LITESPARK-005: Belzutifan sustains PFS, ORR benefits in advanced renal cell carcinoma

Treatment with belzutifan led to sustained improvements in progression-free survival (PFS) and objective response rate (ORR) among previously treated patients with advanced clear-cell renal cell carcinoma (RCC) compared with everolimus, according to findings from the final analysis of the phase III LITESPARK-005 trial presented at ESMO 2024.

In the previous LITESPARK-005 trial, belzutifan showed significant PFS and ORR benefits over everolimus in patients with advanced clear-cell RCC following previous immune checkpoint and antiangiogenic treatments. [N Engl J Med 2024;391:710-721] “Based on these results, belzutifan was approved in the US for advanced RCC following a PD-1/-L1* inhibitor and a VEGFR-TKI**,” said lead author Dr Brian Rini from Vanderbilt Ingram Cancer Center, Nashville, Tennessee, US.

The phase III LITESPARK-005 trial included 746 patients with advanced clear-cell RCC who had disease progression after treatment with a PD-1/-L1 inhibitor and a VEGFR-TKI. Participants were randomized in a 1:1 ratio to receive either oral belzutifan 120 mg/day (n=374; median age 62 years, 79.4 percent male) or everolimus 10 mg/day (n=372; median age 63 years, 76.3 percent male).

After a median follow-up of 35.8 months, the median PFS was 5.6 months in both treatment arms (hazard ratio [HR], 0.75), but higher PFS rates at 12 months (33.7 percent vs 17.6 percent) and 24 months (17.5 percent vs 4.1 percent) were observed with belzutifan compared with everolimus. [ESMO 2024, abstract LBA74]

There was also a trend toward improved overall survival (OS) with belzutifan compared with everolimus (median 21.4 vs 18.2 months; HR, 0.92; p=0.18), although no significant difference was observed between the treatment arms.

The 12- and 24-week OS rates were higher among those treated with belzutifan vs those on everolimus (67.9 percent vs 65.8 percent and 45.2 percent vs 41.2 percent, respectively).

Based on the survival follow-up data, 173 patients in the belzutifan arm and 121 in the everolimus arm did not receive subsequent therapy, but more patients in the belzutifan arm were still alive at final analysis (61 vs 12 patients).

The PFS and OS benefits with belzutifan vs everolimus were also seen across all subgroups, including age, sex, race, religion, and IMDC*** risk categories, as well as number of prior lines of therapy and VEGF/VEGFR regimen, Rini noted.

Consistent with the previous report, more patients on belzutifan had a confirmed objective response than those on everolimus (22.7 percent vs 3.5 percent), with an estimated difference of 19.2 percent between the treatment arms.

Moreover, the median duration of response was longer with belzutifan compared with everolimus (19.3 vs 13.7 months).

“[In this final analysis,] belzutifan continued to show PFS and ORR benefits vs everolimus, including durable responses lasting >2 years,” said Rini. “With >2 years of follow-up, more participants remained on treatment with belzutifan compared with everolimus.”

Adverse events

In terms of safety, the incidence of grade ≥3 treatment-related adverse events (AEs; 39.5 percent vs 40 percent) and serious AEs (13.2 percent vs 13.4 percent) was comparable between the belzutifan and everolimus arms.

Anaemia, fatigue, nausea, and dyspnoea were the most common any-grade adverse drug reactions associated with belzutifan, but these only occurred within the first 2 months of treatment, Rini noted.

No new safety signals were observed with belzutifan, he added.

“Overall, the final analysis results of LITESPARK-005 support belzutifan as a treatment option in advanced clear-cell RCC after PD-1/-L1 inhibitor and VEGFR-TKI therapy,” Rini concluded.