Pembrolizumab-belzutifan combo improves disease-free survival in clear cell renal cell carcinoma

Treatment with pembrolizumab plus belzutifan results in a significant and clinically meaningful improvement in disease-free survival (DFS) compared with pembrolizumab monotherapy in patients with clear cell renal cell carcinoma (ccRCC) who are at greater risk of recurrence following nephrectomy, results from the phase III LITESPARK-022 study have shown.

Furthermore, the combination treatment has a manageable safety profile, but its use is associated with increased grade ≥3 treatment-emergent adverse events (TEAEs) relative to monotherapy.

“Adjuvant pembrolizumab is a standard of care for patients with ccRCC at increased risk of recurrence following nephrectomy based on the phase 3 KEYNOTE-564 study,” said lead author and presenter Dr Toni K. Choueiri, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, US. [N Engl J Med 2021;385:683-694; N Engl J Med 2024;390:1359-1371]

“Combination strategies may further improve outcomes in this setting,” he added.

In LITESPARK-022, 1,841 patients with ccRCC stage M0 and intermediate-high (pT2 Gr 4 or sarcomatoid, or pT3 any Gr, N0) or high (pT4 any Gr, N0, or any pT and Gr, N+) risk of recurrence after nephrectomy, or ccRCC stage M1 with no disease evidence after surgery were randomized to receive 9 doses of intravenous pembrolizumab 400 mg Q6W (~1 year) with either oral belzutifan 120 mg QD (n=921) or placebo (n=920). [ASCO GU 2026, abstract LBA418]

DFS was the primary endpoint, while overall survival (OS) and safety were secondary. Results presented at the 2026 ASCO GU were from the first interim analysis (after 87 percent of DFS events occurred with a minimum of 15 months of follow-up), according to Choueiri.

Over a median follow-up of 28.4 months, pembrolizumab plus belzutifan therapy led to 28-percent improvement in DFS compared with pembrolizumab plus placebo (hazard ratio [HR], 0.72, 95 percent confidence interval [CI], 0.59‒0.87; p=0.0003). The median DFS in both arms was not reached, with an estimated 24-month DFS rate of 80.7 percent (95 percent CI, 77.7‒83.2) for the combination treatment vs 73.7 percent (95 percent CI, 70.6‒76.6) for monotherapy.

Secondary outcomes

At the first interim analysis, OS was immature with a total of 87 OS events (38 in the combination arm vs 49 in the monotherapy arm) and was not statistically significant (HR, 0.78, 95 percent CI, 0.51‒1.19; p=0.1220) at 29 percent of the events needed for the final OS analysis.

Completion of the assigned treatment was similar between treatment groups (70 percent vs 71 percent).

Among treated participants, grade ≥3 TEAEs occurred more frequently among patients who received pembrolizumab plus belzutifan than those who received pembrolizumab plus placebo (52.1 percent vs 30.2 percent). The most common TEAEs were anaemia (12.1 percent vs 0.4 percent), increased alanine aminotransferase (6.4 percent vs 2.0 percent), and hypoxia (4.6 percent vs 0 percent).

Grade 5 TEAEs (1.1 percent vs 1.2 percent) and treatment-related AEs (0.3 percent vs 0.3 percent) did not significantly differ between arms. Moreover, no new safety signals were reported.

“LITESPARK-022 is the first adjuvant phase III trial in RCC to show a significant benefit for a combination treatment vs an active immunotherapy comparator,” Choueiri said.

“These results support adjuvant pembrolizumab plus belzutifan as a potential new standard of care in RCC at increased risk of recurrence,” he added.