The combination of belzutifan (Welireg) and lenvatinib (Lenvima) led to superior outcomes, compared with cabozantinib (Cabometyx), in a phase 3 trial of patients with advanced clear cell renal cell carcinoma (RCC) whose disease had progressed after prior anti-PD-L1/anti-PD-1 therapy.

At the second interim analysis of LITESPARK-011, the combination was associated with longer progression-free survival, higher objective response rate, longer duration of response, and a trend toward prolonged overall survival, compared with cabozantinib. The duration of response was essentially double with belzutifan plus lenvatinib compared with cabozantinib.

"That's remarkable for this patient population," lead investigator Robert Motzer, MD, medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, said during a press briefing at the American Society of Clinical Oncology (ASCO) 2026 Genitourinary Cancers Symposium.

Belzutifan plus lenvatinib "addresses an unmet clinical need and represents a potential new treatment option" for patients with advanced kidney cancer that progressed after immune checkpoint inhibitor therapy. 

No Clear Standard of Care 

There is currently no clear standard of care for patients with advanced RCC following disease progression on anti-PD-(L)1 therapy. Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), including cabozantinib and lenvatinib-based combinations, are commonly used following disease progression, Motzer explained.

Belzutifan is a first-in-class hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor approved for patients with advanced RCC following both anti-PD-(L)1 and VEGFR-TKI therapy. 

The rationale behind the phase 3 LITESPARK-011 trial was that combining the belzutifan with lenvatinib might provide more comprehensive tumor control than VEGFR inhibition alone. 

The trial enrolled 747 patients with unresectable, locally advanced or metastatic clear cell RCC that had progressed on or after first- or second-line anti-PD-(L)1 therapy, or within 6 months of completing adjuvant anti-PD-(L)1 therapy.

They were randomly allocated (1:1) to receive one of two oral regimens: belzutifan (120 mg plus lenvatinib 20 mg once daily) or cabozantinib (60 mg once daily). Baseline characteristics were balanced between the groups and were typical for an RCC trial, Motzer noted. 

The trial had dual primary endpoints: progression-free survival (PFS) by blinded independent central review (RECIST 1.1) and overall survival. Key secondary endpoints included objective response rate, duration of response, and safety.

At the second interim analysis, with a median follow-up of 29 months, belzutifan plus lenvatinib demonstrated a statistically significant improvement in PFS compared with cabozantinib (median PFS 14.8 months vs 10.7 months; hazard ratio [HR], 0.70, P = .00007).

The Kaplan-Meier curves showed "clear separation" between the treatment groups over time, with higher PFS with the combination seen at 12 months (55% vs 41%) and 24 months (36% vs 19%), Motzer reported. 

Overall survival numerically favored the combination but did not reach statistical significance at the second interim analysis. At 2 years, 63% of patients on the belzutifan/lenvatinib combination were alive, compared with 55% of those on cabozantinib. 

Median OS was 34.9 months with the combination vs 27.6 months with cabozantinib (HR 0.85; P = .06075). Overall survival will be further analyzed at the final analysis.

Secondary outcomes also favored combination therapy. The objective response rate was 53% with belzutifan plus lenvatinib vs 40% with cabozantinib, with 20 (5%) complete responses in the combination group, compared with only four (1%) in the cabozantinib group.

In addition to the higher response rate, the duration of response was also significantly higher with the combination than with cabozantinib (50% vs 25% at 2 years). The median duration of response was 23.0 months vs 12.3 months. 

"Some of the responses on the combination arm are ongoing for more than 3 years. To me, these are some of the most striking aspects of the results of this trial — the durability of response that we see in patients on the combination," Motzer noted during his presentation of the study results at the meeting.

Trade-Off in Side Effects? 

Essentially all patients had a treatment‑emergent adverse event (TEAE), but the rate of grade 3 or higher events was nearly identical between the two groups (84% with belzutifan plus lenvatinib and 83% with cabozantinib). TEAEs that led to discontinuation of all study drugs were identical at 11% in the two groups. 

Overall, Motzer said the safety profile of the two regimens was consistent with the known profiles of the individual drugs.

The most common AEs in the belzutifan plus lenvatinib group were anemia, diarrhea, and hypertension. With cabozantinib, the most common AEs were diarrhea, hypertension, and hand-foot syndrome.

Hypoxia is well known to be associated with belzutifan and occurred in about 15% of patients. Cardiac dysfunction occurred in about 7% of patients on the combination vs 1% on cabozantinib but was grade 3 or higher in about 5% on the combination vs 0.5% on cabozantinib. 

There were two (5.4%) treatment-related deaths in the combination group (from thrombotic microangiopathy and pneumonitis) and one (3.2%) in the cabozantinib group (hemoptysis).

There were no significant between-group differences on the exploratory endpoint of time to deterioration in patient-reported outcomes or quality of life, as measured by two validated measures.

Patient Selection Key: No One-Size-Fits-All

Weighing in on the results in a statement, Sumanta Kumar Pal, MD, ASCO expert in kidney cancer, and co-director the kidney cancer program at City of Hope, Duarte, California, agreed that the LITESPARK-011 data "support this combination as a potential new option" in patients with advanced clear cell RCC that recurs after previous immunotherapy.

ASCO expert Brian Rini, MD, chief of clinical trials at Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, agreed, but he told the briefing that "it's not going to be a one-size-fits all approach, where every single patient gets this combination."

"That will be the conversation from this point forward — there are benefits, but there are some toxicities. How do we apply that and in whom do we apply that?" he said. 

Study discussant Kathryn Beckermann, MD, PhD, with Tennessee Oncology, Nashville, noted that while there were no significant differences in key subgroups, the data suggested that the patients with "favorable or good risk disease benefited the most from the combination, while those with poor risk more aggressive biology benefited similarly between arms."

She told attendees the questions that are still in her mind are "who are those durable responders, and do we have a way of identifying them?"

The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Motzer disclosed relationships with Merck and numerous other pharmaceutical companies. Rini disclosed relationships with Formedics, Eisai, Exelixis, and Merck. Pal disclosed relationships with CRISPR and Ipsen. Beckermann disclosed relationships with Merck, Adicet Bio, Aravive, and other pharmaceutical companies.