Belzutifan (Welireg) continues to demonstrate promising results in patients with previously treated advanced clear cell renal cell carcinoma (RCC), according to the final analysis of the phase 3 LITESPARK-005 trial presented at the 2024 European Society for Medical Oncology (ESMO) Congress. While the study showed sustained improvements in progression-free survival (PFS) and objective response rate (ORR) compared to everolimus, it did not demonstrate a statistically significant improvement in overall survival (OS).
At a median follow-up of 35.8 months, the median PFS was 5.6 months (95% CI, 3.8-6.5) with belzutifan compared to 5.6 months (95% CI, 4.8-5.8) with everolimus (HR, 0.75; 95% CI, 0.63-0.88). The 12- and 24-month PFS rates with belzutifan were 33.7% and 17.5%, respectively, versus 17.6% and 4.1% with everolimus. The median OS was 21.4 months (95% CI, 18.2-24.3) with belzutifan versus 18.2 months (95% CI, 15.8-21.8) with everolimus (HR, 0.92; 95% CI, 0.77-1.10; P =.18). The 12- and 24-month OS rates with belzutifan were 67.9% and 45.2%, respectively, versus 65.8% and 41.2% with everolimus.
Key Efficacy Findings
"At the final analysis of the phase 3 LITESPARK-005 study, belzutifan continued to show PFS and ORR benefits vs everolimus, including durable responses lasting over 2 years," said Brian Rini, MD, lead study author and chief of clinical trials at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. "With over 2 years of minimum follow-up, more participants remained on treatment with belzutifan vs everolimus, [but] significant improvement in OS was not observed."
Belzutifan, a first-in-class oral HIF-2α inhibitor, works by impeding heterodimerization with HIF-1β and downstream oncogenic pathways. It received FDA approval in December 2023 for advanced RCC patients following a PD-(L)1 inhibitor and a VEGF TKI, based on earlier LITESPARK-005 findings.
Objective Response and Duration
Belzutifan demonstrated a substantially higher ORR compared to everolimus, with 22.7% (95% CI, 18.6%-27.3%) versus 3.5% (95% CI, 1.9%-5.9%), reflecting an estimated difference of 19.2% (95% CI, 14.8%-24.1%). In the belzutifan arm, confirmed best objective responses included complete response (CR; 3.5%), partial response (PR; 19.3%), stable disease (SD; 38.2%), and progressive disease (PD; 34.0%). In the everolimus arm, confirmed best objective responses included PR (3.5%), SD (65.9%), and PD (21.5%).
In the belzutifan arm, the median time to response (TTR) among responders (n = 85) was 3.8 months (range, 1.7-22.0), and the median duration of response (DOR) was 19.3 months (range, 1.9+ to 40.1+). The rate of belzutifan-treated patients in ongoing response at 12 and 24 months was 71.1% and 43.7%, respectively. In the everolimus arm, the median TTR among responders (n = 13) was 3.7 months (range, 1.8-5.7), and the median DOR was 13.7 months (range, 3.8 to 29.5+). The rate of everolimus-treated patients in ongoing response at 12 and 24 months was 61.5% and 23.1%, respectively.
Safety Profile
The median duration of study therapy was 7.6 months (range, 0.1-45.9) with belzutifan and 3.9 months (range, 0.03-41.8) with everolimus. Despite longer exposure to treatment, patients in the belzutifan arm experienced comparable or reduced toxicities to those in the everolimus arm. Grade 3 or greater AEs occurred in 62.9% and 62.8% of patients in the belzutifan and everolimus arms, respectively. AEs leading to discontinuation or death occurred in 6.2% and 3.8% of patients in the belzutifan arm, respectively, versus 15.3% and 5.3% in the everolimus arm.
"No new safety signals for belzutifan were observed," Rini said. "The most common any-grade adverse drug reactions had a median time to onset of less than 2 months."
The median times to onset for anemia, hypoxia, dizziness, dyspnea, fatigue, nausea, and weight increase were 1.0 month (range, 0.03-27.4), 1.0 month (range, 0.03-21.1), 2.3 months (range, 0.03-34.2), 1.9 months (range, 0.03-25.8), 1.5 months (range, 0.03-29.9), 1.4 months (range, 0.03-24.0), and 3.3 months (range, 0.5-15.0), respectively.
Conclusion
"Final analysis results of LITESPARK-005 support belzutifan as a treatment option in advanced clear cell RCC after PD-[L]1 inhibitor and VEGFR TKI therapy," Rini concluded.
