Patients with previously treated advanced clear cell renal cell carcinoma (RCC) — a type of kidney cancer — experienced improvements in progression and response via treatment with Welireg (belzutifan) when compared with Afinitor (everolimus), although those benefits did not extend to survival, study results have shown.
Findings from the final analysis of the phase 3 LITESPARK-005 trial were presented at the 2024 European Society of Medical Oncology Congress (ESMO).
Study highlights:
- Patients with previously treated advanced RCC who received Welireg experienced significant improvements in progression-free survival (PFS) compared to those treated with Afinitor.
- While Welireg showed benefits in PFS and objective response rate (ORR), it did not significantly improve overall survival compared to Afinitor.
- Based on the results of the LITESPARK-005 trial, Welireg was approved by the FDA for patients with advanced RCC who have progressed after receiving a PD-(L)1 inhibitor and a VEGF TKI.
At a median follow-up of 35.8 months, the median progression-free survival (PFS; the time a patient lives without their disease spreading or worsening) was 5.6 months with belzutifan (374 patients) versus 5.6 months with Afinitor (372 patients). The 12- and 24-month PFS rates with Welireg were 33.7% and 17.5%, respectively, versus 17.6% and 4.1% with Afinitor.
The median overall survival (OS; the time a patient lives, regardless of disease status) was 21.4 months with Welireg versus 18.2 months with Afinitor. The 12- and 24-month OS rates with Welireg were 67.9% and 45.2%, respectively, versus 65.8% and 41.2% with Afinitor.
The dual primary end points were PFS and OS. The study would be deemed positive if either primary end point was met. Secondary end points included objective response rate (ORR; patients who responded partially or completely to treatment), duration of response (DOR) and safety.
“At the final analysis of the phase 3 LITESPARK-005 study, [Welireg] continued to show PFS and ORR benefits versus [Afinitor], including durable responses lasting over two years,” Dr. Brian Rini, lead study author and chief of clinical trials at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, said in a presentation of the data. “With over two years of minimum follow-up, more participants remained on treatment with [Welireg] versus [Afinitor], [but] significant improvement in OS was not observed.”
In December 2023, the FDA approved Welireg for patients with advanced RCC following a PD-(L)1 inhibitor and a VEGF TKI, based on earlier findings from LITESPARK-005 that demonstrated a statistically significant improvement in PFS with Welireg versus Afinitor. The agent also led to an improved ORR of 22% versus 4% with Afinitor. OS results were immature at the time of the analysis with 59% of deaths reported, but no detrimental trend was observed.
READ MORE: What Patients With Kidney Cancer Need to Know About Welireg
To be eligible for enrollment patients had to have unresectable (not removable by surgery), locally advanced (cancer that has spread to nearby tissue or lymph nodes but no other parts of the body) or metastatic (cancer that has spread to other parts of the body) clear cell RCC with disease progression after one to three prior lines of systemic therapy, including at least one anti-PD-(L)1 monoclonal antibody and at least one VEGFR TKI. A Karnofsky performance status (KPS, which measures patients’ ability to perform daily tasks) of at least 70% was also required.
Between March 10, 2020, and January 19, 2022, 746 patients were randomly assigned; 374 and 372 were ultimately treated with Welireg and Afinitor, respectively. Fifty-four (14.5%) and five (1.4%) patients remained on treatment with Welireg and Afinitor, respectively.
In the Welireg group, reasons for treatment discontinuation were progressive disease (68.5%), side effects (6.2%), clinical progression (5.9%), patient withdrawal (3%), receipt of non-study anticancer therapy (1.3%), physician decision (0.3%) and parent/guardian withdrawal (0.3%).
In the Afinitor group, reasons for discontinuation were progressive disease (68.9%), side effects (15.3%), clinical progression (7.2%), patient withdrawal (3.9%), receipt of non-study anticancer therapy (2.8%) and physician decision (0.6%).
Additional efficacy findings demonstrated that Welireg led to a substantially higher ORR than Afinitor at 22.7% versus 3.5%, reflecting an estimated difference of 19.2%. In the Welireg group, confirmed best objective responses included complete response (CR, the disappearance of cancer; 3.5%), partial response (PR; 19.3%), stable disease (SD; 38.2%), and progressive disease (PD; 34.0%); 5% of patients were not evaluable or had no assessment because of insufficient data or lack of an available post-baseline evaluation. In the Afinitor group, confirmed best objective responses included PR (3.5%), SD (65.9%), and PD (21.5%); 9.1% of patients were not evaluable or had no assessment for the same reason.
In the Welireg group, the median time to response (TTR) among responders (85 patients) was 3.8 months and the median DOR was 19.3 months. The rate of Welireg-treated patients in ongoing response at 12 and 24 months was 71.1% and 43.7%, respectively. In the Afinitor group, the median TTR among responders (13 patients) was 3.7 months and the median DOR was 13.7 months. The rate of Afinitor-treated patients in ongoing response at 12 and 24 months was 61.5% and 23.1%, respectively.
Survival follow-up in patients who did not receive subsequent therapy in the Welireg (173 patients; alive at follow-up, 61 patients) and Afinitor (121 patients; alive at follow-up, 12 patients) groups were also presented.
“The point [here is that] there are many more [patients alive without need of subsequent therapy] in the [Welireg] group and very few of such patients in the [Afinitor] group,” Rini said.
The median duration of study therapy was 7.6 months with Welireg and 3.9 months with Afinitor. Despite longer exposure to treatment, patients in the Welireg group experienced comparable or reduced toxicities to those in the Afinitor group. Grade 3 (severe) or greater side effects occurred in 62.9% and 62.8% of patients in the Welireg and Afinitor groups, respectively. Side effects leading to discontinuation or death occurred in 6.2% and 3.8% of patients in the Welireg group, respectively, versus 15.3% and 5.3% in the Afinitor group. Grade 3 or greater treatment-related side effects occurred in 39.5% and 40% of patients in the Welireg and Afinitor groups, respectively. Treatment-related side effects leading to death occurred in 0.3% and 0.6% of patients in the Welireg and Afinitor groups, respectively.
Rini also presented the time to first onset of common any-grade side effects attributed to Welireg, which illustrated that most treatment-related side effects had quick onset. The respective median times to onset for anemia, hypoxia, dizziness, dyspnea, fatigue, nausea, and weight increase were one month, one month, 2.3 months, 1.9 months, 1.5 months, 1.4 months and 3.3 months.
“No new safety signals for [Welireg] were observed,” Rini said. “The most common any-grade adverse drug reactions had a median time to onset of less than two months.”
The median duration of anemia (low red blood cell count), hypoxia (low oxygen in body tissues), dizziness, dyspnea (shortness of breath), fatigue, nausea and weight increase were 4.6 months, 0.5 months, 1.1 months, 3.3 months, not reached, 1.2 months and 16.6 months, respectively.
“Final analysis results of LITESPARK-005 support [Welireg] as a treatment option in advanced clear cell RCC after PD-[L]1 inhibitor and VEGFR TKI therapy,” Rini concluded.
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