The LenCabo trial conducted the first head-to-head comparison of second-line treatments for metastatic clear cell renal cell carcinoma (ccRCC). Dr Andrew W. Hahn, (Assistant Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA), highlights the randomized phase II LenCabo trial, comparing lenvatinib plus everolimus to cabozantinib after PD-1 checkpoint inhibitor therapy. The combination demonstrated a 49% reduction in disease progression and a median progression-free survival of 15.7 months, offering a potential strategy for aggressive disease.
The late-breaking abstract, ‘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)’ (LBA94) was presented at the European Society for Medical Oncology (ESMO) congress on 17th-21st October 2025 in Berlin, Germany.
Q1. What are the limitations and unmet needs in current second-line therapy for patients with metastatic clear cell RCC (ccRCC)?
Currently, first-line treatment for metastatic ccRCC typically involves a PD-1 checkpoint inhibitor combined with either a CTLA-4 inhibitor or an angiogenesis-targeted therapy. When patients require second-line therapy, guidelines list 5–7 different angiogenesis-targeted therapies, mostly single agents, with only one approved combination: lenvatinib plus everolimus. The major limitation is that none of these therapies have been directly compared in head-to-head trials. Existing studies use historical controls and different designs, leaving clinicians without clear guidance on the optimal choice for second- or third-line treatment.
Q2. The LenCabo trial is the first clinical trial to directly compare two standard second-line treatments for metastatic ccRCC. What was the rationale and main aims of this study?
The LenCabo trial aimed to conduct the first contemporary head-to-head comparison of second-line treatments following first-line PD-1 checkpoint inhibitor therapy. Lenvatinib plus everolimus represents a distinct combination: lenvatinib is a multitargeted angiogenesis inhibitor, while everolimus is an mTOR inhibitor, providing a complementary mechanism of action. This randomized phase II trial compared lenvatinib plus everolimus to cabozantinib, with progression-free survival as the primary endpoint.
Q3. How does combining a TKI (lenvatinib) with another targeted therapy (everolimus) enhance treatment outcomes, compared with using a single agent?
The combination met the primary endpoint, demonstrating a 49% reduction in the hazard of disease progression compared with cabozantinib (p=0.02). Median progression-free survival was 15.7 months with lenvatinib plus everolimus versus 10.2 months with cabozantinib. Objective response rates were 53% versus 39%, respectively. Although the difference in response rate was not statistically significant, the numerical improvement suggests potential clinical benefit.
Q4. How do these findings impact the current treatment landscape for patients with metastatic ccRCC who progress after immunotherapy?
These results may influence clinical decision-making for patients progressing after first-line immunotherapy, including nivolumab plus ipilimumab, pembrolizumab plus axitinib, or adjuvant pembrolizumab. For patients seeking aggressive management and prioritizing longer progression-free survival, lenvatinib plus everolimus represents a compelling second-line option, provided patients are willing to accept a potential increase in side effects.
Disclosure: Andrew W Hahn has received grant/research support from Bayer, Bristol Myers Squibb, Eisai and Halda Therapeutics. He is a member of the Advisory Board for Janssen, Intellisphere, AVEO, Exelixis, Eisai, Pfizer and Tolmar. He has received honoraria/honorarium from Medscape, Binaytara Foundation, Projects in Knowledge, Curio Science, Dava Oncology, IDEOlogy Health, Mashup Media and MJH Life Sciences..
This content has been developed independently by Touch Medical Media for touchONCOLOGY. It is not affiliated with the European Society for Medical Oncology (ESMO). Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Cite: ESMO25 Late-breaker: LenCabo head-to-head highlights lenvatinib-everolimus benefit after immunotherapy in metastatic ccRCC. touchONCOLOGY. October 22nd, 2025
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