Welireg/Lenvima Combo Improves Outcomes in Advanced Kidney Cancer

The hypoxia-inducible factor inhibitor Welireg (belzutifan) combined with Lenvima (lenvatinib) demonstrated superior progression-free survival and objective response rate versus Cabometyx (cabozantinib) in patients with advanced clear cell renal cell carcinoma whose disease progressed after immune checkpoint inhibitor therapy, according to results presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium.

Median progression-free survival was 14.8 months with Welireg plus Lenvima versus 10.7 months with Cabometyx. According to Robert J. Motzer, the combination showed consistent improvement in progression-free survival across interim analyses. Objective response rate was also higher with the combination, demonstrating deeper and more frequent tumor shrinkage compared with Cabometyx.

At 24 months overall survival was 62.8% with Welireg plus Lenvima versus 55.4% with Cabometyx. Median overall survival was 34.9 months in the combination arm and 27.6 months in the Cabometyx arm. Although this difference was not statistically significant at the time of analysis, overall survival will continue to be evaluated in the final analysis.

Objective response rate was 52.6% with Welireg plus Lenvima compared with 40.2% with Cabometyx. There were 20 complete responses in the combination arm compared with 4 in the Cabometyx arm, highlighting the potential for more profound tumor control. Duration of response also favored the combination. At 24 months duration of response was 49.5% with Welireg plus Lenvima versus 25.5% with Cabometyx. Median duration of response was 23 months with the combination compared with 12.3 months with Cabometyx. Motzer noted that the durability of responses was one of the most striking findings of the study.

The trial enrolled patients with locally advanced or metastatic clear cell renal cell carcinoma who experienced disease progression after first- or second-line immune checkpoint inhibitor therapy. A total of 747 patients were randomly assigned to receive Welireg at 120 mg plus Lenvima at 20 mg or Cabometyx at 60 mg. Dual primary end points were progression-free survival and overall survival, and secondary end points included objective response rate and duration of response.

Investigators aimed to evaluate the strategy of combining a first-in-class hypoxia-inducible factor inhibitor with a vascular endothelial growth factor tyrosine kinase inhibitor. Welireg is already approved for advanced disease following both immunotherapy and vascular endothelial growth factor tyrosine kinase inhibitor therapy. This study provides important data supporting the use of the combination earlier in the treatment sequence for patients whose disease progresses on checkpoint inhibition.

Patients remained on Welireg plus Lenvima longer than on Cabometyx, with a median treatment duration of 16.8 months versus 13.2 months. Baseline characteristics were balanced between treatment arms and reflected a typical advanced renal cell carcinoma population.

Nearly all patients in both groups experienced side effects, and the proportion of patients with grade 3 or higher side effects was similar between arms. There were 2 deaths in the Welireg plus Lenvima group and 1 death in the Cabometyx group.
The most common treatment-related side effects in the combination arm were anemia, diarrhea and hypertension. In the Cabometyx arm, the most common side effects were diarrhea, hypertension and skin toxicity. These safety findings were consistent with the known side effect profiles of the individual drugs.

Time to worsening of disease-related symptoms and quality of life was similar between the two treatment groups, suggesting that the improved tumor control with the combination did not come at the cost of worse patient-reported outcomes.

Overall, Welireg plus Lenvima represents a potential new treatment option for patients with advanced clear cell renal cell carcinoma whose disease has progressed after anti–programmed death ligand 1 therapy. The combination improved progression-free survival and objective response rate compared with Cabometyx and produced deeper and more durable responses, with a manageable safety profile. Ongoing follow-up will determine whether the observed trend toward improved overall survival translates into a statistically significant benefit.

These findings support the continued investigation of Welireg-based combinations and may help redefine treatment sequencing in the post–immune checkpoint inhibitor setting for advanced kidney cancer.

References

1. "RC48G001: a phase 2 study of disitamab vedotin in HER2-expressing previously treated advanced UC," by Dr. Robert J. Motzer. Journal of Clinical Oncology.

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