The Food and Drug Administration (FDA) has approved belzutifan (120 mg) plus lenvatinib (20 mg) orally once daily for adults with advanced renal cell carcinoma containing a clear cell component following a PD-1 or PD-L1 inhibitor.

The indication differs from belzutifan monotherapy, which requires prior exposure to both a PD-1 or PD-L1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. It is also separate from the adjuvant indication for belzutifan with pembrolizumab after nephrectomy in patients at intermediate-high or high risk of recurrence.

The approval was based on promising results from the LITESPARK-011 trial, which show the combination improved progression free survival compared to cabozantinib.

“While there was no significant difference in overall survival when compared to single agent cabozantinib, the improvement in PFS and the signal for improved overall survival provide meaningful evidence supporting the use of combination therapy employing different mechanisms of action,” Dr. Cameron Britton, a urologic oncologist at UAB Medicine, tells SurvivorNet Connect.

The trial also indicates that the treatment combination leads to durable responses.

“The most impressive result … was that for patients who responded, their likelihood of continuing to respond was much higher on the combination at almost two years compared to 12 months on cabozantinib,” Dr. Sandy Srinivas, a medical oncologist at the Stanford Cancer Center, tells SurvivorNet Connect.

“However, when you combine two drugs, there is an increased price that you pay in toxicity,” Dr. Srinivas adds.

LITESPARK-011 Establishes Clear Benefit

The approval rests on LITESPARK-011, a randomized, open-label, active-controlled phase 3 trial of 747 patients. Participants were assigned 1:1 to belzutifan plus lenvatinib or cabozantinib 60 mg once daily.

Eligible patients had unresectable, locally advanced, or metastatic clear cell RCC, a Karnofsky performance status of at least 70%, and no more than two previous systemic regimens. Disease had progressed on or after a PD-1 or PD-L1 antibody given as first- or second-line therapy, or within six months after adjuvant PD-1 therapy. Prior VEGFR-TKI treatment was permitted, and approximately 57% of participants had received at least one.

Patients with hypoxia, active central nervous system metastases, or clinically significant recent cardiac disease were excluded, a consideration when applying the findings to patients with greater cardiopulmonary comorbidity.

Dual primary endpoints were progression-free survival by blinded independent central review under RECIST 1.1 and overall survival. Objective response rate was a key secondary endpoint.

At the FDA-reported analysis:

• Median progression-free survival was 14.6 months with belzutifan-lenvatinib and 10.6 months with cabozantinib (hazard ratio, 0.74; 95% confidence interval, 0.61-0.89; one-sided P = .00095).
• Objective response rates were 53% and 40%, respectively (one-sided P = .0002).
• Final median overall survival was 33.7 versus 28.6 months (hazard ratio, 0.85; 95% confidence interval, 0.70-1.03). The overall-survival endpoint did not reach statistical significance.

These regulatory figures should not be combined with the later interim dataset reported in the Lancet publication. At the April 9, 2025 cutoff, median progression-free survival was 14.8 versus 10.7 months, and interim median overall survival was 34.9 versus 27.6 months. Median duration of response at that earlier cutoff was 23.0 versus 12.3 months. The differences reflect additional follow-up and prespecified analyses, not contradictory trial results.

Toxicity Will Shape Patient Selection

The safety profile reflects overlapping burdens from HIF-2α and VEGFR inhibition. Serious adverse reactions occurred in 54% of patients receiving the combination, while fatal adverse reactions were reported in 5%.

Decreased hemoglobin occurred in 87% of patients, with 20% experiencing a grade 3 event or requiring transfusion. Hypoxia occurred in 16%, including grade 3 or 4 events in 12%. These toxicities support baseline and serial complete blood counts and oxygen-saturation assessment, with prompt evaluation of dyspnea, fatigue, dizziness, or declining exercise tolerance.

Hypertension, proteinuria, renal dysfunction, hepatotoxicity, diarrhea, electrolyte abnormalities, and thyroid dysfunction remain relevant lenvatinib-associated risks. Blood pressure, renal and hepatic indices, urinalysis, electrolytes, and thyroid function require routine surveillance.

Grade 3 or higher cardiac dysfunction occurred in 6% of combination-treated patients. An absolute left ventricular ejection fraction decrease greater than 20% occurred in 6%. Baseline echocardiography or multigated acquisition imaging should be considered, particularly in patients with cardiovascular risk, followed by reassessment when signs or symptoms suggest heart failure. Safety has not been established in patients with a baseline ejection fraction below 50%.

Dose modification was common. Adverse reactions led to:

• Treatment interruption in 69% for belzutifan and 72% for lenvatinib
• Dose reduction in 35% and 67%
• Permanent discontinuation in 17% and 23%, respectively.

What the Approval Leaves Unanswered

“This is a good step moving forward to have another option for our patients, but I would choose this combo for selective patients, perhaps those who have bulky disease and who need a response more quickly, and patients would have to be told about the side effects of anemia,” Dr. Srinivas explains.

Belzutifan targets HIF-2α-driven transcription, while lenvatinib inhibits VEGFR and other receptor tyrosine kinases. This dual targeted approach differs biologically from sequencing another VEGFR-TKI or using belzutifan monotherapy after both checkpoint and VEGFR exposure.

LITESPARK-011 establishes superior progression-free survival and response probability over cabozantinib in the studied population. It does not establish an overall-survival advantage, define the optimal treatment after every first-line immunotherapy combination, or identify which patients require both agents rather than sequential therapy.

Comparisons with tivozanib, lenvatinib-everolimus, belzutifan monotherapy, or other later-line approaches remain indirect. Differences in prior VEGFR exposure, line of therapy, prognostic risk, follow-up, and endpoint assessment make cross-trial rankings unreliable. Treatment selection will depend on prior therapy, tempo of disease, need for response, cardiopulmonary reserve, and tolerance for two-drug toxicity.