Andrew Hahn, MD, MD Anderson Cancer Center, Houston, Texas, discusses results from the phase 2 LenCabo trial comparing lenvatinib plus everolimus with cabozantinib in patients with metastatic clear cell renal cell carcinoma who experienced disease progression after PD-1–based therapy. 

The study showed that lenvatinib plus everolimus significantly prolonged progression-free survival compared with cabozantinib, providing important insights for second-line treatment decisions. 

These findings were presented at the 2025 European Society for Medical Oncology (ESMO) Congress in Berlin, Germany.

Transcript: 

My name is Andy Hahn. I'm an assistant professor of GU Medical Oncology at MD Anderson Cancer Center in Houston, Texas, and I'm here at the ESMO Congress in Berlin. 

Patients with metastatic clear cell kidney cancer typically are treated with [a] first-line PD-1 checkpoint inhibitor plus either a CTLA-4 inhibitor or an angiogenesis-targeted therapy. When patients experience disease progression on one of these PD-1 checkpoint inhibitor combinations, the ESMO guidelines and other consensus guidelines recommend just choosing from one of a smorgasbord of different angiogenesis-targeted therapies, we have up to 7 to choose from. Now most of these drugs were approved when compared to old historical controls that we no longer use and we've never had direct head-to-head comparisons of these contemporary angiogenesis-targeted therapies. Additional background is that lenvatinib plus everolimus was approved based off of a phase 2 study, study 205, and in that study it had impressive efficacy data — PFS of over 12 months, objective response rate of 35%, and a median overall survival of 25 months but that was all after an angiogenesis-targeted therapy. We hypothesized that after PD-1 checkpoint inhibition, the combination of lenvatinib plus everolimus would significantly improve progression-free survival compared to another contemporary angiogenesis-targeted therapy, which is cabozantinib. 

LenCabo, this was an investigator-initiated phase 2 clinical trial where we randomized 90 total patients to either lenvatinib 18 mg plus everolimus 5 mg daily versus cabozantinib 60 mg daily. At randomization, patients were stratified based off of their prior receipt of angiogenesis-targeted therapy and their IMDC risk score. The primary end point for this study was progression-free survival. Secondary end points included objective response rate by RECIST, safety, and overall survival. You can look into the paper to see all the stats and the assumptions that we used. This study was designed and powered for progression-free survival. It was not designed, from a statistical perspective, for overall survival where you would ultimately need a much larger study.

For the primary end point of progression-free survival, lenvatinib plus everolimus significantly reduced the hazard for disease progression by 49% compared to cabozantinib. The median PFS in the lenvatinib plus everolimus arm was 15.7 months and it was 10.2 months with cabozantinib. This result was statistically significant. For some of the other secondary end points of interest, the objective response rate by RECIST was 53% with lenvatinib plus everolimus compared to 39% with cabozantinib and very few patients in either arm experienced primary progressive disease. That difference in objective response rate was not statistically significant between the 2 arms. For the final efficacy end point of overall survival, this was a very immature analysis of overall survival. Again, this study was not designed to assess overall survival. I believe 20 or 24 patients in total had passed away of the 86 who started treatment. For that analysis, lenvatinib plus everolimus was associated with a 5% increase in the hazard for death compared to cabozantinib but, the result was really inconclusive with a high p-value and a very wide 95% confidence interval where the results were still compatible with a lot of benefit favoring lenvatinib plus everolimus or a lot of harm against it — so just purely inconclusive for overall survival. We did look at toxicity and safety with the 2 different treatment arms. There were numerical differences between the 2 groups that were not significantly different. Lenvatinib plus everolimus had a higher incidence of treatment-related serious adverse events, grade ≥ 3 adverse events, and treatment discontinuation at 20% compared to 11% with cabozantinib. In contrast, cabozantinib had a higher numerical incidence of dose interruptions and dose reductions than lenvatinib plus everolimus did. Again, those results were not statistically significant between the 2 treatment arms. 

In conclusion, lenvatinib plus everolimus significantly improved progression-free survival versus cabozantinib after patients experienced disease progression on a PD-1 checkpoint inhibitor. Moving forward — where do we go from here.I think this study really asked the question and forces us as oncologists to reconsider what is the utility of mTOR inhibition. Everolimus is distinct in that it's an mTOR inhibitor, and that combination of lenvatinib plus everolimus is combining an angiogenesis-targeted therapy with an mTOR inhibitor. Looking forward, there are a lot of other novel combinations coming down the pipeline that will be reported out in the next couple of years. Many of these are looking at angiogenesis-targeted therapies plus HIF-2α inhibition, with either belzutifan or casdatifan, and we're going to have to weigh the results of those against what we just produced with the LenCabo study.[A] final statement would be that I think these results do inform clinical practice next week when people go into clinic. When physicians are seeing a patient who's experiencing disease progression on nivolumab plus ipilimumab, pembrolizumab plus axitinib, or adjuvant pembrolizumab within 12 months of discontinuing adjuvant pembrolizumab, I think you should think of these results when you're trying to choose that next angiogenesis-targeted therapy among the 7 different options listed. 

Source: 

Hahn A, 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 the 2025 ESMO Congress. October 17-21, 2025; Berlin, Germany. LBA94