Contemporary RCC trial adds fresh lenvatinib/everolimus PFS perspective

A new phase 2 study revealed intriguing efficacy findings for the combination of lenvatinib (Lenvima) plus everolimus (Afinitor), shedding fresh light on the combinations potential role in the treatment sequence for patients with metastatic clear cell renal cell carcinoma (ccRCC).

The phase 2 study assessed the combination for patients with ccRCC following progression on a PD-1 inhibitor, offering perspective on a key treatment setting. In the study, the lenvatinib/everolimus combination reduced the risk of progression or death by 49% when compared with cabozantinib (Cabometyx), according to findings presented at the 2025 European Society for Medical Oncology Congress in Berlin, Germany and simultaneously published in the Annals of Oncology.^1,2

The combination of lenvatinib and everolimus was approved by the FDA in 2016 for the treatment of patients with advanced RCC after a prior anti-angiogenic agent.³ The phase 2 study was completed to assess the combination in a more contemporary treatment setting, according to lead investigator Andrew W. Hahn, MD.

"Lenvatinib plus everolimus significantly prolonged progression-free survival over cabozantinib," Hahn, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, said during a presentation of the results. "As the first head-to-head randomized comparison of contemporary second-line or later treatments after immune checkpoint inhibition, these results are relevant to treatment sequencing and inform oncology practice."

The study enrolled 86 patients, with 40 receiving the combination and 46 receiving cabozantinib. The most common prior treatment was the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), which was received by 70.9% of patients enrolled in the study.

Baseline characteristics were well balanced between the groups with most patients (69.8%) in each group having received 1 prior line of therapy and 30.2% having received 2 prior lines of therapy. Nearly half of patients had received prior VEGF-targeted therapy (45% for the combination arm and 41.3% for the single agent group). The IMDC risk was primarily intermediate in both groups (80% for combination and 73.9% for single agent). The IMDC risk was poor for 7.5% of those in the combination arm and for 8.7% of those in the control arm.

The median progression-free survival (PFS), which was the primary end point of the study, was 15.7 months with the combination of lenvatinib plus everolimus compared with 10.2 months with cabozantinib (HR, 0.51; 95% CI, 0.29-0.89; P = .02).

The objective response rate was 52.6% with lenvatinib plus everolimus compared with 38.6% with cabozantinib (OR, 1.87; 95% CI, 0.75-4.6; P = .17). In addition to responses, stable disease was observed in 39.5% of those receiving the combination and for 54.5% of those in the single-agent arm.

The study was not designed to assess differences in overall survival (OS) and findings for this end point were still immature, Hahn noted. After a median of 20 months of follow-up, the 1-year OS probability was 87.0% with lenvatinib plus everolimus compared with 84.6% with cabozantinib (HR, 1.05; 95% CI, 0.47-2.38; P = .86).

“This result was not statistically significant, and this is inconclusive immature analysis,” Hahn cautioned. “There are very wide 95% confidence intervals here due to the low number of events observed.”

There were more adverse events (AEs) observed with the combination, but these differences were not deemed statistically significant. Grade 3/4 AEs were experienced by 67.5% of those treated with lenvatinib plus everolimus compared with for 50% of those receiving cabozantinib (odds ratio [OR], 2.08; 95% CI, 0.86-5.02). Treatment discontinuation was more common in the combination group at 20% compared with the single agent at 10.9% (OR, 2.05; 95% CI, 0.61-6.91).

"Of the 8 patients who discontinued treatment with lenvatinib plus everolimus, 5 of those were due to proteinuria," said Hahn. The most observed AEs in the study aligned with those historically associated with each agent, he added.

For the combination and single agent arms, respectively, the most common all-grade AEs were diarrhea (70% vs 73.9%), fatigue (72.5% vs 60.9%), proteinuria (65% vs 37%), hypertension (57.5% vs 39.1%), nausea (40% vs 39.1%), palmar-plantar erythrodysesthesia (20% vs 52.2%), vomiting (32.5% vs 34.8%), and oral mucositis (15% vs 43.5%).

DISCLOSURES: Hahn noted disclosures with Janssen, Intellisphere, AVEO, Exelixis, Eisai, Pfizer Tolmar, Medscape, Binaytara Foundation, Curio Science, Dava Oncology, Mashup Media; Financial Interests, Bayer, and Halda Therapeutics.

REFERENCES

1. Hahn AW, Chahoud J, Skelton W, et al. LenCabo: A randomized phase II multicenter trial of lenvatinib plus everolimus (len/eve) versus (vs) cabozantinib (cabo) in patients (pts) with metastatic clear cell RCC (ccRCC) that progressed on PD-1 immune checkpoint inhibition (ICI). Presented at: 2025 European Society for Medical Oncology Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA94. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA94.html.pdf

2. Hahn AW, Chahoud J, Skelton WP, et al. A multicenter randomized phase II trial of lenvatinib plus everolimus versus cabozantinib in patients with metastatic clear cell RCC that progressed on PD-1 immune checkpoint inhibition (LenCabo). Ann Oncol. 2025. doi:10.1016/j.annonc.2025.10.009.

3. Lenvatinib in combination with Everolimus. FDA. May 16, 2016. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/lenvatinib-combination-everolimus