Belzutifan Improves PFS Across Subgroups for Advanced ccRCC

“In LITESPARK-005, PFS and response rates favored belzutifan vs everolimus across [several patient subgroups, including] IMDC risk, number of prior lines [of therapy], and number of prior VEGF TKIs, specifically,” said Laurence Albiges, MD, PhD.

The subgroup analysis from the phase 3 LITESPARK-005 trial (NCT04195750) found belzutifan (Welireg) plus everolimus (Afinitor) improved progression-free survival (PFS) for patients with previously treated advanced clear cell renal cell carcinoma (ccRCC), according to a study 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.²

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