Dr McDermott on the Ongoing LITESPARK-024 Trial in Pretreated Advanced RCC

David F. McDermott, MD, director of the Biologic Therapy and Cutaneous Oncology Programs at Beth Israel Deaconess Medical Center, professor of medicine, Harvard Medical School, discusses the randomized phase 2 LITESPARK-024 trial (NCT05468697).

Clear cell kidney cancer is commonly driven by increased expression of the transcription factor HIF2α, McDermott explains. Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is a common driver of clear cell RCC, leading to the buildup of HIF-2α. In August 2021, the FDA approved the HIF2α inhibitor belzutifan (Welireg) for the treatment of adult patients with VHL disease who require therapy for associated renal cell carcinoma (RCC). However, the agent has been shown to have an objective response rate of only 49%. As such, investigators are looking to build upon this response rate with other targeted therapies in oncology, McDermott says.

Preclinical data from the laboratory, led by William G. Kaelin Jr., MD, of Dana-Farber Cancer Institute, have shown that the addition of a HIF2α inhibitor to a CDK4/6 inhibitor may lead to synergistic activity. The research, which was published in Science Signaling in 2019, showed that the antiproliferative effects of CDK4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α-dependent VHL-/- clear cell RCC cells and not antagonistic with HIF-2α inhibition in HIF-2α–independent cells. This work served as the basis for the randomized phase 2 trial, which is evaluating belzutifan with or without palbociclib (Ibrance) in previously treated patients with advanced RCC, McDermott explains.

To be eligible for enrollment in the phase 2 trial, patients must have metastatic clear cell RCC and have previously been treated with at least 2 systemic treatments for stage IV disease including VEGF and PD-1 inhibition, McDermott says. Efficacy will be measured by objective response. Key secondary efficacy measures include clinical benefit rate, duration of response, progression-free survival, and overall survival.