A New Hope for RCC Patients

In a significant development for patients battling advanced renal cell carcinoma (RCC), belzutifan (Welireg) has demonstrated superior outcomes in disease-specific symptoms and overall quality of life (QOL) compared to everolimus (Afinitor).These findings stem from patient-reported outcome (PRO) results of the phase 3 LITESPARK-005 trial (NCT04195750), recently published in Lancet Oncology.

LITESPARK-005: A Closer Look

The LITESPARK-005 trial, a phase 3 study, randomly assigned patients with unresectable, locally advanced or metastatic clear cell RCC, who had experienced disease progression after one to three lines of systemic therapy, to receive either 120 mg of oral daily belzutifan or 10 mg of oral daily everolimus.Treatment continued until unacceptable toxicity, investigator-initiated discontinuation, or patient withdrawal.

The trial’s primary endpoints focused on progression-free survival and overall survival. Secondary outcomes included changes from baseline in the functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index: Disease Related Symptoms (FKSI-DRS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), along with the time to deterioration in physical functioning per EORTC QLQ-C30.

Key Data points

• Patient Population: The PRO full analysis set included 720 patients, with 366 in the belzutifan group and 354 in the everolimus group.
• High Completion Rates: Completion rates for both FKSI-DRS and EORTC QLQ-C30 assessments were notably high, at 96% and 94% respectively.
• Compliance: FKSI-DRS compliance rates at week 17 were 90% in the belzutifan group and 91% in the everolimus group, with completion rates of 64% and 56%, respectively. EORTC QLQ-C30 compliance rates were 90% vs 91%, with week 17 completion rates of 64% and 56%.
• Symptom Stability: Least-squares mean change from baseline to week 17 showed stability in FKSI-DRS scores with belzutifan, but a worsening with everolimus (difference in least-squares mean, 1.5; 95% CI, 0.7-2.2).
• Quality of Life: A similar trend was observed for EORTC QLQ-C30 (difference in least-squares mean,6.4; 95% CI, 3.2-9.6).
• Physical Functioning: Least-squares mean change over the same period was similar between groups for physical functioning at 2.5 (95% CI, –0.6 to 5.5) and role functioning at 4.2 (95% CI, 0.1-8.4).
• Cognitive functioning: Greater worsening with belzutifan vs everolimus was onyl observed for cognitive functioning.

Insights from the Lead Investigator

[Patients] with pretreated advanced [RCC] who received belzutifan reported better disease-specific symptoms and QOL than those who received everolimus.
Thomas Powles, MBBS, MRCP, MD, professor of Genitourinary Oncology, lead for Solid Tumor Research, and director of the Barts Cancer Center at St. Bartholomew’s Hospital

Powles further noted the exploratory nature of the PRO results, emphasizing the need for further research to support these findings. He added,

The PRO results are exploratory, and further research is required to support these findings. Taken together with efficacy and safety data from LITESPARK-005, belzutifan could offer a clinical benefit without compromising patient health-related QOL [HRQOL] in this setting.
Thomas Powles, MBBS, MRCP, MD

patient Demographics

Data presented at the 2024 European Society for Medical Oncology Congress (ESMO) indicated that patient characteristics were well matched at baseline between the belzutifan and everolimus groups. The median age in the belzutifan group was 62 years (range, 22-90), with a majority being male (79.4%). Regarding International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk, 21.7% were considered favorable risk, 66.3% intermediate risk, and 12.0% poor risk. Prior lines of therapy included 12.0% receiving one prior line, 42.2% receiving two, and 45.2% receiving three.

Progression and Deterioration

The median time to EORTC QLQ-C30 physical functioning deterioration was 19.3 months (95% CI, 11.1-not reached [NR]) in the belzutifan arm vs 13.8 months (95% CI, 10.6-NR) in the everolimus arm (HR, 0.93; 95% CI, 0.72-1.20). The median time to deterioration for EORTC QLQ-C30 role functioning was 12.0 months (95% CI, 9.2-NR) vs 10.2 months (95% CI, 4.7-14.4) in the respective groups (HR, 0.88; 95% CI, 0.69-1.11).

EU Approval

In February 2025, belzutifan received EU approval for adult patients with advanced clear cell RCC that progressed following two or more lines of therapy, including PD-1 or PD-L1 inhibition and at least two VEGF-targeted therapies, based on data from the LITESPARK-005 trial.

The Future of RCC Treatment

The LITESPARK-005 trial underscores the potential of belzutifan to improve the quality of life for patients with advanced RCC.While further research is warranted, these findings offer a promising outlook for a patient population with limited treatment options.