Merck's HIF-2α Inhibitor Belzutifan (Welireg) Receives FDA Approval for Advanced Renal Cell Carcinoma Following PD-(L)1 and Anti-VEGF Therapy

On December 14, MSD announced that Belzutifan (trade name: Welireg) received FDA approval for the treatment of patients with advanced renal cell carcinoma (RCC) who have been treated with PD-(L)1 drugs and anti-VEGF drugs.

The FDA's approval this time is mainly based on the positive results of the Phase III LITESPARK-005 study. This study is a randomized, open-label clinical trial that enrolled a total of 746 patients with advanced RCC whose disease had progressed after prior treatment with PD-(L)1 inhibitors and anti-VEGF drugs. The aim was to compare the efficacy and safety of Belzutifan (120mg, once daily) and Everolimus (10mg, once daily).

The results showed that, after receiving Belzutifan treatment, the risk of disease progression or death was significantly reduced in patients (HR=0.75, 95% CI: 0.63-0.90; p=0.0008), with an overall survival (OS) trend showing extension (21.0 vs. 17.2 months; p=0.09583), but without statistical significance. Moreover, the objective response rate (ORR) was significantly improved in Belzutifan-treated patients (21.9% vs. 3.5%; p<0.00001).

Source: ESMO 2023

In terms of safety, the most common adverse events (AEs) (incidence rate ≥25%) in the Belzutifan group included decreased hemoglobin levels, fatigue, musculoskeletal pain, increased creatinine, decreased lymphocyte count, elevated alanine aminotransferase (ALT), decreased sodium, increased potassium, and elevated aspartate aminotransferase (AST). Additionally, 38% of patients in the Belzutifan group reported serious AEs, 3.2% experienced fatal AEs (including sepsis and hemorrhage, each 0.5%), and 6% permanently discontinued the drug due to AEs.

In addition to the LITESPARK-005 study, MSD has also initiated three Phase III clinical trials of Belzutifan:

• LITESPARK-011 Study: Combination of Pembrolizumab and LenvatinibFirst-line treatmentPatients with advanced RCC;

• LITESPARK-012 Study: Combination with LenvatinibSecond-line TreatmentPatients with advanced RCC;

• LITESPARK-022 Study: Combination with PembrolizumabAdjuvant TherapyPatients with clear cell renal cell carcinoma (ccRCC) who have undergone nephrectomy.

Belzutifan is a small-molecule hypoxia-inducible factor 2α (HIF-2α) inhibitor that reduces the transcription and expression of HIF-2α target genes associated with cell proliferation, angiogenesis, and tumor growth. In August 2021, Belzutifan received FDA accelerated approval for treatment based on Phase II clinical data.Patients with VHL-associated renal cell carcinoma, central nervous system hemangioblastoma, or pancreatic neuroendocrine tumors who do not require immediate surgery, becoming the world's first and currently only approved HIF-2α inhibitor to reach the market. Currently, there are only eight HIF-2α inhibitors in clinical development globally, one of which comes from a pharmaceutical company in China.

Renal cell carcinoma (RCC) is the most common type of kidney cancer, with approximately 90% of patients diagnosed with kidney cancer having RCC. The incidence of renal cell carcinoma in men is about twice that in women. In the United States, approximately 15% of kidney cancer patients are diagnosed at an advanced stage.

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