On December 15, the U.S. Food and Drug Administration (FDA) approved Merck's oral treatment Welireg (belzutifan) for the treatment of adult patients with advanced renal cell carcinoma (RCC) following treatment with programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors and vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs).
Welireg is an oral hypoxia-inducible factor-2α (HIF-2α) inhibitor that was initially approved by the FDA in 2021 for the treatment of adult patients with Hipper-Lindau syndrome (VHL syndrome), a rare genetic disorder that causes tumors to grow in various organs, particularly the kidneys.
Renal cell carcinoma is by far the most common type of kidney cancer, accounting for approximately nine out of ten kidney cancer diagnoses, with about 15% of these patients diagnosed at an advanced stage. This cancer is about twice as common in men as in women, and most cases are discovered incidentally during imaging for other abdominal conditions. Advanced renal cell carcinoma has historically been difficult to treat with traditional chemotherapy.
Merck stated that the approval of Welireg for the treatment of advanced renal cell carcinoma makes it the first drug in its class approved for this disease, and the first drug in a new treatment category since 2015. As an inhibitor of HIF-2α, Welireg reduces the transcription and expression of HIF-2α target genes associated with cell proliferation, angiogenesis, and tumor growth. HIF-2α is a key regulator of renal cell carcinoma development.
This approval is based on data from the open-label, randomized, active-controlled phase 3 LITESPARK-005 trial (NCT04195750), which evaluated the efficacy and safety of the hypoxia-inducible factor inhibitor Belzutifan in patients with unresectable locally advanced or metastatic clear cell renal cell carcinoma whose disease had progressed after sequential or combination therapy with PD-1 or PD-L1 checkpoint inhibitors and VEGF receptor-targeted therapy.
Study participants were randomly assigned to receive either once-daily oral Belzutifan 120 mg (n=374) or everolimus 10 mg (n=372). The co-primary endpoints were progression-free survival (PFS) and overall survival (OS).
Results showed that belzutifan significantly improved PFS compared to everolimus (hazard ratio, 0.75 [95% CI, 0.63–0.90]; one-sided P=.0008). The median PFS was estimated at 5.6 months (95% CI, 3.9–7.0) in the Belzutifan group and 5.6 months (95% CI, 4.8–5.8) in the everolimus group. At the time of analysis, OS data were immature; 59% of patients had died, however, the FDA stated that "no harmful trend was observed."
In patients with detectable disease at initiation, the objective response rate (ORR) in the belzutifan group was 22% (n=82/373) (95% CI, 18–27); 3% of patients achieved complete remission and 19% achieved partial remission. Among those who responded to belzutifan treatment, 30% (n=25) of the responses lasted at least 12 months. In the everolimus group, the ORR was 4% (n=13) (95% CI, 2–6); all of these patients achieved partial remission.
The most common adverse reactions to belzutifan were decreased hemoglobin, fatigue, musculoskeletal pain, increased creatinine, lymphopenia, increased alanine aminotransferase (ALT), decreased sodium, increased potassium, and increased aspartate aminotransferase (AST).
Welireg prescribing information includes a boxed warning regarding embryo-fetal toxicity. Pregnancy should be verified before initiating treatment, and patients are advised to use effective non-hormonal contraception during treatment.
Welireg is available in 40 mg tablets. The recommended dose is 120 mg orally once daily until disease progression or unacceptable toxicity. Dosage adjustments may be necessary if adverse reactions occur. Welireg 40 mg is priced at approximately $29,755, and a supply of 90 tablets is approximately one month's supply.
“In 2021, Welireg became the first HIF-2α inhibitor therapy approved in the United States for the treatment of adult patients with certain VHL disease-related tumors, and it is now approved for eligible patients with advanced renal cell carcinoma,” said Dr. Marjorie Green, Senior Vice President and Head of Global Clinical Development for Advanced Oncology at Merck Research Laboratories. “The approval of Welireg marks the first new treatment class available for eligible patients with advanced renal cell carcinoma in nearly a decade, based on a statistically significant progression-free survival benefit observed in patients treated with PD-1 or PD-L1 inhibitors and VEGF-TKIs compared to everolimus.”
LITESPARK-005 is one of four pivotal trials testing the potential of Welireg in renal cell carcinoma. The other two are LITESPARK-011 and LITESPARK-012, which are being evaluated in second-line and treatment-naïve advanced disease settings, respectively, and LITESPARK-022, which is being tested in adjuvant settings for locally advanced renal cell carcinoma.
