Clinical trial data from researchers at Memorial Sloan Kettering Cancer Center (MSK) supports the use of a novel combination therapy for patients with advanced clear cell renal cell carcinoma (RCC), who experience disease progression after treatment with immune checkpoint inhibitors. The new research was published in The Lancet on August 12, 2026.
Immune checkpoint inhibitors, like pembrolizumab (Keytruda®), a programmed cell death protein 1 (PD-1) inhibitor and avelumab (Bavencio®), a programmed cell death ligand 1 (PD-L1) inhibitor are commonly used in the treatment of advanced RCC, along with either a tyrosine kinase inhibitor (TKI), such as cabozantinib (Cabometyx®), or another type of immunotherapy. However, not all patients respond or respond only partially to these treatments. Even when patients do respond, disease eventually progresses. There is currently no clear treatment path for these patients.
“Previously, evidence for efficacy benefit for one therapy over another has been lacking in this clinical setting. Cabozantinib has been commonly used and was chosen for comparison to the novel combination of belzutifan plus lenvatinb,” said lead author Robert J. Motzer, MD, who is a genitourinary medical oncologist at MSK.
Dr. Motzer and colleagues reported on second interim analysis of the phase 3 open-label trial (LITESPARK-011), which showed improved progression-free survival (PFS) in patients treated with belzutifan (Welireg®) plus lenvatinib (Lenvima®) versus cabozantinib. PFS was significantly longer for patients who received belzutifan and lenvatinib compared with those who received cabozantinib alone — median 14·8 months vs 10·7 months respectively. In this second interim analysis, median overall survival (OS) was longer with belzutifan plus lenvatinib than with cabozantinib (34.9 vs. 27.6 months), although the difference did not reach statistical significance.
Lenvatinib and cabozatinib are multikinase TKIs that help block the formation of new blood vessels that tumors need to grow and spread by blocking vascular endothelial growth factor receptors (VEGFR). The two have overlapping but distinct kinase targets.
Belzutifan — the first in its class — is a hypoxia-inducible factor 2α (HIF-2 α) inhibitor that blocks a key pathway that tumors use to respond to low oxygen conditions. HIF-2a is a central driver of clear cell renal cell carcinoma, making it an attractive therapeutic target. Belzutifan was approved by the U.S. Food and Drug Administration in 2025 for treatment of adult patients with advanced clear cell RCC after one or more previous anti-PD-1 or anti-PD-L1 therapies and one or more previous VEGFR-TKIs.
“Orthogonal inhibition of angiogenesis pathways with the HIF-2alpha inhibitor and a VEGR-TKI was undertaken to improve upon the efficacy of the VEGR-TKI alone,” said Dr. Motzer.
Safety was comparable for the two groups. Treatment-emergent adverse events (AEs) occurred in nearly all patients who received belzutifan and lenvatinib (>99%) or cabozatinib (99%). Grade 3 or worse AEs occurred in 84% and 83% in the combination and monotherapy groups. Just over half (52%) of patients who received belzutifan–lenvatinib and 44% who received cabozantinib had treatment-emergent serious AEs.
The most common AE of any grade was anemia (69%) in the belzutifan–lenvatinib group and diarrhea in the cabozantinib group (70%). The most common grade 3 or worse AE in both groups was hypertension — 31% with belzutifan–lenvatinib and 29% with cabozantinib.
Methods
The international study involved 747 patients randomly allocated to receive either belzutifan–lenvatinib (n=371) or cabozantinib (n=376). Patients had unresectable, locally advanced or metastatic stage 4 clear-cell RCC with measurable disease and experienced disease progression on or after one previous anti-PD-1 or anti-PD-L1 therapy as first-or second-line treatment or received their last dose of anti-PD-1 or anti-PD-L1 therapy as adjuvant or neoadjuvant-adjuvant treatment within the last 6 months.
Participants could have no more than two previous systemic treatments with anti-PD-1 or anti-PD-L1 therapy as the most recent. Patients received 120 mg oral belzutifan plus 20 mg oral lenvatinib or 60 mg oral cabozantinib once daily until documented radiographic disease progression, discontinuation, or death. Dose adjustments were permitted.
Tumor imaging was performed using either CT scan (preferred) or MRI at screening and then every 8 weeks for 80 weeks. After that period, patients were scanned every 12 weeks thereafter. Adverse events (AEs) were reported from randomization to 30 days after treatment was stopped.
Limitations
The study had several limitations including the open-label design. The researchers noted that PFS assessment involved masked independent central review, which could limit potential bias in the efficacy assessment. Also, subgroup analyses were not under multiplicity (multiple statistical comparisons) control and were limited by small sample sizes or event numbers. As such, they should be considered hypothesis-generating only. Subsequent therapy was up to clinicians and not specified by the trial protocol. While this reflects real-world patterns of care, differences in subsequent therapy selection could confound OS analysis.
The study population was also overwhelmingly White, with Black participants accounting for less than 1% of the overall study population. Lastly, it was not possible to directly evaluate the relative contribution of effects of lenvatinib and belzutifan individually.
Disclosures
Merck Sharp & Dohme, a subsidiary of Merck & Co., provided study funding and study authors included Merck employees. Dr. Motzer reported receiving funding from Merck Sharp & Dohme and AstraZeneca, and relationships with Exelixis, EMD Serono, Eisai, Incyte, Bristol Myers Squibb, Pfizer, Janssen, Astellas, Novartis, and Bayer.