FDA Approves Merck’s Welireg for Advanced Renal Cell Carcinoma

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Welireg (belzutifan) approved for the treatment of adults with advanced renal cell carcinoma that progressed after a regimen of a PD-1 or PD-L1 inhibitor and a VEGF-TKI.

The FDA has approved Merck’s Welireg (belzutifan) for the treatment of adults with advanced renal cell carcinoma (RCC) that progressed after a regimen of a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).1 Welireg, an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, was previously granted priority review by the FDA.2

“Despite recent progress in the treatment of advanced RCC, there is yet to be an option specifically approved for patients whose disease progresses following a PD-1 or PD-L1 inhibitor and a TKI therapy,” Toni K. Choueiri, MD, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Jerome and Nancy Kohlberg professor of medicine, Harvard Medical School, said in a press release. “This approval of [Welireg] introduces a meaningful new treatment option for certain patients, as [Welireg] reduced the risk of disease progression or death compared to everolimus.”1

The FDA based the approval on findings from the randomized, open-label, Phase III LITESPARK-005 trial (NCT04195750), which compared Welireg to Afinitor (everolimus; Novartis) for the treatment of advanced RCC that has progressed after prior treatment with PD-1/L1 and VEGF-TKI therapies, either in sequence or in combination. The study found that Welireg produced a statistically significant improvement in survival compared to Afinitor. Welireg lowered the risk of disease progression or death by 25% (HR=0.75 [95% CI, 0.63-0.90]; p=0.0008) compared with Afinitor in this patient population.1

Among 82 patients administered Welireg who achieved a confirmed response based on BICR per RECIST 1.1, 30% had a duration of response ≥12 months. Median progression-free survival (PFS) was 5.6 months (95% CI, 3.9-7.0) with Welireg compared with 5.6 months (95% CI, 4.8-5.8) with Afinitor. Overall survival (OS) data were immature at the time of the current analysis, with 59% of deaths reported in the randomized patient population. Patient-reported symptom and functional outcomes analysis favored Welireg over Afinitor.1

LITESPARK-005 investigators enrolled 746 patients with unresectable locally advanced or metastatic clear cell RCC that had progressed after treatment with a PD-1 or PD-L1 inhibitor and a VEGF TKI. The trial’s coprimary end points were PFS assessed by blinded independent central review and OS. Patients were randomly assigned to receive 120 mg of Welireg or 10 mg of Afinitor once daily.

The most common adverse effects reported in at least 25% of patients administered Welireg were reduced hemoglobin, fatigue, musculoskeletal pain, elevated creatinine, reduced lymphocytes, elevated alanine aminotransferase, reduced sodium, elevated potassium, and elevated aspartate aminotransferase. Welireg has a boxed warning that exposure during pregnancy may cause embryo-fetal harm.

“In 2021, Welireg became the first HIF-2α inhibitor therapy approved in the US for the treatment of adult patients with certain VHL disease-associated tumors and is now approved for eligible patients with advanced RCC,” said Marjorie Green, MD, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories, in a press release.1 “This approval of Welireg marks the first new therapeutic class available for eligible patients with advanced RCC in nearly a decade, and was based on the statistically significant progression-free survival benefit observed in patients following treatment with a PD-1 or PD-L1 inhibitor and a VEGF-TKI when compared to everolimus.”


1. 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. 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/

2. FDA accepts for priority review Merck’s supplemental new drug application for Welireg (belzutifan) in certain previously treated patients with advanced renal cell carcinoma (RCC). News release. Merck. September 19, 2023. Accessed December 15, 2023. https://www.merck.com/news/fda-accepts-for-priority-review-mercks-supplemental-new-drug-application-for-welireg-belzutifan-in-certain-previously-treated-patients-with-advanced-renal-cell-carcinoma-rcc/

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