Baseline and On-Treatment QOL Improvements Track With Survival Benefits With Belzutifan or Everolimus in ccRCC

Baseline and longitudinal improvements in patient-reported health-related quality of life (QOL) were associated with a reduced risk of disease progression and death among patients with previously treated advanced clear cell renal cell carcinoma (ccRCC) treated with belzutifan (Welireg) or everolimus (Afinitor), according to a post hoc analysis of the phase 3 LITESPARK-005 trial (NCT04195750) presented at the 2026 Kidney Cancer Research Summit.¹

In the pooled population (n = 720), each 3-point improvement in baseline Functional Assessment of Cancer Therapy–Kidney Cancer Symptom Index–Disease-Related Symptoms (FKSI-DRS) score was associated with a lower risk of progression-free survival (PFS) events (HR, 0.91; 95% CI, 0.86-0.96) and death (HR, 0.86; 95% CI, 0.81-0.91).¹ In the longitudinal, time-dependent model, on-treatment improvements in FKSI-DRS and EORTC QLQ-C30 Global Health Status/Quality of Life (GHS/QOL) scores were associated with even greater reductions in risk of progression or death (HR, 0.80; 95% CI, 0.74-0.85 for both instruments) and death (FKSI-DRS HR, 0.57; 95% CI, 0.53-0.62; QLQ-C30 GHS/QoL HR, 0.64; 95% CI, 0.60-0.69).

“These hypothesis-generating findings support health-related QOL as a potential prognostic marker; however, given the pooled treatment arms and potential for time-dependent confounding and reverse causation, results should be interpreted cautiously,” Pooja Ghatalia, MD, an associate professor in the Department of Hematology/Oncology and a collaborating member in cancer epigenetics in the Nuclear Dynamics and Cancer Research Program at Fox Chase Cancer Center in Philadelphia, Pennsylvania, and her coauthors wrote in a poster presentation of the data.

What was the design of the LITESPARK-005 analysis?

LITESPARK-005 was a randomized, open-label trial comparing belzutifan with everolimus in adults with unresectable, locally advanced, or metastatic clear cell RCC who had disease progression after 1 to 3 prior systemic therapies, including at least 1 anti–PD-(L)1 antibody and at least 1 VEGFR-targeted TKI, and a Karnofsky performance status score of 70% or higher.¹,²

Participants were randomly assigned 1:1 to belzutifan at 120 mg orally once daily or everolimus at 10 mg orally once daily until unacceptable toxicity, disease progression, or withdrawal. Patients were stratified by IMDC prognostic score (0 vs 1 or 2 vs 3-6) and number of prior VEGFR-targeted therapies (1 vs 2 or 3).²

This post-hoc analysis evaluated the association between health-related QOL and PFS and overall survival (OS) among the 720 participants (belzutifan, n = 366; everolimus, n = 354) who received at least 1 dose of study treatment and had at least 1 patient-reported outcome (PRO) assessment using the FKSI-DRS or QLQ-C30 GHS/QoL instruments, at a median of 35.8 months (range, 26.9-49.2) from random assignment to the April 15, 2024, data cutoff.¹

HRQoL was assessed at baseline, longitudinally as a time-dependent covariate, and at landmark time points at weeks 13, 25, and 53, with PFS and OS HRs estimated using Cox proportional hazards models; no adjustments were made for multiplicity, and no formal hypothesis testing was performed.

How did QOL scores track with progression and survival at baseline and over time?

In the baseline analysis, each 3-point improvement in FKSI-DRS score was associated with a lower risk of PFS events (HR, 0.91; 95% CI, 0.86-0.96) and death (HR, 0.86; 95% CI, 0.81-0.91) in the pooled population, with similar OS associations within the belzutifan (HR, 0.84; 95% CI, 0.77-0.92) and everolimus (HR, 0.86; 95% CI, 0.80-0.93) arms individually. Baseline QLQ-C30 GHS/QoL scores were not associated with PFS benefit (pooled HR, 0.98; 95% CI, 0.94-1.03) but were associated with a modest OS benefit per 10-point improvement (pooled HR, 0.92; 95% CI, 0.88-0.96).

In the longitudinal, time-dependent model, on-treatment improvements in both instruments corresponded to larger reductions in risk than baseline scores alone. Each 3-point improvement in FKSI-DRS score was associated with a lower risk of PFS events (pooled HR, 0.80; 95% CI, 0.74-0.85) and death (pooled HR, 0.57; 95% CI, 0.53-0.62), and each 10-point improvement in QLQ-C30 GHS/QoL score was associated with a lower risk of PFS events (pooled HR, 0.80; 95% CI, 0.74-0.85) and death (pooled HR, 0.64; 95% CI, 0.60-0.69).¹ These associations were directionally consistent when the belzutifan and everolimus arms were analyzed separately.

What did the landmark analyses at weeks 13, 25, and 53 show?

At the week 13 landmark, participants with stable or improved FKSI-DRS scores (change of more than -3 points) had a lower risk of PFS events (HR, 0.67; 95% CI, 0.51-0.87) and death (HR, 0.52; 95% CI, 0.41-0.67) than those with deteriorated scores. Findings were directionally similar for QLQ-C30 GHS/QoL (change of more than -10 points) at week 13 (PFS HR, 0.79; 95% CI, 0.60-1.05; OS HR, 0.53; 95% CI, 0.41-0.69). Median PFS with stable or improved FKSI-DRS scores was 7.9 months (95% CI, 6.0-10.5) vs 4.2 months (95% CI, 3.0-6.0) with deteriorated scores, and median OS was 24.9 months (95% CI, 21.8-29.1) vs 14.4 months (95% CI, 9.1-19.9), respectively.

At week 25, stable or improved FKSI-DRS scores were associated with a lower risk of PFS events (HR, 0.61; 95% CI, 0.42-0.88), and at week 53 with a lower risk of death (HR, 0.53; 95% CI, 0.31-0.91). QLQ-C30 GHS/QoL associations with OS were also observed at weeks 25 (HR, 0.64; 95% CI, 0.46-0.90) and 53 (HR, 0.51; 95% CI, 0.31-0.85), though PFS and OS estimates grew less precise at later landmarks as fewer participants remained on study. Associations at all landmark time points were reported as consistent between the belzutifan and everolimus arms.

References

1. Ghatalia P, Powles T, Albiges L, et al. Relationship between health-related quality of life and efficacy in the phase 3 LITESPARK-005 study of belzutifan vs everolimus in previously treated advanced clear cell renal cell carcinoma. Presented at: Kidney Cancer Research Summit; July 23-24, 2026. Boston, Massachusetts.
2. 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