Belzutifan Maintains PFS, ORR Benefits in Previously Treated Advanced Clear Cell RCC

Belzutifan (Welireg) retained a statistically significant improvement in progression-free survival (PFS) and objective response rate (ORR) vs everolimus (Afinitor) in previously treated patients with advanced clear cell renal cell carcinoma (RCC); however, the agent fell short in terms of an overall survival (OS) advantage, according to findings from the final analysis of the phase 3 LITESPARK-005 trial (NCT04195750) presented at the 2024 ESMO Congress.¹

At a median follow-up of 35.8 months (range, 26.9-49.2), the median PFS was 5.6 months (95% CI, 3.8-6.5) with belzutifan (n = 374) vs 5.6 months (95% CI, 4.8-5.8) with everolimus (n = 372; HR, 0.75; 95% CI, 0.63-0.88). The 12- and 24-month PFS rates with belzutifan were 33.7% and 17.5%, respectively, vs 17.6% and 4.1% with everolimus. The median OS was 21.4 months (95% CI, 18.2-24.3) with belzutifan vs 18.2 months (95% CI, 15.8-21.8) with everolimus (HR, 0.92; 95% CI, 0.77-1.10; P =.18). The 12- and 24-month OS rates with belzutifan were 67.9% and 45.2%, respectively, vs 65.8% and 41.2% with everolimus.

“At the final analysis of the phase 3 LITESPARK-005 study, belzutifan continued to show PFS and ORR benefits vs everolimus, including durable responses lasting over 2 years,” Brian Rini, MD, 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 2 years of minimum follow-up, more participants remained on treatment with belzutifan vs everolimus, [but] significant improvement in OS was not observed.”

Belzutifan is a first-in-class oral HIF-2a inhibitor that impedes heterodimerization with HIF-1b and downstream oncogenic pathways.

In December 2023, the FDA approved belzutifan 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 belzutifan vs everolimus (HR, 0.75; 95% CI, 0.63-0.90; 1-sided P =.0008). The agent also led to an improved ORR of 22% (95% CI, 18%-27%) vs 4% (95% CI, 2%-6%) with everolimus. OS results were immature at the time of the analysis with 59% of deaths reported, but no detrimental trend was observed.^2,3

To be eligible for enrollment patients had to have unresectable, locally advanced or metastatic clear cell RCC with disease progression after 1 to 3 prior lines of systemic therapy, including at least 1 anti–PD-(L)1 monoclonal antibody and at least 1 VEGFR TKI. A Karnofsky performance status (KPS) of at least 70% was also required.¹

Patients were randomly assigned 1:1 to 120 mg of oral belzutifan once daily or 10 mg of oral everolimus once daily. The dual primary end points were PFS per RECIST 1.1 criteria by blinded independent central review (BICR) and OS. The study would be deemed positive if either primary end point was met. Secondary end points included ORR and duration of response (DOR) per RECIST 1.1 criteria by BICR, and safety.

Patients were stratified by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic score (0 vs 1-2 vs 3-6) and the number of prior VEGFR TKIs (1 vs 2-3).

Between March 10, 2020, and January 19, 2022, 746 patients were randomly assigned; 374 and 372 were ultimately treated with belzutifan and everolimus, respectively. Fifty-four (14.5%) and 5 (1.4%) patients remained on treatment with belzutifan and everolimus, respectively. In the belzutifan arm, reasons for treatment discontinuation were progressive disease (68.5%), adverse effects (AEs; 6.2%), clinical progression (5.9%), patient withdrawal (3.0%), receipt of non-study anticancer therapy (1.3%), physician decision (0.3%), and parent/guardian withdrawal (0.3%). In the everolimus arm, reasons for discontinuation were progressive disease (68.9%), AEs (15.3%), clinical progression (7.2%), patient withdrawal (3.9%), receipt of non-study anticancer therapy (2.8%), and physician decision (0.6%).

Baseline characteristics were well matched in both arms. In the belzutifan arm, the median age was 62 years (range, 22-90), and most patients were male (79.4%). Most patients had a KPS of 90% or 100% (63.6%) as opposed to 70% or 80% (36.1%); 0.3% of patients in each arm had a missing KPS score. Patients with all IMDC risk categories were represented: favorable (21.7%), intermediate (66.3%), and poor (12.0%), and 11.2% had sarcomatoid features. Prior nephrectomy had been performed in 69.8% of patients. The number of prior lines of VEGFR TKI therapy was evenly split between 1 (49.7%) and 2 or 3 (50.3%). Regarding overall prior lines of therapy, 12.0% of patients had received 1, 42.2% had received 2, and 45.2% had received 3.

Among the patients still on belzutifan at the time of the analysis (n = 54), most had a KPS of 90% or 100% (81.5%), IMDC intermediate risk (59.3%), prior nephrectomy (83.3%), and 2 or 3 prior VEGFR TKIs (53.7%).

Additional efficacy findings demonstrated that belzutifan led to a substantially higher ORR than everolimus at 22.7% (95% CI, 18.6%-27.3%) vs 3.5% (95% CI, 1.9%-5.9%), reflecting an estimated difference of 19.2% (95% CI, 14.8%-24.1%). In the belzutifan arm, confirmed best objective responses included complete response (CR; 3.5%), partial response (PR; 19.3%), stable disease (SD; 38.2%), and progressive disease (PD; 34.0%); 5.0% of patients were not evaluable or had no assessment because of insufficient data or lack of an available post-baseline evaluation. In the everolimus arm, 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 belzutifan arm, the median time to response (TTR) among responders (n = 85) was 3.8 months (range, 1.7-22.0) and the median DOR was 19.3 months (range, 1.9+ to 40.1+). The rate of belzutifan-treated patients in ongoing response at 12 and 24 months was 71.1% and 43.7%, respectively. In the everolimus arm, the median TTR among responders (n = 13) was 3.7 months (range, 1.8-5.7) and the median DOR was 13.7 months (range, 3.8 to 29.5+). The rate of everolimus-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 belzutifan (n = 173; alive at follow-up, n = 61) and everolimus (n = 121; alive at follow-up, n = 12) arms was also presented.

“The point [here is that] there are many more [patients alive without need of subsequent therapy] in the belzutifan arm and very few of such patients in the everolimus arm,” Rini said.

The median duration of study therapy was 7.6 months (range, 0.1-45.9) with belzutifan and 3.9 months (range, 0.03-41.8) with everolimus. Despite longer exposure to treatment, patients in the belzutifan arm experienced comparable or reduced toxicities to those in the everolimus arm. Grade 3 or greater AEs occurred in 62.9% and 62.8% of patients in the belzutifan and everolimus arms, respectively. AEs leading to discontinuation or death occurred in 6.2% and 3.8% of patients in the belzutifan arm, respectively, vs 15.3% and 5.3% in the everolimus arm. Grade 3 or greater treatment-related AEs (TRAEs) occurred in 39.5% and 40.0% of patients in the belzutifan and everolimus arms, respectively. TRAEs leading to death occurred in 0.3% and 0.6% of patients in the belzutifan and everolimus arms, respectively.

Rini also presented the time to first onset of common any-grade AEs attributed to belzutifan, which illustrated that most TRAEs had quick onset. The respective median times to onset for anemia, hypoxia, dizziness, dyspnea, fatigue, nausea, and weight increase were 1.0 month (range, 0.03-27.4), 1.0 month (range, 0.03-21.1), 2.3 months (range, 0.03-34.2), 1.9 months (range, 0.03-25.8), 1.5 months (range, 0.03-29.9), 1.4 months (range, 0.03-24.0), and 3.3 months (range, 0.5-15.0).

“No new safety signals for belzutifan were observed,” Rini said. “The most common any-grade adverse drug reactions had a median time to onset of less than 2 months.”

The median durations of anemia, hypoxia, dizziness, dyspnea, fatigue, nausea, and weight increase were 4.6 months (range, 0.1+ to 47.1+), 0.5 months (range, 0.03 to 31.9+), 1.1 months (range, 0.03-35.2), 3.3 months (range, 0.03 to 39.5+), not reached (range, 0.1 to 43.9+), 1.2 months (range, 0.03 to 38.6), and 16.6 months (range, 0.6 to 40.0+), respectively.

“Final analysis results of LITESPARK-005 support belzutifan as a treatment option in advanced clear cell RCC after PD-[L]1 inhibitor and VEGFR TKI therapy,” Rini concluded.

Disclosures: Dr Rini reported institutional research funding from AVEO, Arcus, MSD, Dragonfly Therapeutics, HiberCell, Incyte, Stata Oncology, ADC Therapeutics, Dracen Pharmaceutical, Janssen, Adela, AstraZeneca, Tempus, Gilead, POINT Biopharma, BMS, Pfizer, Daiichi Sankyo, Genentech, Exelixis, and Surface Oncology; consulting for Eisai, BMS, Pfizer, Genentech, AstraZeneca, Aveo, MSD, Debiopharm, Exelixis, and MashupMD; and study funding, medical writing, and editorial support from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD).

References

1. Rini B, Suarez C, Albiges L, et al. Final analysis of the phase 3 LITESPARK-005 study of belzutifan versus everolimus in participants with previously treated clear cell renal cell carcinoma. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain. Abstract LBA74.
2. FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed September 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma
3. Welireg. Prescribing information. Merck Sharp & Dohme LCC; 2023. Accessed September 13, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215383s006lbl.pdf