Editor's Note: In a recent academic session, Professor David F. McDermott from Beth Israel Deaconess Medical Center presented the latest findings from Part 1 of the LITESPARK-024 study. This trial evaluated the safety and preliminary efficacy of the HIF-2α inhibitor belzutifan in combination with the CDK4/6 inhibitor palbociclib in patients with previously treated advanced clear cell renal cell carcinoma (ccRCC).01 Background: Exploring Combination Therapy Based on Synthetic Lethality
Belzutifan has demonstrated clinical benefit both as a monotherapy and in combination with agents targeting the tumor microenvironment. Palbociclib, an oral CDK4/6 inhibitor widely used in breast cancer, showed both synthetic lethality and additive benefit when combined with HIF-2α inhibition in VHL-mutant renal cancer models in preclinical studies from the Kaelin Lab. Based on these findings, the LITESPARK-024 study was designed to explore the first HIF-2α blockade-based, tumor-targeted combination therapy in metastatic ccRCC.
02 Study Design: Dose Escalation of Belzutifan plus Palbociclib
Part 1 of the LITESPARK-024 study followed a dose-escalation design. The study enrolled patients with advanced ccRCC eligible for belzutifan who had received prior treatment. The regimen consisted of a full dose of belzutifan (120 mg once daily) combined with escalating doses of palbociclib. Primary endpoints focused on defining dose-limiting toxicities (DLTs), safety, and the rate of treatment discontinuation. Following regulatory feedback, enrollment was expanded across all three dose arms, leading to a total of 59 patients, 22 of whom remained on therapy at the last data cut-off.
03 Safety Analysis: Anemia and Neutropenia as Key Considerations
No DLTs were observed at the first two dose levels. At the highest dose level, two DLTs were identified: one episode of Grade 3 anemia and one of hypoxia, the latter leading to treatment discontinuation. There were no treatment-related deaths.
Grade 3 or higher treatment-related adverse events (TRAEs) were frequent. Grade 3 anemia was the most common event, with a similar incidence across all three dose arms. The incidence of neutropenia increased with the dose of palbociclib, consistent with the drug’s known safety profile. No new safety signals were identified.
04 Clinical Efficacy: Stable Disease Control and PFS Performance
At the recommended Phase 2 dose (RP2D)—full doses of both belzutifan and palbociclib—the investigator-assessed objective response rate (ORR) was 21%, consistent with historical belzutifan monotherapy data. However, the combination demonstrated an improved disease control rate (DCR) and a lower primary progressive disease (PD) rate. Deep responses were observed on the waterfall plot within this group.
Regarding durability, the median progression-free survival (mPFS) was 9.1 months at the RP2D. This result is particularly noteworthy given that the study population consisted of heavily pretreated, biomarker-unselected patients.
05 Conclusion and Outlook: Supporting the HIF-2α Combination Hypothesis
Professor David F. McDermott noted that while Part 2 of LITESPARK-024 will not be initiated, the Part 1 results support the combination therapy hypothesis proposed by the Kaelin Lab. Belzutifan plus palbociclib demonstrated a manageable safety profile and preliminary anti-tumor activity in advanced ccRCC. These findings encourage further investigation of HIF-2α inhibitor-based tumor-targeted combinations, which remain a high area of interest for clinical practice.
