Belzutifan Yields PFS Advantage in Pretreated Advanced ccRCC Across Subgroups

Belzutifan (Welireg) generated superior efficacy and safety outcomes vs everolimus (Afinitor) across prespecified subgroups of patients with previously treated advanced clear cell renal cell carcinoma (ccRCC), according to findings from a subgroup analysis of the phase 3 LITESPARK-005 trial (NCT04195750) presented at the 2024 Kidney Cancer Research Summit.¹

“In LITESPARK-005, progression-free survival [PFS] and response rates favored belzutifan vs everolimus across [several patient subgroups, including] International Metastatic RCC Database Consortium [IMDC] risk, number of prior lines [of therapy], and number of prior VEGF TKIs, specifically,” lead study author Laurence Albiges, MD, PhD, of the Institut Gustave Roussy in Villejuif, France, stated in the presentation.

At a data cutoff of June 13, 2023, among patients with IMDC favorable-risk disease, the median PFS by blinded independent central review (BICR) assessment per RECIST 1.1 criteria was 10.9 months with belzutifan (n = 79) vs 6.8 months with everolimus (n = 83; HR, 0.74; 95% CI, 0.51-1.09). The 18-month PFS rates were 35.0% and 18.6% with belzutifan and everolimus, respectively. Among patients with IMDC intermediate- or poor-risk disease, the median PFS was 5.3 months with belzutifan (n = 295) vs 5.0 months with everolimus (n = 289; HR, 0.74; 95% CI, 0.61-0.89). The 18-month PFS rates were 19.3% and 6.1% with belzutifan and everolimus, respectively.

Among patients with favorable-risk disease, the median overall survival (OS) was 30.4 months with belzutifan vs 25.4 months with everolimus (HR, 0.75; 95% CI, 0.47-1.21). The 18-month OS rates were 73.3% and 65.0% with belzutifan and everolimus, respectively. Among patients with intermediate- or poor-risk disease, the median OS was 18.5 months with belzutifan vs 16.0 months with everolimus (HR, 0.90; 95% CI, 0.73-1.10). The 18-month OS rates were 19.3% and 6.1% with belzutifan and everolimus, respectively.

LITESPARK-005 enrolled patients with ccRCC who had been previously treated with at least 1 PD-1 inhibitor and 1 VEGF TKI and had received up to 3 systemic regimens. This trial randomly assigned patients to receive either belzutifan or everolimus daily. The primary end point was BICR-assessed PFS.

“I have stressed that [the patients enrolled in the trial] were pretreated,” Albiges noted. “We anticipated to have few patients who were still [had favorable] IMDC risk…the vast majority…were intermediate/poor[-risk] in each arm. [Patients who received] 1 prior line [of therapy had received] a VEGF-TKI plus immune-oncology combination regimen [in the] frontline, and then were [randomly assigned] to the study [in the] second line. But the vast majority of patients were either pretreated with 2 or 3 prior lines [of therapy].”

Previously presented findings from LITESPARK-005 showed that belzutifan yielded a statistically significant improvement in PFS vs everolimus (HR, 0.85; 95% CI, 0.63-0.90; 1-sided P = .0008).² Although OS data were immature at data cutoff, investigators did not observe a trend toward OS detriment with belzutifan. Based on these findings, belzutifan was FDA approved in 2023 for the treatment of patients with advanced RCC who have received a prior PD-1/PD-L1 inhibitor and a prior VEGF TKI.

Additional data from the subgroup analysis demonstrated that among patients who had received 1 prior line of therapy, the median PFS was 9.1 months with belzutifan (n = 46) vs 5.6 months with everolimus (n = 52; HR, 0.54; 95% CI, 0.34-0.87).¹ The 18-month PFS rates in these respective arms were 28.9% and 10.1%.

Among patients who had received 2 prior lines of therapy, the median PFS was 3.8 months with belzutifan (n = 157) vs 4.6 months with everolimus (n = 166; HR, 0.81; 95% CI, 0.62-1.05). The 18-month PFS rates in these respective arms were 19.4% and 8.3%. Among patients who had received 3 prior lines of therapy, the median PFS was 5.5 months with belzutifan (n = 171) vs 5.6 months with everolimus (n = 154; HR, 0.77; 95% CI, 0.60-1.00). The 18-month PFS rates in these respective arms were 23.2% and 9.0%.

Among patients who had received 1 prior line of therapy, the median OS was not reached with belzutifan vs 24.5 months with everolimus (HR, 0.83; 95% CI, 0.46-1.50). The 18-month OS rates in these respective arms were 71.7% and 68.9%. Among patients who had received 2 prior lines of therapy, the median OS was 20.8 months with belzutifan vs 15.8 months with everolimus (HR, 0.84; 95% CI, 0.63-1.10). The 18-month OS rates in these respective arms were 52.1% and 44.1%. Among patients who had received 3 prior lines of therapy, the median OS was 19.6 months with belzutifan vs 18.2 months with everolimus (HR, 0.93; 95% CI, 0.70-1.24). The 18-month PFS rates in these respective arms were 53.7% and 51.2%.

Among patients who had received 1 prior VEGF TKI, the median PFS was 5.7 months with belzutifan (n = 187) vs 5.6 months with everolimus (n = 190; HR, 0.77 [95% CI, 0.61-0.96]). The 18-month PFS rates in these respective arms were 20.9% and 10.9%. Among patients who had received 2 or 3 prior VEGF TKIs, the median PFS was 4.6 months with belzutifan (n = 187) vs 5.4 months with everolimus (n = 182; HR, 0.73; 95% CI, 0.57-0.93). The 18-month PFS rates in these respective arms were 24.1% and 6.9%.

Among patients who had received 1 prior VEGF TKI, the median OS was 21.4 months with belzutifan vs 18.5 months with everolimus (HR, 0.87; 95% CI, 0.67-1.13). The 18-month PFS rates in these respective arms were 55.6% and 50.7%. Among patients who had received 2 or 3 prior VEGF TKIs, the median OS was 21.5 months with belzutifan vs 18.0 months with everolimus (HR, 0.89; 95% CI, 0.68-1.16). The 18-month PFS rates in these respective arms were 54.9% and 50.4%.

“Irrespective of the subgroup you’re looking at…we have a very consistent HR [for overall response rate (ORR)],” Albiges emphasized. “That shows us that belzutifan was able to achieve significant tumor shrinkage in about 1 patient out of 4, and this compares well with everolimus activity.”

When ORR was broken down by subgroup, in patients with favorable-risk disease, the ORR was 22.8% with belzutifan vs 6.0% with everolimus. In patients with intermediate- or poor-risk disease, the ORR was 22.7% with belzutifan vs 2.8% with everolimus.

Among patients in the belzutifan arm who had received 1, 2, and 3 prior lines of therapy, the ORRs were 28.3%, 19.1%, and 24.6%, respectively. In the everolimus arm, the ORRs in these respective populations were 5.8%, 2.4%, and 3.9%, respectively.

Among patients who had received 1 prior VEGF TKI, the ORR was 19.8% with belzutifan vs 3.7% with everolimus. Among patients who had received 2 prior VEGF TKIs, the ORR was 25.7% with belzutifan vs 3.3% with everolimus.

Albiges noted that no new safety signals were observed in this subgroup analysis.

“Belzutifan is associated with a very interesting safety profile that makes it the right candidate to go from combination therapy.”

Among patients with favorable-risk disease, all-cause, any-grade adverse effects (AEs) occurred in 100.0% of patients each in the belzutifan and everolimus arms. Grade 3 or higher AEs occurred in 48.1% and 54.9% of favorable-risk patients in these arms, respectively. AEs led to treatment discontinuation in 3.8% and 15.9% of favorable-risk patients in these respective arms. Among patients with intermediate- or poor-risk disease, all-cause, any-grade AEs occurred in 99.0% and 98.9% of patients in the belzutifan and everolimus arms, respectively. Grade 3 or higher AEs occurred in 65.5% and 64.7% of intermediate- and poor-risk patients in these arms, respectively. AEs led to treatment discontinuation in 6.5% and 14.4% of intermediate- or poor-risk patients in these respective arms.

All patients who had received 1 prior line of therapy had any-grade AEs in both arms. In this population, grade 3 or higher AEs occurred in 52.2% and 55.8% of patients in the belzutifan and everolimus arms, respectively. AEs led to treatment discontinuation in 2.2% and 13.5% of patients who had received 1 prior line of therapy in these respective arms. Among patients who had received 2 prior lines of therapy, any-grade AEs occurred in 98.7% of patients each in the belzutifan and everolimus arms; grade 3 or higher AEs occurred in 65.0% and 67.3% of patients in each arm, respectively. AEs led to treatment discontinuation in 5.1% and 16.4% of patients who had received 2 prior lines of therapy in these respective arms. Among patients who had received 3 prior lines of therapy, any-grade AEs occurred in 99.4% of those who received belzutifan and 99.3% of those who received everolimus. In this population, the rates of grade 3 or higher AEs in these respective arms were 61.5% and 59.7%. AEs led to treatment discontinuation in 7.7% and 13.4% of patients who had received 3 prior lines of therapy in these respective arms.

Among patients who had received 1 prior VEGF TKI, any-grade AEs occurred in 98.9% and 99.5% of patients who received belzutifan and everolimus, respectively; the respective rates of grade 3 or higher AEs were 59.4% and 65.6%. AEs led to treatment discontinuation in 5.3% and 16.4% of patients who had received 1 prior VEGF TKI in these respective arms. Among patients who had received 2 or 3 prior VEGF TKIs, any-grade AEs occurred in 99.5% and 98.9% of patients who received belzutifan and everolimus, respectively; the respective rates of grade 3 or higher AEs were 64.3% and 59.3%. AEs led to treatment discontinuation in 6.5% and 13.0% of patients who had received 2 or 3 prior VEGF TKIs in these respective arms.

“These results support the use of belzutifan as a new treatment option for patients with advanced RCC who have received at least 1 prior TKI and 1 PD-1 inhibitor,” Albiges concluded.

References

1. Albiges L, Choueiri TK, Peltola K, et al. Belzutifan versus everolimus for previously treated advanced clear cell renal cell carcinoma: subgroup analysis of the phase 3 LITESPARK-005 study. Presented at: 2024 Kidney Cancer Research Summit; July 11-12, 2024; Boston, MA. Abstract 42.
2. FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed July 12, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma?utm_medium=email&utm_source=govdelivery