PFS Benefit With Lenvatinib/Everolimus Shows Importance of Prioritizing Efficacy Data in ccRCC Treatment Decision-Making

The combination of lenvatinib (Lenvima) and everolimus (Afinitor) significantly prolonged progression-free survival (PFS) vs cabozantinib (Cabometyx) in patients with metastatic clear cell renal cell carcinoma (ccRCC) who had progressed on prior PD-1–directed immune checkpoint inhibitors, although the toxicity profile of this regimen remains crucial to consider when weighing the risks vs benefits for individual patients, according to Andrew W. Hahn, MD. 

In an interview with OncLive® during the 2025 ESMO Congress, Hahn discussed the efficacy and safety of combining lenvatinib with everolimus in this population, the need for more conclusive follow-up data from the phase 2 LenCabo trial (NCT05012371), topics for future analyses of the LenCabo results, and the importance of managing treatment-related toxicities and balancing PFS outcomes with quality of life (QOL) considerations.

“There’s been a lot of discussion of balancing the benefit we’ve observed with PFS [with lenvatinib plus everolimus] with an increase in toxicity, although [this increase] wasn’t statistically significant between the 2 groups,” Hahn said in the interview.

Hahn is an assistant professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

Notably, lenvatinib plus everolimus was FDA approved in 2016 for the treatment of patients with advanced RCC following antiangiogenic therapy based on findings from the phase 2 Study 205 (NCT01136733).¹ However, this combination had not been studied against contemporary second- and later-line treatments for patients who have progressed on an immune checkpoint inhibitor (ICI).² Thus, the LenCabo trial compared lenvatinib plus everolimus vs the TKI cabozantinib, which is FDA approved for the treatment of patients with advanced RCC who had previously received antiangiogenic therapy.^2,3

OncLive: What was the mechanistic rationale for combining lenvatinib with the mTOR inhibitor everolimus in metastatic ccRCC? How might this dual mechanism of action contribute to overcoming resistance after ICIs?

Hahn: In second-line or later treatments for metastatic clear cell kidney cancer, a group of 5 to 7 different angiogenesis-targeted therapies are potential treatment options. Of those, the only one that combines with an mTOR inhibitor is lenvatinib. The underlying hypothesis was that by combining an angiogenesis-targeted therapy with an mTOR inhibitor, we would end up prolonging the time to disease progression compared with an angiogenesis inhibitor by itself. That was the rationale and why we suspected that lenvatinib plus everolimus would improve time to disease progression compared with cabozantinib.

What was the design of the LenCabo study?

This was a randomized, multicenter clinical trial [conducted at] 3 total centers. It was an investigator-initiated trial, and the patients who were enrolled had metastatic ccRCC, had previously been treated with 1 to 2 prior lines of systemic therapy, and had previously progressed on a PD-1–directed checkpoint inhibitor, or had become intolerant to PD-1–directed checkpoint inhibitors and then subsequently experienced disease progression. In total, we enrolled 90 patients and randomly assigned them in a 1:1 fashion to receive either lenvatinib at 18 mg [per day] plus everolimus at 5 mg [per day] vs [daily] cabozantinib at the 60-mg dose.

Patients were stratified at randomization based on their International Metastatic Renal Cell Carcinoma Database Consortium risk score, as well as whether they had previously received an angiogenesis-targeted therapy. The primary end point was PFS. Secondary end points included overall response rate [ORR], overall survival [OS], and safety.

How did the efficacy of lenvatinib plus everolimus compare with that of cabozantinib in patients with metastatic ccRCC?

Lenvatinib plus everolimus was associated with a significant 49% reduction in [the risk of] disease progression compared with cabozantinib [HR, 0.51; 95% CI, 0.29-0.89; P = .02]. The median PFS with lenvatinib plus everolimus was 15.7 months compared with 10.2 months with cabozantinib. For secondary end points, we evaluated ORR by RECIST [criteria]. This was [52.6%] with lenvatinib plus everolimus compared with [38.6%] with cabozantinib. That result was not statistically significant between the 2 groups.

For the final efficacy end point, we evaluated OS. This was an immature evaluation. Twenty-four of 86 patients had died; most of the patients are still alive and doing well. But from an OS evaluation standpoint, we had broad 95% CIs. The 95% CI [for the OS HR] ranged from a [53%] improvement with lenvatinib plus everolimus to an approximate 100% worsening with it. [These findings were] inconclusive.

Although lenvatinib and cabozantinib share several targets, their toxicity profiles differ. What safety considerations should guide the selection between these two agents for patients who are eligible for either option?

We saw more serious adverse effects [AEs], grade 3 or higher treatment-related AEs, and treatment discontinuation with lenvatinib plus everolimus compared with cabozantinib. The treatment discontinuation rate was 20% with lenvatinib plus everolimus compared with [10.9%] with cabozantinib. The toxicity that drove most treatment discontinuations with lenvatinib plus everolimus was nephrotic-range proteinuria. I suspect that there are many [oncologists] who are not routinely checking urine protein-to-creatinine ratios, so [this result] may not apply to everyone’s clinic. [However, we needed to be] dogmatic on a clinical trial. [Regarding] common AEs that we expect from angiogenesis-targeted therapies, the incidence of fatigue and diarrhea was similar between the 2 arms. We saw more proteinuria and hypertension with lenvatinib plus everolimus, and more mucositis and hand-foot syndrome with cabozantinib.

How do you choose between the 2 [study] regimens? If a patient is young, healthy, doing well, and has handled prior therapies, I would argue that you’d prioritize the PFS data and manage the toxicities. These toxicities are manageable with dose interruptions and dose reductions. For that patient, I’d favor lenvatinib plus everolimus. In contrast, if you have a patient who’s older, frailer, or has had prior significant issues with handling angiogenesis-targeted therapies, maybe you’d argue for cabozantinib, although the difference [in toxicities] was not statistically significant between the 2 groups.

What additional questions will be important to address to optimally position lenvatinib plus cabozantinib in the metastatic ccRCC treatment paradigm?

In the future, there will be [a few] main subsequent analyses, papers, and presentations coming out of this clinical trial. One will evaluate QOL and changes in body composition, asking: How much do we know about how these medicines can cause loss of muscle mass? How much muscle mass loss do we see? Does this differ between the [2 regimens]? That will be investigating the tolerability of the 2 regimens.

[Additionally], hopefully in approximately 1 year, we’re going to be reporting the final OS data. The study is not designed to test OS. I doubt we’re going to see a significant difference because the study is not powered in that way, but hopefully we’ll see trends that’ll give oncologists more confidence in whatever decisions they make from these data.

The final [additional study] is going to ask translational questions using plasma or blood that’s available from the patients who were treated. We’re trying to figure out exactly what those questions are going to be. They might be: Which patients benefit from mTOR inhibition and which patients do not? [We may also] collapse the two treatment arms into one and evaluate bigger prognostic markers like KIM-1 or residual circulating tumor DNA.

Disclosures: Hahn reported serving in advisory board consulting roles with Janssen, Intellisphere, AVEO, Exelixis, Eisai, Pfizer, and Tolmar; receiving honoraria from Medscape, Binaytara Foundation, Projects in Knowledge, Curio Science, Dava Oncology, IDEOlogy Health, Mashup Media, and MJH Life Sciences; receiving travel support from Dava Oncology and Tolmar; and receiving institutional funding from Bayer, Bristol Myers Squibb, Eisai, and Halda Therapeutics.

References

1. Lenvatinib in combination with Everolimus. FDA. Updated May 16, 2016. Accessed January 9, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/lenvatinib-combination-everolimus
2. Hahn AW, Chahoud J, Skelton WP, 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). Ann Oncol. Published online October 17, 2025. doi:10.1016/j.annonc.2025.10.009
3. Cabozantinib (Cabometyx). FDA. April 25, 2016. Accessed January 9, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/cabozantinib-cabometyx