Belzutifan Yields 6x Better Results, but Half Survive Under 2 Years

In a recent clinical trial, two groups of patients were administered either 120 mg of Belzutifan (n=374) or 10 mg of everolimus (n=372) orally once daily until disease progression or the onset of unacceptable toxic reactions. The primary endpoints were progression-free survival (PFS) and overall survival (OS), while the key secondary endpoint was the objective response rate (ORR), which included confirmed complete response (CR) or partial response (PR).

The first interim analysis, with a median follow-up of 18.4 months, showed that the median PFS for both groups was 5.6 months. At the 18-month mark, 24.0% of participants in the Belzutifan group were alive and without disease progression, compared to 8.3% in the active control group (P=0.002). Additionally, the objective response rate in the Belzutifan group was six times higher than that in the active control group. Specifically, 21.9% of patients in the Belzutifan group achieved an objective response (95% CI: 17.8-26.5), compared to only 3.5% in the control group (95% CI: 1.9-5.9), a statistically significant difference (P<0.001).

In a second interim analysis, with a median follow-up period of 25.7 months, the median OS was 21.4 months for the Belzutifan group and 18.1 months for the active control group. At 18 months, 55.2% of subjects in the Belzutifan group and 50.6% in the control group were still alive (HR=0.88; 95% CI: 0.73-1.07; P=0.20).

Regarding safety, 61.8% of patients in the Belzutifan group experienced grade 3 or higher adverse events, with 3.5% experiencing grade 5 events. In the active control group, 62.5% experienced grade 3 or higher adverse events, with 5.3% experiencing grade 5 events. Treatment discontinuation due to adverse events occurred in 5.9% of patients in the Belzutifan group and 14.7% in the control group. No new safety signals were reported for Belzutifan.

Belzutifan, the first HIF-2α inhibitor to receive accelerated FDA approval, has been approved in the United States, the United Kingdom, Canada, and several other countries for the treatment of adults with von Hippel-Lindau (VHL) disease, particularly those with associated renal cell carcinoma (RCC), central nervous system hemangioblastoma, or pancreatic neuroendocrine tumors not requiring immediate surgery. As of December 2023, Belzutifan also became the first HIF-2α inhibitor approved for patients with advanced RCC, marking the first new mechanistic therapy for this condition since 2015.

Merck is dedicated to broadening the application potential of Belzutifan, promoting its use alone or in combination with the PD-1 inhibitor Pembrolizumab for treating RCC, endometrial cancer, esophageal cancer, liver cancer, prostate cancer, and rare cancers. Currently, Belzutifan is in phase two clinical trials for these conditions, with the hope of benefiting more patients soon.

In addition, the industry continues to advance RCC therapies. A notable small molecule therapy is Zanzalintinib, developed by Exelixis, which inhibits tyrosine kinase activity in receptors associated with cancer growth, including VEGF receptors, MET, AXL, and MER. In a Phase 1b trial, a median follow-up of 8.3 months revealed that 12 out of 32 treated clear cell RCC patients achieved a confirmed partial response (PR), with an objective response rate (ORR) of 38% and a disease control rate (DCR) of 88%. Fruzaqla (Fruquintinib), another promising VEGFR-1, -2, and -3 inhibitor, is also under study for RCC treatment.

New molecular therapies have brought renewed hope for RCC patients. The personalized mRNA cancer vaccine MRNA-4157 (V940), co-developed by Moderna and Merck, has recently commenced a phase 2 study for RCC treatment. Arsenal Biosciences' AB-2100, a T-cell therapy using CRISPR technology, has also begun a phase 1/2 trial for clear cell RCC. This therapy aims to engineer T cells to selectively target tumors, allowing the immune system to destroy RCC cells without harming normal tissue. Additionally, Adicet Bio plans to start a Phase 1 clinical trial for ADI-270, a gamma-δ CAR-T cell candidate for CD70-positive cancer, in the second half of 2024 to evaluate its safety and antitumor activity in RCC patients.

These developments highlight the ongoing advancements in RCC therapies and the potential for new treatments to improve patient outcomes.