At the first and second interim analyses of the phase III LITESPARK-011 trial, treatment with the novel first-in-class hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor belzutifan plus lenvatinib improved progression-free survival, produced a higher objective response rate, and showed a trend toward improved overall survival compared with cabozantinib alone in patients with advanced clear cell renal cell carcinoma whose disease progressed after anti–PD-(L)1 therapy.
These results were presented by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, at the 2026 ASCO Genitourinary (GU) Cancers Symposium.1
As Dr. Motzer explained during a press briefing, “The treatment paradigm has changed quite dramatically over the years,” shifting from single-agent tyrosine kinase inhibitors (TKIs) to immune checkpoint combinations. However, “it has left us with a dearth of information in terms of how to best manage patients when they progress on those front-line [immunotherapy] combination programs.” He added that little evidence shows one drug is better than another.
Belzutifan plus lenvatinib addresses an unmet clinical need and represents a potential new treatment option….— ROBERT J. MOTZER, MD
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Dr. Motzer also highlighted that belzutifan received approval in 2023 in heavily pretreated patients and said there is a “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.
“LITESPARK-011 is the first phase III study of a HIF inhibitor plus a VEGFR TKI and the first phase III study in [renal cell carcinoma] in the post–checkpoint inhibitor setting to show improved outcomes vs a contemporary VEGFR TKI,” Dr. Motzer stated.
About LITESPARK-011
This open-label 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 during or after first- or second-line anti–PD-(L)1 therapy or within 6 months of their last dose of such therapy in the adjuvant setting; prior VEGFR TKI therapy was permitted. Eligible patients were randomly assigned in a 1:1 ratio to receive once-daily treatment with 120 mg of oral belzutifan plus 20 mg of oral lenvatinib (n = 371 randomized, 370 treated; 37.6% ongoing) or 60 mg of oral cabozantinib alone (n = 376 randomized, 371 treated; 22.6% ongoing). Follow-up data were provided for a median of 29.0 months.
Baseline characteristics were balanced between the treatment arms and typical for a trial of patients with renal cell carcinoma in this setting, Dr. Motzer said. Regarding prior therapy, he noted that relatively few patients had received adjuvant-only treatment, approximately two-thirds had one prior line of therapy, and about half had previously been treated with a VEGFR TKI.
The dual primary endpoints were progression-free survival by blinded independent central review (BICR) and overall survival. Objective response rate by BICR was identified as a key secondary endpoint; other secondary endpoints included duration of response by BICR and safety. The investigators evaluated time to deterioration in patient-reported outcomes as an exploratory endpoint.
According to Dr. Motzer, the study was considered positive if either of the dual primary endpoints was met. His presentation covered the results of both the first (interim progression-free survival, overall survival, final objective response rate) and second (final progression-free survival, interim overall survival) interim analyses, highlighting the second because its nearly 9 additional months of follow-up make it “more informative.”
Efficacy Findings
According to Dr. Motzer, both the first and second interim analyses demonstrated a significant progression-free survival benefit with belzutifan plus lenvatinib vs cabozantinib. In the second interim analysis, at 24 months, 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).
Overall, all key subgroups favored the combination over cabozantinib for progression-free survival, Dr. Motzer noted. He cautioned, however, that some subgroups were small and that individual subgroup analyses should be considered hypothesis-generating only.
Dr. Motzer noted that the objective response rate, formally evaluated only in the first interim analysis, was significantly higher with the combination at that time (52.6% vs 39.6%; P = .0002) and called the increase at the second interim analysis “modest” (52.6% vs 40.2%); more complete responses were seen with the combination (5.4% vs 1.1%).
Among responders, the median duration of response with the combination was nearly double that with cabozantinib, at 23.0 vs 12.3 months; at 24 months, 49.5% vs 25.5% of responses were ongoing. Dr. Motzer added that some patients treated with the combination have remained in response for nearly 3.5 years. “These are some of the most striking aspects of the results of this trial,” he remarked.
Overall survival appeared to favor the combination, with a median of 34.9 vs 27.6 months (HR = 0.85; P = .06075) at the second interim analysis and “at least a numerically higher” 24-month survival rate (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.
Treatment Exposure and Safety
Treatment duration was longer with belzutifan plus lenvatinib than with cabozantinib (16.8 vs 13.2 months). Overall safety was comparable between the arms, Dr. Motzer suggested, with severe adverse events (grade ≥ 3; 84.1% vs 82.7%), treatment discontinuations (11.1% vs 11.3%), and deaths (0.5% vs 0.3%) occurring at similar rates.
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]) was an exception, attributing it to belzutifan in the combination arm.
The most common adverse events were diarrhea, hypertension, and anemia with the combination and diarrhea, hypertension, and skin toxicity with cabozantinib. Rates of diarrhea and skin toxicity—“really troublesome for patients,” Dr. Motzer noted—were lower with the combination (52.7% vs 70.1% and 20.5% vs 51.2%, respectively).
Dr. Motzer highlighted adverse events of clinical interest, including hypoxia (15.4% vs 0%), a known effect of belzutifan, and cardiac dysfunction (7.0% vs 1.1%), emphasizing that grade 3 or higher cardiac dysfunction occurred in 4.6% of patients treated with the combination. He told the press that investigators are “digging into this deeper” to determine whether the cardiac findings are related to the combination itself or reflect the individual TKI.
Exploratory Data
Patient-reported outcomes were assessed using the Functional Assessment of Cancer Therapy–Kidney Symptom Index—Disease-Related Symptoms (FKSI-DRS) and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) scale. Time to deterioration—defined as a worsening from baseline of more than 3 points on the FKSI-DRS or more than 10 points on the EORTC QLQ-C30—yielded HRs of 1.02 and 1.07, respectively.
“Worsening of symptoms and quality of life, at least by these scales, appeared similar between arms,” Dr. Motzer said.
He concluded, “Belzutifan plus lenvatinib addresses an unmet clinical need and represents a potential new treatment option for patients with [renal cell carcinoma whose disease] progressed after PD-(L)1 therapy.”
Julie R. Gralow, MD, FACP, FASCO
Julie R. Gralow, MD, FACP, FASCO, ASCO's Chief Medical Officer and Executive Vice President, commented on the findings during a press briefing: “[It is] interesting to contrast this trial in the metastatic setting after prior exposure to immune checkpoint inhibitors with [LITESPARK-022]2 in the adjuvant setting, [which evaluated] belzutifan in combination with immune checkpoint inhibitors. I think after these two trials, we’ll be sorting out what order and what combinations to give these in down the line.”
DISCLOSURE: Dr. Motzer has served as a consultant or advisor for Merck; and has received institutional research funding from AVEO, Bristol Myers Squibb, Eisai, Exelixis, Merck, and Pfizer. Dr. Gralow reported no conflicts of interest.
REFERENCES
1. Motzer RJ, Park SH, McDermott RS, et al: Belzutifan plus lenvatinib versus cabozantinib for advanced renal cell carcinoma after anti–PD-(L)1 therapy: Open-label phase 3 LITESPARK-011 study. 2026 ASCO GU Cancers Symposium. Abstract LBA417. Presented February 28, 2026.
2. Choueiri TK, Motzer RJ, Karam JA, et al: Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma: The randomized phase 3 LITESPARK-022 study. 2026 ASCO GU Cancers Symposium. Abstract LBA418. Presented February 28, 2026.
Expert Point of View
Discussing the phase III LITESPARK-011 trial of the hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor belzutifan plus lenvatinib vs cabozantinib in patients with advanced clear cell renal cell carcinoma whose disease progressed after anti–PD-(L)1 therapy,1 Kathryn E. Beckermann, MD, PhD, Medical Director of Genitourinary (GU) Oncology, Tennessee Oncology, and Chair of the GU Disease Group, OneOncology, Nashville, placed the findings in the broader context of treatment options in this setting.“Once patients progress on front-line checkpoint inhibitor combinations, we have largely been left to sequence tyrosine kinase inhibitor (TKI) therapy with limited comparative data to guide those decisions,” she noted, underscoring the evidence gap that LITESPARK-011 was designed to fill.
To contextualize the LITESPARK-011 results, Dr. Beckermann reviewed several recent trials conducted in the post–PD-1 setting. If we look historically at lenvatinib and cabozantinib in the refractory setting we see that the control arm of cabozantinib here performed similar to that seen in CONTACT-03, demonstrated a median progression-free survival of 10.8 months and an objective response rate of 41%.2 Dr. Beckermann also referenced the phase II LenCabo trial of lenvatinib plus everolimus vs cabozantinib in the second- or third-line setting, which showed a median progression-free survival of 15.7 months for the lenvatinib and everolimus arm and an objective response rate of 52.6% with the combination also quite similar to the outcomes of the Litespark-011 investigational arm.5
The LITESPARK-005 study a third or fourth line patient population which led to the approval of belzutifan in later lines of therapy, reported a median progression-free survival of 5.6 months and an objective response rate of 22.7%.3,4 The challenge of belzutifan monotherapy in this refractory setting is the high primary progressive disease as best response of 34.0% but certainly it is the durability of response—19.5 months—that was notable.
Turning to LITESPARK-011, she noted that most patients entered the trial after experiencing disease progression on first-line therapy, and approximately 43% were TKI-naive. Highlighting the positive progression-free survival results and trend in the immature overall survival data, she drew attention to the shape of the survival curves. “The most instructive feature of these curves is the early overlap for the first 6 months where both treatment arms appear to deliver comparable near-term benefit,” she explained. “The later curve separation is consistent with what we have seen across other HIF-2 inhibitor trials: patients with HIF-2–dependent tumor biology continue to derive sustained benefit over time, and that is where the combination earns its advantage.” The durability of response with the combination regimen vs cabozantinib was also highlighted, with Dr. Beckermann describing the median duration of approximately 23 vs 12 months as “quite striking and clinically meaningful for our patients….”
She then briefly reviewed the subgroup findings, stating that the majority showed a trend toward benefit with the combination, but patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable-risk disease appeared to benefit the most, whereas those with IMDC poor-risk disease showed no progression-free survival advantage compared with cabozantinib. Although small numbers precluded statistical conclusions and are hypothesis generating only, she observed that this pattern parallels findings from LITESPARK-022.6
Regarding safety, Dr. Beckermann found it “notably reassuring” that the combination’s toxicity profile was not substantially more burdensome than cabozantinib alone. The adverse events observed—including anemia, hypoxia, and cardiac dysfunction—were consistent with the established on-target effects of HIF-2α inhibition and VEGFR-directed TKI therapy. Dose reductions occurred in both arms, and rates of treatment discontinuation were comparable.
Dr. Beckermann also highlighted the inclusion of patient-reported outcomes as a methodological strength, noting that comparable time to deterioration and quality-of-life measures across both arms reinforce the tolerability data and provide important reassurance that the added complexity of the doublet regimen does not come at the expense of patient experience.
In summary, Dr. Beckermann characterized belzutifan plus lenvatinib as a clinically meaningful advance for patients with post–checkpoint inhibitor advanced clear cell RCC, while emphasizing that individual patient comorbidities, prior TKI exposure, and performance status will ultimately guide treatment selection in real-world practice.
DISCLOSURE: Dr. Beckermann has served as a consultant or advisor for Adicet Bio, Aravive, Arcus Biosciences, AstraZeneca, AVEO, Bristol Myers Squibb, Eisai, Exelixis, Janssen Oncology, Merck, Nimbus Therapeutics, Novartis, Pfizer, and Xencor; and has received research funding from Aravive, ArsenalBio, Bristol Myers Squibb, and Pionyr.
REFERENCES
1. Motzer RJ, Park SH, McDermott RS, et al: Belzutifan plus lenvatinib versus cabozantinib for advanced renal cell carcinoma after anti–PD-(L)1 therapy: Open-label phase 3 LITESPARK-011 study. 2026 ASCO GU Cancers Symposium. Abstract LBA417. Presented February 28, 2026.
2. Pal SK, Albiges L, Tomczak P, et al: Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): A multicentre, randomised, open-label, phase 3 trial. Lancet 402:185-195, 2023.
3. Choueiri TK, Powles T, Peltola K, et al: Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med 391:710-721, 2024.
4. Rini BI, Suarez Rodriguez C, Albiges L, et al: LBA74 Final analysis of the phase III LITESPARK-005 study of belzutifan versus everolimus in participants with previously treated advanced clear cell renal cell carcinoma. Ann Oncol 35(suppl 2):S1262-S1263, 2024.
5. Hahn AW, Chahoud J, Skelton WP, et al: A multicenter randomized phase II trial of lenvatinib plus everolimus versus cabozantinib in patients with metastatic clear-cell RCC that progressed on PD-1 immune checkpoint inhibition (LenCabo). Ann Oncol 37:241-249, 2026.
6. Choueiri TK, Motzer RJ, Karam JA, et al: Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma: The randomized phase 3 LITESPARK-022 study. 2026 ASCO GU Cancers Symposium. Abstract LBA418. Presented February 28, 2026.
