Belzutifan/Palbociclib Fails to Yield High ORR in Pretreated ccRCC

The combination of belzutifan (Welireg) and palbociclib (Ibrance) demonstrated a manageable safety profile but had a similar overall response rate (ORR) to belzutifan monotherapy in patients with clear cell renal cell carcinoma (ccRCC), according to results from part 1 of the phase 1/2 LITESPARK-024 trial (NCT05468697) presented at the 2026 Genitourinary Cancers Symposium.¹

At the maximum tolerated dose, the combination resulted in an ORR of 21.1% and 2 dose-limiting toxicities (DLTs) were observed in the first 10 treated patients. Treatment was overall tolerated but grade 3 treatment-related adverse events (TRAEs) were frequent.

LITESPARK-024 Study Design

In part 1, patients with unresectable stage 4 ccRCC received 120 mg of belzutifan either 75 mg (n = 20), 100 mg (n = 19), or 125 mg of palbociclib (n = 19). The lower dose levels were expanded to better characterize the combination. The primary end points focused on defining DLTs, safety, and cause of treatment discontinuation due to AEs.

“By protocol, the full dose of both belzutifan and palbociclib would have been the recommended phase 2 dose, and as such, will be the dose level that I focus on primarily when discussing antitumor activity,” said lead author David F. McDermott, MD, medical oncologist at Beth Israel Lahey Health, Beth Israel Deaconess Medical Center, Boston, Massachusetts, in his presentation.

A total of 59 patients were enrolled, 22 of whom were still on therapy at the data cutoff of July 28, 2025, after a median follow-up of 8.7 months (range, 3.0-35.0).

Patient baseline characteristics were similar across dose levels. Overall, the median age was 65.0 years (range 37-85), 34 patients were older than 65 years, and 69.0% were male. In this heavily pretreated population, 39.7% underwent 2 prior lines of therapy, whereas 25.9% underwent 3 or 4 prior lines of therapy. Nearly 7% underwent at least 5 lines of therapy.

Safety and Tolerability Outcomes

No dose-limiting toxicities (DLTs) were observed in the 2 lower dose levels but 2 DLTs were observed with 125 mg of palbociclib. These were grade 3 anemia and grade 3 hypoxia (n = 1 each). Although there were no treatment-related deaths, 1 death was caused by cerebral hemorrhage.

Grade 3 or higher TRAEs occurred in 65.0%, 78.9%, and 78.9% of the 75 mg, 100 mg, and 125 mg palbociclib dose levels; 50.0%, 52.6%, and 57.9% had grade 3 or higher anemia in the respective groups. There were 3 cases (15.0%) of grade 3 neutropenia reported with 75 mg palbociclib, 4 cases (21.1%) with 100 mg, and 6 cases (31.6%) with 125 mg, which increased with increasing doses of palbociclib. However, no new safety signals were identified.

The ORR for all patients was 12.1% (95% CI, 5.0%-23.3%). The ORR was 15.0% (95% CI, 3.2%-38.9%) with the lowest dose, 0% (95% CI, 0.0%-17.6%) with the 100-mg dose, and 21.1% (95% CI, 6.1%-90.9%) with the maximum dose of palbociclib.

“At the recommended phase 2 dose, response rate was consistent with single-agent belzutifan, at 21%, and disease control rate and primary disease progression rate were improved,” McDermott said. There was only 1 patient (5.3%) with primary disease progression at the highest dose level. In the phase 3 LITESPARK-005 trial (NCT04195750) which led to the FDA approval of belzutifan monotherapy, the ORR was 21.9% but the primary progressive disease rate was 33.7%.²

The median duration of response with the combination was not reached (range, 1.9+ to 17.5+ months). The progression-free survival (PFS) at 12 months was 29.2% (95% CI, 6.2%-58.0%) for 75 mg palbociclib, 30.7% (95% CI, 6.9%-59.3%) for 100 mg, and 44.4% (95% CI, 18.2%-67.9%) for 125 mg.¹ At the full dose, the median PFS was 9.1 months (95% CI, 3.7-not reached) for the combination.

“These results are exploratory, however, given the limitations of the small sample size and single-arm design in this heavily pretreated population,” McDermott said. “Part 2 of LITESPARK-024 will not be initiated, although the study supports further investigation of combination therapy,” he concluded.

DISCLOSURES: Dr McDermott has served in a consulting or advisory role to alkermes; Arcus Biosciences; Bristol-Myers Squibb; Cullinan Oncology; Eisai; EMD Serono; exelixis; Iovance Biotherapeutics; Lilly; Merck; Pfizer; Synthekine; Werewolf Therapeutics; and Xilio Therapeutics. He has received research funding for alkermes (Inst); Bristol-Myers Squibb (Inst); Genentech (Inst); Merck (Inst); and Novartis (Inst).

REFERENCES

1. McDermott DF, Peer A, Gurney H, et al. Ascending dose escalation of belzutifan plus palbociclib for previous treated advanced clear cell renal cell carcinoma (ccRCC): Phase 1/2 LITESPARK-024 study part 1. J Clin Oncol. 2026;44(suppl 7):423. doi:10.1200/JCO.2026.44.7_suppl.423

2. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906