Belzutifan Maintains Efficacy After a PD-(L)1 Inhibitor and Multiple VEGFR TKIs in ccRCC

Belzutifan (Welireg) displayed an efficacy benefit over everolimus (Afinitor) consistent with that observed in the intention-to-treat (ITT) population in patients with pretreated clear cell renal cell carcinoma (ccRCC) who received at least 1 anti–PD-(L)1 therapy and at least 2 VEGFR TKIs, according to data from an exploratory analysis of the LITESPARK-005 (NCT04195750) presented at the 2025 ESMO Congress.¹

Findings from the analysis showed that patients who received at least 2 VEGFR TKIs and were treated with belzutifan (n = 187) achieved a median progression-free survival (PFS) per blinded independent central review (BICR) of 4.6 months (95% CI, 3.5-7.3) vs 5.4 months (95% CI, 3.8-6.5) with everolimus (n = 182; HR, 0.73; 95% CI, 0.57-0.94). The median overall survival (OS) values were 21.8 months (95% CI, 17.4-25.8) and 18.1 months (95% CI, 14.2-23.9), respectively (HR, 0.94; 95% CI, 0.74-1.21).

The overall response rates (ORRs) per RECIST 1.1 criteria by BICR in the belzutifan and everolimus groups were 24.1% (95% CI, 18.1%-30.8%) and 3.3% (95% CI, 1.2%-7.0%), respectively, representing an estimated difference of 20.8% (95% CI, 14.3%-27.7%). Five patients who received belzutifan achieved a complete response whereas no patients did so in the everolimus arm. The median duration of response (DOR) values were 17.5 months (95% CI, 1.9+ to 39.8+) and 10.9 months (95% CI, 3.8-28.4+). The median times to response (TTR) were 3.7 months (range, 1.7-22.0) and 3.0 months (range, 1.8-5.4), respectively.

“… Consistent with the ITT population, belzutifan improves PFS, ORR, and time to confirmed deterioration [TTD] of disease-related symptom and health-related quality of life scores in the subgroup of participants who received at least 2 prior lines of therapy,” Guillermo Antonio De Velasco Oria, MD, PhD, an attending physician and independent clinical investigator at Hospital Universitario 12 de Octubre in Madrid, Spain, and his coauthors wrote in a poster presentation of the data.

Prior data from LITESPARK-005 supported the December 2023 FDA approval of belzutifan for the treatment of patients with advanced RCC following treatment with a PD-1 or PD-L1 inhibitor and a VEGF TKI.² The approval was supported by prior data from LITESPARK-005.

How was LITESPARK-005 designed?

LITESPARK-005 enrolled patients with unresectable, locally advanced or metastatic ccRCC who experienced disease progression following 1 to 3 prior lines of therapy.¹ Prior treatments needed to include at least 1 anti–PD(L)1 monoclonal antibody and at least 1 VEGFR TKI. A Karnofsky Performance Status score of at least 70% was also required.

Patients were randomly assigned 1:1 to receive either 120 mg of belzutifan or 10 mg of everolimus, both of which were once daily oral doses. Stratification occurred based on International Metastatic RCC Database Consortium (IMDC) prognostic score (0 vs 1-2 vs 3-6) and the number of prior VEGFR-targeted therapies (1 vs 2-3).

The coprimary end points were PFS per BICR and OS. ORR per RECIST 1.1 criteria assessed by BICR was the key secondary end point. Other secondary end points included DOR per RECIST 1.1 criteria by BICR, safety, and TTD in disease-related symptoms.

At baseline, patients who received belzutifan who were treated with at least 2 prior VEGFR TKIs had a median age of 62.0 years (range, 40-81). Most patients were male (79.1%), had a Karnofsky Performance Status score of 90 or 100 (62.0%), had IMDC intermediate–risk disease (65.2%), and received 3 or 4 prior lines of therapy (85.6%).

What were the ITT efficacy findings and the safety profile in the subgroup analysis?

In the ITT population of LITESPARK-005, the median PFS values in the belzutifan (n = 374) and everolimus (n = 372) were 5.6 months (95% CI, 3.9-7.0) and 5.6 months (95% CI, 4.8-5.8), respectively (HR, 0.75; 95% CI, 0.63-0.90; 1-sided P < .001). The median OS values were 21.4 months (95% CI, 18.2-24.3) and 18.2 months (95% CI, 15.8-21.8), resepectively (HR, 0.92; 95% CI, 0.77-1.10; 1-sided P = .018). The respective ORRs were 21.9% (95% CI, 17.8%-26.5%) and 3.5% (95% CI, 1.9%-5.9%). The respective median DOR values were 19.3 months (range, 1.9+ to 40.1+) and 13.7 months (range, 3.8-29.5+).

In terms of safety, patients included in the subgroup analysis who received belzutifan (n = 186) or everolimus (n = 177) experienced any-grade adverse effects (AEs) at respective rates of 99.5% and 98.9%. Grade 3 or higher AEs (66.1% vs 59.3%), serious AEs (44.6% vs 39.0%), and AEs leading to dose reduction (15.6% vs 13.6%), dose discontinuation (7.0% vs 14.1%), or death (5.4% vs 4.5%) were reported in both subgroups.

“No meaningfully different frequencies of AEs were observed in this subgroup compared with the ITT population of the LITESPARK-005 study,” De Velasco Oria and coauthors wrote in a presentation of the data.

Disclosures: De Velasco received honoraria from Pfizer, Ipsen, BMS, Astellas Pharma; holds consulting or advisory roles with Pfizer, Novartis, Bayer, Astellas, Medivation, Bristol Myers Squibb, Ipsen, MSD, Merck, Roche, Pierre Fabre, Arcus Ventures, Genmab; and received research funding from Ipsen; and received travel, accommodations, or expenses from Roche, BMS.

References

1. De Velasco Oria GA, Jalkanen K, Albiges K, et al. Belzutifan for advanced clear cell renal cell carcinoma (ccRCC) after a PD-(L)1 inhibitor and ≥2 VEGFR-TKIs in LITESPARK-005. Ann Oncol. 2025;36(suppl 2):S1399-S1400. doi:10.1016/j.annonc.2025.08.3223
2. FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed December 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma