At the 2026 ASCO Genitourinary Cancers Symposium, Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, presented results from the second interim analysis of the phase III LITESPARK-011 trial showing improved progression-free survival, higher objective response rate, and a trend toward improved overall survival with the novel first-in-class HIF-2α inhibitor belzutifan plus the multitarget tyrosine kinase inhibitor (TKI) lenvatinib compared with cabozantinib alone in patients with advanced clear cell renal cell carcinoma whose disease progressed after anti–PD-(L)1 therapy (Abstract LBA417).
Robert J. Motzer, MD
Cabozantinib, another multitarget TKI, is frequently used in this clinical context. However, Dr. Motzer said the treatment paradigm has shifted from single-agent TKIs to immune checkpoint combinations and noted there remains a “dearth” of information on how best to manage patients whose disease progresses on front-line immunotherapy combinations. He added that little evidence shows one drug is better than another.
He also noted that belzutifan received FDA approval in 2023 in heavily pretreated patients and said there is “strong rationale” for combining it with vascular endothelial growth factor receptor (VEGFR) TKIs such as lenvatinib, as targeting tumor blood vessel growth in different ways may be more efficacious than using a VEGFR TKI alone.
In the first interim analysis of LITESPARK-011, the combination of belzutifan plus lenvatinib vs standard cabozantinib therapy met the coprimary endpoint of progression-free survival, though Dr. Motzer noted that “more follow-up would better characterize the data.”
About LITESPARK-011
The trial enrolled patients with unresectable locally advanced or metastatic clear cell renal cell carcinoma who had received up to two prior systemic therapies and experienced disease progression immediately following immune checkpoint inhibition. They were randomly assigned 1:1 to receive oral belzutifan plus lenvatinib (n = 371) or cabozantinib (n = 376).
The dual primary endpoints of the study were progression-free survival by blinded independent central review and overall survival; objective response rate by blinded independent central review was identified as a key secondary endpoint.
Efficacy Findings
At 2 years, 35.6% of patients treated with the combination were progression-free vs 19.1% of those who received cabozantinib. Median progression-free survival was 14.8 vs 10.7 months, respectively (hazard ratio [HR] = 0.70; P = .00007).
Dr. Motzer noted that the objective response rate was higher with the combination and described the improvement as “modest,” with an estimated 12.4% difference (52.6% vs 40.2%); more complete responses were seen with the combination (5.4% vs 1.1%).
“One of the most striking aspects of the data,” he said, “is the duration of response.” Among responders, the median duration of response was 23.0 months with the combination vs 12.3 months with cabozantinib; at 2 years, 49.5% vs 25.5% of responses were ongoing. He added that some patients have remained in response for nearly 3.5 years.
Overall survival favored the combination, with a median of 34.9 vs 27.6 months (HR = 0.85; P = .06075) and “at least numerically higher” survival at 24 months or more (62.8% vs 55.4%). Because the result did not reach statistical significance, Dr. Motzer said a final overall survival analysis will be conducted when the data are more mature.
Safety Profile
Dr. Motzer reported that common treatment-emergent adverse events largely reflected the known safety profile of the administered TKI. He noted that anemia (69.2% [combination] vs 25.6% [cabozantinib]) and hypoxia (15.4% vs 0%) were exceptions, attributing these events to belzutifan in the combination arm.
He added that diarrhea (52.7% vs 70.1%) and skin toxicity (20.5% vs 51.2%) “are really troublesome for patients,” with lower rates observed with the combination compared with cabozantinib.
Regarding adverse events of clinical interest, he highlighted hypoxia and cardiac dysfunction, the latter of which was “slightly” higher with the combination (7.0% vs 1.1%). He stated that investigators are “digging into this deeper” to determine whether the cardiac findings are related to the combination itself or reflect the individual TKI.
Based on his experience treating patients on the study, Dr. Motzer said he felt the combination was “really pretty well tolerated,” with side effects that were manageable.
He concluded, “I believe that belzutifan plus lenvatinib, based on these data, addresses an unmet need and could represent a potential new treatment option for patients with renal cell carcinoma who have progressed on immune checkpoint inhibitor therapy.”
DISCLOSURE: For full disclosures of the study authors, visit meetings.asco.org.
