal Marsden in London, UK, remarked that the outlook for advanced ccRCC has grown brighter in recent years, particularly with the advent of immune checkpoint inhibitors (ICI). Even so, “these improvements, although durable in some cases, are often still of time-limited benefit. We need new strategies, and it looks like belzutifan is indeed one.”

The HIF-2α inhibitor “clearly beats everolimus,” Pickering added. “I'll confess I thought OS would be positive by now. That's a key goal, of course, so [LITESPARK-005’s] final analysis will be of much interest.” She cautioned, though, that because most patients had received multiple prior therapies, including cabozantinib (Cabometyx; Exelixis) and lenvatinib (Lenvima; Eisai)—tyrosine kinase inhibitors (TKI) aimed primarily at VEGFR—which are quite effective in ccRCC, “this could be a tough space to see OS benefit.”

What about belzutifan's combination potential? In the phase II LITESPARK-003 trial, Toni Choueiri, MD, of Dana-Farber Cancer Institute in Boston, MA, and his colleagues evaluated the HIF-2α inhibitor alongside cabozantinib. Among 50 patients in cohort 1 who were given belzutifan–cabozantinib up front, the objective response rate (ORR) was 70%, including four CRs; the disease control rate (DCR) was 98%; and the median duration of response (DOR) was 28.6 months. In cohort 2—52 patients who had received one or two prior therapies, including at least one ICI—the ORR was 31%, including two CRs; the DCR was 92%; and the median DOR was 31.5 months.

“This durable antitumor activity provides a scientific rationale for further investigating belzutifan plus a VEGFR-directed TKI,” Choueiri said, which is already happening: LITESPARK-011, a phase III trial, is pitting the combination of belzutifan with lenvatinib against cabozantinib in previously treated patients.

Choueiri pointed out, too, that for patients “who are clearly contraindicated for first-line ICI,” belzutifan could be a good option given the high ORR in LITESPARK-003’s cohort 1, “which was unlikely driven just by cabozantinib, in my opinion.”

Deploying belzutifan earlier in general “may present even greater opportunities,” Pickering concurred. Trials are warranted, but more importantly, “with the meaningful, practice-changing data we've seen, I do want this drug to be made available—and soon—for all patients” with advanced ccRCC. –Alissa Poh