Immune checkpoint inhibitors and antiangiogenic agents have become a standard part of first and second-line therapies for metastatic clear cell renal cell carcinoma (ccRCC), though most patients with advanced RCC face low survival rates, and for those whose cancer progresses following PD-1/L1 and VEGF-TKI therapies, there is a need for new treatment options that can reduce their risk of disease progression or death. 

LITESPARK-005 is the first Phase III trial with positive topline results, evaluating belzutifan, an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor for the treatment of adult patients with advanced RCC. This study is one of four LITESPARK phase III trials assessing WELIREG’S potential in ccRCC. Belzutifan is already approved in the United States for certain VHL disease associated RCC, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas. Furthermore, the drug has demonstrated clinical activity in previously treated, advanced ccRCC.

At the first pre-specified interim analysis (IA1) at a median follow-up of 18.4 months, WELIREG significantly reduced the risk of disease progression or death by 25% compared to 9% with everolimus in these patients. Results at the second pre-specified interim analysis (IA2) were consistent with IA1. At a median follow-up of 25.7 months, WELIREG reduced the risk of disease progression or death by 26%.

Treatment with WELIREG was also associated with a statistically significant improvement in objective response rate (ORR). Results indicated that at a median follow-up of 18.4 months, the belzutifan group had a notably higher ORR compared to the everolimus group. Specifically, the ORR was 21.9% for patients receiving belzutifan, in contrast to a mere 3.5% for those on everolimus. In the subsequent IA2 analysis, the belzutifan group saw a further increase in ORR over time, reaching 22.7%. A complete response was observed in 3.5% of belzutifan patients, compared to none with everolimus.

To date, no overall survival benefits have been observed for belzutifan, compared to everolimus, in this study.

Regarding safety outcomes, there was a comparable occurrence of Grade 3 or more severe adverse events in both treatment groups, approximately around 62%. However, adverse events leading to treatment discontinuation occurred in 6% of belzutifan patients, compared to 15% of those receiving everolimus. The most common adverse events were anemia and fatigue, with approximately 30% of patients having Grade 3 or worse anemia in the belzutifan arm.

These results shed light on the evolving landscape of RCC therapy, emphasizing the need for diverse treatment options tailored to individual patient needs. WELIREG's positive impact on PFS is an encouraging sign, and its potential to enhance the quality of life for advanced RCC patients cannot be understated.

KOL insights

“There are limited treatment options for patients with advanced RCC whose cancer progresses after both immune checkpoint and anti-angiogenic therapies. It is an important step forward to see that in LITESPARK-005 study, belzutifan demonstrated a statistically significant reduction in the risk of disease progression or death, and an improvement in overall response rate.” – MD, United States

“If these data lead to the approval of belzutifan for the treatment of refractory RCC, it provides patients and practitioners with an active, well-tolerated treatment option when patients progress on prior lines of therapy. The [AE] profile, with anemia, fatigue and hypoxemia being most common AEs, is easily manageable, making it an attractive choice” –MD, United States.

Conclusion 

WELIREG, which Merck obtained in acquisition of Peloton Therapeutics in 2019, is a first-in-class oral hypoxia-inducible factor-2 alpha (HIF-2a) inhibitor. The Hypoxia-Inducible Factor (HIF) pathway is central to the pathophysiology of ccRCC and von Hippel-Lindau (VHL) disease. WELIREG showed a statistically significant and clinically meaningful improvement in PFS compared to everolimus, based on the initial interim analysis of a Phase III LITESPARK-005. There appears to be a 25% reduction in risk for progression or death with belzutifan versus everolimus. In addition, a statistically significant improvement in the ORR was also demonstrated. Notably, the magnitude of improvement remained consistent with extended follow-up at 25.7 months in the 2nd interim analysis. 

However, it's important to note that the overall survival (OS) outcome did not demonstrate statistical significance, and further analysis will be conducted in subsequent assessments. In terms of safety, WELIREG exhibited a consistent safety profile in this trial. It was well-received by patients, and the observed adverse events were in line with the known safety profile of the drug. 

As known, WELIREG was already approved by the FDA two years ago for the rare von Hippel-Lindau (VHL) disease. In addition, Merck is aiming to add indications for WELIREG and turn it into a blockbuster. Following the positive results from the LITESPARK-005 trial, the FDA has accepted and granted priority review for a supplemental new drug application (sNDA) seeking approval for WELIREG. The FDA has set a Prescription Drug User Fee Act (PDUFA) date of January 17, 2024.

For or more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the Renal Cell Carcinoma - Market Insight, Epidemiology And Market Forecast - 2032 report.