Welireg Shows Survival Advantage Over Everolimus Treating Advanced Clear-Cell Renal Cell Carcinoma

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Welireg (belzutifan) produced a significant benefit compared to everolimus (Afintior; Afinitor Disperz; Zortress) in progression-free survival (PFS) and objective response in patients with advanced clear-cell renal cell carcinoma (RCC) who received prior treatment with immune checkpoint and antiangiogenic therapies, according to findings from the Phase III LITESPARK-005 trial (NCT04195750) published by The New England Journal of Medicine.^1,2 Welireg, an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, was approved in December 2023 to treat adults with advanced RCC that progressed following treatment with a PD-1 or PD-L1 inhibitor and a VEGF-tyrosine kinase inhibitor (TKI).³

“Antiangiogenic and immune checkpoint therapies as first-line treatment have been shown to improve outcomes in patients with advanced clear-cell [RCC]. After disease progression, treatment options include [VEGF] receptor–[VEGFR-TKI] monotherapy and lenvatinib plus everolimus,” the study authors wrote. “Monotherapy with everolimus, an inhibitor of the mammalian target of rapamycin, is considered to be useful in certain circumstances. Current guidance on the use of these agents is based on evidence from older clinical trials or exploratory subgroup analyses with small sample sizes.”¹

For the multicenter, open-label, active-controlled LITESPARK-005 trial, a total of 374 patients were randomly assigned to receive 120 mg of Welireg and 372 patients were randomly assigned to receive 10 mg of oral everolimus once daily until disease progression or unacceptable toxic adverse events (AE) were reported. The trial’s dual primary endpoints were PFS and overall survival (OS), with a key secondary endpoint of a confirmed objective response, being a complete or partial response.

The first interim analysis conducted at a median follow-up of 18.4 months showed a median PFS of 5.6 months in both cohorts. At 18 months, 24.0% of patients in the Welireg cohort were alive and free of progression compared with 8.3% in the everolimus cohort (two-sided P=0.002, which achieved the prespecified significance criterion).

Among patients in the Welireg cohort, a confirmed objective response was observed in 21.9% of patients (95% confidence interval [CI], 17.8 to 26.5) compared to 3.5% (95% CI, 1.9 to 5.9) in the everolimus cohort (P<0.001, achieving the prespecified significance criterion). A second interim analysis at a median follow-up of 25.7 months, median OS was 21.4 months in the Welireg cohort compared to 18.1 months in the everolimus cohort. At 18 months, 55.2% of patients in the Welireg cohort and were alive compared to 50.6% of patients in the everolimus cohort (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P=0.20, which did not achieve the prespecified significance criterion).

“To date, in our trial, [Welireg] has shown a significant benefit over everolimus with respect to [PFS],” the study authors wrote. “Most participants in both groups had received two or three previous lines of therapy, and a large percentage had disease progression or died or had their data censored because they started new anticancer therapy within 6 months after randomization. Kaplan–Meier estimates of [PFS] at 12 months and 18 months indicated that a higher percentage of participants in the [Welireg] group than in the everolimus group were alive and without disease progression. A significant difference between the two groups with respect to the occurrence of an objective response was also observed.”¹

In terms of safety, grade 3 or higher AEs of any cause were reported by 61.8% of patients in the Welireg cohort compared to 62.5% in the everolimus cohort. AEs leading to treatment discontinuation occurred in 5.9% of patients in the Welireg cohort compared to 14.7% of patients in the everolimus cohort.

“After the approval of [Welireg] in the United States for patients with advanced [RCC] who had previously received a PD-1 or PD-L1 inhibitor and a VEGFR-TKI, the drug could be used by clinicians in the context of heavily pretreated disease as described in the LITESPARK-005 trial. Studies investigating [Welireg] combinations as compared with other therapies are ongoing,” the study authors wrote. “The LITESPARK-005 trial introduced HIF-2α inhibition as an active therapeutic mechanism and established [Welireg] as a treatment option in patients with advanced [RCC] after both immune checkpoint and antiangiogenic therapies.”¹

References

1. Choueiri T, et al. Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. Published August 21, 2024 N Engl J Med 2024;391:710-721. DOI: 10.1056/NEJMoa2313906. Vol. 391 No. 8.

2. A Study of Belzutifan (MK-6482) Versus Everolimus in Participants With Advanced Renal Cell Carcinoma (MK-6482-005). ClinicalTrials.gov. June 28, 2024. https://clinicaltrials.gov/study/NCT04195750

3. FDA Approves Merck’s WELIREG® (belzutifan) for the Treatment of Patients With Advanced Renal Cell Carcinoma (RCC) Following a PD-1 or PD-L1 Inhibitor and a VEGF-TKI. Merck. News release. December 14, 2023. Accessed August 22, 2024. https://www.merck.com/news/fda-approves-mercks-welireg-belzutifan-for-the-treatment-of-patients-with-advanced-renal-cell-carcinoma-rcc-following-a-pd-1-or-pd-l1-inhibitor-and-a-vegf-tki/