Overall, our findings show that casdatifan achieves meaningful, durable responses with manageable safety. These data establish a link between on-target HIF-2α pathway modulation, tumour biology and clinical efficacy.

Treatment with pembrolizumab-belzutifan led to significantly higher disease-free survival, with a greater risk of grade 3 or higher toxic effects, than treatment with pembrolizumab monotherapy after nephrectomy in participants with clear-cell renal-cell carcinoma at increased risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; LITESPARK-022 ClinicalTrials.gov number, NCT05239728.).

Upregulated in ccRCC in a VHL-HIF2α-dependent manner, TRAIL is selectively essential in ccRCC cells, promoting cell proliferation by activating the p38 MAPK pathway and facilitating G1/S phase transition. Depletion of endogenous TRAIL or inhibition of HIF2α with belzutifan sensitizes ccRCC cell and tumor models to recombinant TRAIL, presenting a promising avenue for combination therapy in ccRCC.

P2, N=120, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

HIFs have been recognized as major drivers of VHL disease pathology and based on this notion, the HIF-2α inhibitor belzutifan was developed, which has marked a major breakthrough in the treatment of this disease...Interestingly, recent studies suggest that pVHL has functions beyond controlling HIF levels, and loss of these HIF-independent functions may further contribute to tumorigenesis in VHL disease. This review summarizes the most recent advances in pathophysiology, genotype-phenotype correlation, treatment guidelines, and potential future treatment options related to VHL disease.

Remaining challenges include uncertainty regarding the identification of predictive biomarkers, optimization of patient selection, and integration of combination or sequencing strategies. Beyond its immediate clinical impact, belzutifan establishes a foundation for next-generation hypoxia-targeted therapies.

P1, N=24, Recruiting, Arcus Biosciences, Inc. | Not yet recruiting --> Recruiting

P1, N=24, Not yet recruiting, Arcus Biosciences, Inc.

Among the selected common selenium species, including Selenocystine (SeCys2), selenomethionine (SeMet) and selenium nanoparticles (SeNPs), SeNPs were found to effectively reverse abnormal lipid metabolism-mediated NK cell immune exhaustion induced by palmitic acid, oleic acid, or tumor-conditioned media...Furthermore, we also found that there is a positive correlation between high GPX1 expression and tumor-infiltrating NK cells in human breast tumor tissues, which further highlights the importance of elevated GPX1 expression in NK cell-mediated antitumor activity. Taken together, this study identifies SeNPs as a metabolic regulator that reprograms dysregulated lipid metabolism to restore NK cell antitumor immunity, which provides a mechanistic framework for developing selenium-based metabolic strategies to enhance cancer immunotherapy.

Belzutifan led to radiographic improvement in pulmonary metastases and symptoms, while other lesions remained stable. This suggests its potential therapeutic use in TFE3-rearranged renal cell carcinoma.

P2, N=355, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Jun 2029 --> Dec 2029 | Trial primary completion date: Jun 2029 --> Dec 2029

Casdatifan has shown promising clinical activity in the ARC-20 ccRCC platform study, both as monotherapy and in combination with the VEGFR tyrosine kinase inhibitor (TKI) cabozantinib. Currently, casdatifan is being evaluated in a Phase 3 trial in combination with cabozantinib (NCT07011719) in patients with advanced ccRCC.