Clinical trialPhase 3Kidney cancer

Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial

Lancet · 2026747 patients

Motzer RJ, McDermott R, Park SH, Burotto M, Iacovelli R, Verzoni E, et al. Lancet. 2026. 408:808-820

Study type: Clinical trial
Study name: LITESPARK-011
Phase: Phase 3
Design: Randomised, open-label, active-controlled trial (184 centres in 25 countries)
Sample size: 747 patients
Source: Lancet · 2026
Trial registration: NCT04586231

In plain words

In patients whose kidney cancer had progressed after immunotherapy, combining two tablets, belzutifan and lenvatinib, kept the disease under control about 4 months longer than the tablet cabozantinib, but the difference in survival was not statistically certain. Severe side effects were common in both groups.

Key results

14.8 vs 10.7 months

Median progression-free survival

HR 0.70 (0.59–0.84); one-sided P <0.0001

34.9 vs 27.6 months

Median overall survival

HR 0.85 (0.68–1.05); one-sided P 0.061 (not significant)

84% vs 83%

Grade 3 or higher adverse events

Most common: hypertension 31% vs 29%

Drugs in this study:Lenvatinib (Lenvima)

Dose and schedule cards

Belzutifan + lenvatinib (LITESPARK-011)

Advanced RCC with a clear-cell component after a PD-1 or PD-L1 inhibitor; better progression-free survival than cabozantinib, with no significant difference in overall survivalCycle length: ContinuousOn the page “Kidney cancer” · Regimens for later lines and immunotherapy-free treatment

Advanced RCC with a clear-cell component after a PD-1 or PD-L1 inhibitor; better progression-free survival than cabozantinib, with no significant difference in overall survival

Drug	Dose	Route	Schedule
Belzutifan	120 mg once daily	Oral	Daily, continuously
Lenvatinib	20 mg once daily	Oral	Daily, continuously

Cycle length: Continuous
Duration: Until progression or unacceptable toxicity

Per the FDA labels and the trial. Grade 3 cardiac dysfunction: withhold both drugs until LVEF recovers to baseline or grade 1; grade 4: permanently discontinue both. Monitoring for lenvatinib (blood pressure, liver, urine protein, thyroid) and belzutifan (haemoglobin, oxygen saturation) as in the regimens above.

On the page “Kidney cancer” · Regimens for later lines and immunotherapy-free treatment

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Belzutifan + lenvatinib

Belzutifan 120 mg + lenvatinib 20 mg, both orally once daily, until disease progression or unacceptable toxicity. According to the FDA label, belzutifan dose reductions are 80 and then 40 mg, and lenvatinib 14, 10 and then 8 mg.

2Cabozantinib

Cabozantinib 60 mg orally once daily (fasting) until disease progression or unacceptable toxicity.

Source of the regimen details: Abstract of the paper (PubMed), ClinicalTrials.gov NCT04586231 and the FDA labels (WELIREG, LENVIMA)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with unresectable advanced or metastatic clear-cell renal cell carcinoma that progressed on or after one anti-PD-1/PD-L1 therapy (first or second line for advanced disease, or adjuvant/neoadjuvant-adjuvant therapy with progression during or within 6 months of the last dose), with or without a prior VEGFR-TKI; up to 2 prior systemic regimens and only one anti-PD-1/PD-L1 therapy; Karnofsky 70% or higher; measurable disease; controlled blood pressure. Patients with resting oxygen saturation below 92% or requiring oxygen were excluded (ClinicalTrials.gov).

Endpoints

Dual primary endpoints: progression-free survival by blinded independent central review and overall survival.

Safety and side effects

Treatment-emergent grade 3 or higher adverse events occurred in 84% (311 of 370) of the belzutifan + lenvatinib group and 83% (307 of 371) of the cabozantinib group; the most common was hypertension (31% versus 29%). Treatment-related adverse events led to 2 deaths in the combination group and 1 death in the cabozantinib group. According to the FDA label, with the combination decreased haemoglobin occurred in 87% (grade 3 or requiring transfusion in 20%) and hypoxia in 16% (grade 3–4 in 12%).

Clinical significance and place in guidelines

This is the first positive phase 3 trial (for progression-free survival) against cabozantinib after immunotherapy; an overall survival benefit was not shown. Its place in guidelines should be checked in new versions.

Limitations

The trial is open-label; the results are from the second interim analysis and overall survival was not significant.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.