Belzutifan Significantly Improves PFS Vs Everolimus in Clear Cell RCC

"The LITESPARK-005 trial introduced HIF-2α inhibition as an active therapeutic mechanism and established belzutifan as a treatment option in patients with advanced [RCC] after both immune checkpoint and antiangiogenic therapies," according to the study authors.

Treatment with belzutifan (Welireg) conferred significant improvements in progression-free survival (PFS) and objective response rate (ORR) compared with everolimus (Afinitor) among patients with advanced clear cell renal cell carcinoma (RCC), according to updated findings from the phase 3 LITESPARK-005 trial (NCT04195750) published in The New England Journal of Medicine.¹

Data from the first interim analysis showed a median PFS of 5.6 months (95% CI, 3.9-7.0) in the belzutifan arm vs 5.6 months (95% CI, 4.8-5.8) in the everolimus arm. The estimated 6-month PFS rates in each arm were 46.6% (95% CI, 41.3%-51.7%) vs 42.5% (95% CI, 36.8%-48.0%), the estimated 12-month rates were 33.4% (95% CI, 28.4%-38.5%) vs 17.1% (95% CI, 12.7%-22.1%), and the estimated 18-month rates were 24.0% (95% CI, 19.0%-29.4%) vs 8.3% (95% CI, 4.9%-12.7%; P = .002).

PFS outcomes in the prespecified patient subgroups across the belzutifan and everolimus arms were comparable with those reported in the intent-to-treat population. Additionally, PFS as determined via central review at the second interim analysis and PFS per investigator assessment at the first and second interim analyses were comparable with the primary results.

The confirmed ORR was 21.9% (95% CI, 17.8%-26.5%) with belzutifan vs 3.5% (95% CI, 1.9%-5.9%) with everolimus at the first interim analysis, representing an estimated difference of 18.4 percentage points between arms (95% CI, 14.0-23.2; P <.001). At the time of the second interim analysis, the confirmed ORR was 22.7% (95% CI, 18.6%-27.3%) vs 3.5% (95% CI, 1.9%-5.9%); the estimated difference in ORR was 19.2 percentage points (95% CI, 14.8-24.0). Additionally, the second interim analysis data highlighted a median duration of response (DOR) of 19.5 months (range, 1.9+ to 31.6+) vs 13.7 months (range, 3.8 to 21.2+) in each respective arm; the median time to response was 3.8 months (range, 1.7-22.0) vs 3.7 months (range, 1.8-5.4).

The FDA previously approved belzutifan for patients with advanced RCC following prior anti–PD-L1 or anti–PD-1 therapy and VEGF tyrosine kinase inhibitors (TKIs) in December 2023 based on findings from the LITESPARK-005 trial.²

“After the approval of belzutifan in the United States for patients with advanced [RCC] who had previously received a PD-1 or PD-L1 inhibitor and a VEGFR-TKI, the drug could be used by clinicians in the context of heavily pretreated disease as described in the LITESPARK-005 trial. Studies investigating belzutifan combinations as compared with other therapies are ongoing,” Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, co-leader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center, and the Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, and coauthors wrote.¹

“The LITESPARK-005 trial introduced HIF-2α inhibition as an active therapeutic mechanism and established belzutifan as a treatment option in patients with advanced [RCC] after both immune checkpoint and antiangiogenic therapies,” they added.

In the multicenter, open-label LITESPARK-005 trial, 746 patients were assigned 1:1 to receive belzutifan at 120 mg orally once daily (n = 374) or everolimus at 10 mg orally once daily (n = 372).

The trial’s dual primary end points were PFS and overall survival (OS). The key secondary end point was ORR.

The median age was 62.0 years (range, 22-90) in the belzutifan arm and 63.0 years (range, 33-87) in the everolimus arm. In each respective arm, most patients were male (79.4% vs 76.3%), White (79.4% vs 78.2%), had International Metastatic RCC Database Consortium intermediate-risk disease (66.6% vs 65.6%), no sarcomatoid features (68.2% vs 66.7%), and prior nephrectomy (69.8% vs 69.6%). Additionally, most patients had 3 (45.2% vs 40.3%) or 2 prior lines of therapy (42.0% vs 44.6%) as well as lung metastases (65.8% vs 63.4%).

As of the second interim analysis, the estimated 12-month OS rate was 67.9% (95% CI, 62.9%-72.4%) in the belzutifan arm vs 65.8% (95% CI, 60.7%-70.3%) in the everolimus arm; the estimated 18-month rates were 55.2% (95% CI, 50.0%-60.1%) vs 50.6% (95% CI, 45.3%-55.5%), respectively. Data showed a median OS of 21.4 months (95% CI, 18.2-24.3) and 18.1 months (95% CI, 15.8-21.8) in each respective arm (HR, 0.88; 95% CI, 0.73-1.07; P = .20).

Any-grade adverse effects (AEs) affected 99.2% of patients treated with belzutifan compared with 99.2% of those who received everolimus, with grade 3 or higher AEs occurring in 61.8% and 62.5% of each respective arm. AEs resulting in treatment discontinuation occurred in 5.9% vs 14.7% of patients, and AEs leading to death were reported in 3.5% and 5.3%.

Common any-grade AEs in the belzutifan and everolimus arms, respectively, included anemia (82.8% vs 56.7%), fatigue (31.5% vs 25.3%), nausea (18.0% vs 11.4%), and constipation (16.7% vs 8.1%). Any-cause hypoxia occurred in 14.5% and 1.1% of patients in each respective treatment group.

The median time to quality of life (QOL) deterioration per EORTC QLQ-C30 global health status and QOL scores was 19.35 months (95% CI, 11.89-not reached) in the belzutifan arm vs 10.19 months (95% CI, 6.47-12.98) in the everolimus arm (HR, 0.75; 95% CI, 0.58-0.96).

References

1. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906
2. FDA approves belzutifan for advanced renal cell carcinoma. News release. FDA. December 14, 2023. Accessed September 3, 2024. https://bit.ly/3NuRveV