LenCabo Trial Reveals Catabolic Trade-Off for Lenvatinib/Everolimus in Metastatic ccRCC
Key Insights
The phase 2 LenCabo trial showed lenvatinib plus everolimus led to significantly greater reductions in BMI, skeletal muscle mass index, and subcutaneous adiposity at 4 months versus cabozantinib in metastatic ccRCC.
Dr. María Teresa Bourlon emphasized that this catabolic signal raises concerns for older, frail, or weight-compromised patients, potentially impacting quality of life and dose delivery.
Quality-of-life comparison at day 60 was inconclusive due to only 38 of 86 patients completing both assessments, limiting interpretability.
Newly presented data from the randomized phase 2 LenCabo trial (NCT05012371) underscore a critical clinical trade-off in the treatment of metastatic clear cell renal cell carcinoma (search) (ccRCC): while lenvatinib (Lenvima) plus everolimus (Afinitor) offers superior progression-free survival (PFS) over cabozantinib (Cabometyx), the combination carries a pronounced catabolic effect that may disproportionately impact vulnerable patients.
Findings presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting revealed that patients receiving lenvatinib plus everolimus experienced significantly greater reductions in body mass index (BMI), skeletal muscle mass index, and subcutaneous adiposity at 4 months compared with those treated with cabozantinib.
Catabolic Effects and Clinical Implications
María Teresa Bourlon, MD, MSc, FASCO, head of the Urologic Oncology Clinic at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City, discussed the implications of these findings in an interview with CancerNetwork®.
"Whenever we're prescribing a tyrosine kinase inhibitor [TKI] in any line of treatment for RCC, we're concerned about its catabolic effect, especially reducing muscle mass and the strength of the patient," Bourlon said. "These results tell us that we could expect patients to become frailer and to lose their muscle mass and strength."
Bourlon emphasized that this toxicity is particularly concerning for older patients from a geriatric population, those who are already frail, or individuals who have experienced significant weight loss. "This is a significant toxicity that may impact outcomes, may preclude patients from receiving full dose, and may even impact their quality of life because they're not going to be able to do their daily activities," she noted.
The findings highlight the importance of baseline patient assessment. Bourlon stressed that clinicians should carefully evaluate fitness and body composition before selecting this combination, particularly in patients who are frail, older, or have already lost considerable muscle mass.
Quality-of-Life Data Remains Inconclusive
The LenCabo trial also assessed quality of life (QOL) using the FKSI-DRS (Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-Related Symptoms) tool. However, the comparison at day 60 yielded inconclusive results, with a non-significant odds ratio of 0.51. Critically, only 38 of 86 patients completed both assessments, meaning fewer than half of participants contributed to this analysis.
Bourlon acknowledged this as a broader challenge in kidney cancer research. "Whichever tool we use to measure QOL, we know it isn't perfect; we can improve these tools, but it's still hard to have a good instrument," she said. "On top of that, in clinical trials we rarely achieve 100% response from patients, and it's particularly notable in this trial that less than 50% of patients answered the QOL questionnaire."
She cautioned that the incomplete data capture limits interpretability. "Having a real difference in QOL would be very meaningful. If the combination had demonstrated better QOL, we'd all lean more toward prescribing it, but knowing the result was inconclusive, we really can't tell whether there's a difference between lenvatinib/everolimus and cabozantinib."
A Call for Better Measurement Tools
Bourlon noted that the field currently lacks adequate clinical measurements to fully capture the impact of these medications on musculoskeletal toxicity. "We're lacking better measurements in clinic to really see the impact of these medications on musculoskeletal toxicity, but this abstract is really informative to help us rethink whether we need to give this combination to patients who are frail, older, or who have lost a lot of muscle mass," she said.
The LenCabo data, drawn from the study by Moura and colleagues published in the Journal of Clinical Oncology, add an important dimension to treatment decision-making in metastatic ccRCC following PD-1 inhibitor progression. While the PFS advantage of lenvatinib plus everolimus remains a compelling efficacy signal, the catabolic burden may tip the risk-benefit calculus for a subset of patients.
"For me, this finding doesn't tip the balance toward one drug or the other at this point," Bourlon concluded regarding the QOL data. The decision, she suggested, must remain individualized, grounded in a thorough assessment of each patient's baseline functional status and body composition.