Belzutifan Shows Durable PFS and ORR in Advanced Clear Cell RCC
Key Insights
Belzutifan maintained improved progression-free survival (PFS) and objective response rate (ORR) compared to everolimus in previously treated advanced clear cell RCC (search).
The median PFS was 5.6 months with belzutifan vs 5.6 months with everolimus; however, belzutifan did not outperform everolimus in overall survival (OS).
Belzutifan led to a higher ORR than everolimus (22.7% vs 3.5%), with durable responses lasting over two years in some patients.
Belzutifan (Welireg) continues to demonstrate promising results in patients with previously treated advanced clear cell renal cell carcinoma (search) (RCC (search)), 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 (search) 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 (search) after PD-[L]1 inhibitor and VEGFR TKI therapy," Rini concluded.