The Food and Drug Administration granted approval for belzutifan (Welireg, Merck & Co., Inc.) on December 14, 2023, for patients with advanced renal cell carcinoma (RCC) who have previously received 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).
The effectiveness was assessed in LITESPARK-005 (NCT04195750), a study where 746 patients with unresectable locally advanced or metastatic clear cell RCC were randomly assigned to different treatments after progressing following a PD-1 or PD-L1 checkpoint inhibitor and a VEGF-TKI. Participants were randomly assigned in a 1:1 ratio to receive either 120 mg of belzutifan or 10 mg of everolimus once a day. Randomization was categorized based on International Metastatic RCC Database Consortium risk group and the quantity of preceding VEGF-TKIs.
The primary effectiveness measures were progression-free survival (PFS) evaluated by blinded independent central review and overall survival (OS).
Belzutifan showed a statistically significant improvement in progression-free survival (PFS) compared to everolimus, with a hazard ratio of 0.75 (95% CI: 0.63, 0.90) and a one-sided p-value of 0.0008. The Kaplan-Meier curves showed non-proportional risks with comparable median progression-free survival estimates of 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. Although the OS data were incomplete at the current study, with 59% of fatalities reported, no negative trend was detected. An examination of patient-reported symptoms and functional outcomes indicated that belzutifan was better tolerated than everolimus.
The predominant adverse effects (≥25% occurrence) observed in patients treated with belzutifan included reduced hemoglobin levels, fatigue, musculoskeletal pain, elevated creatinine levels, decreased lymphocyte count, elevated alanine aminotransferase levels, reduced sodium levels, elevated potassium levels, and increased aspartate aminotransferase levels.
The suggested belzutifan dosage is 120 mg taken orally once a day until disease progression or intolerable toxicity.
Targeting FGFR4 and CD276 with CAR T-cells demonstrates a strong antitumor impact against children rhabdomyosarcoma
Chimeric antigen receptor (CAR) T-cells that specifically target Fibroblast Growth Factor Receptor 4 (FGFR4), a surface tyrosine receptor that is extensively expressed in rhabdomyosarcoma (RMS), are now undergoing clinical research. However, the effectiveness of these CAR T-cells may be hindered by tumor heterogeneity and inadequate activation. In this study, we present a method to enhance the co-stimulatory and targeting characteristics of a FGFR4 CAR through an optimization process. We substituted the hinge and transmembrane domain of CD8 as well as the 4-1BB co-stimulatory domain with the corresponding domains of CD28. The CARs produced exhibit heightened anti-tumor efficacy in multiple RMS xenograft models, with the exception of the RMS559 cell line, which is known for its aggressive nature.
