Frontline Lenvatinib/Everolimus Combo Is Active in Non-Clear Cell RCC

The first-line combination of lenvatinib and everolimus elicited clinical activity in patients with advanced non-clear cell renal cell carcinoma.

The first-line combination of lenvatinib (Lenvima) and everolimus (Afinitor) elicited clinical activity in patients with advanced non-clear cell renal cell carcinoma (RCC), according to single-arm, phase 2 findings that were virtually presented during the 2020 International Kidney Cancer Symposium (IKCS).1

Specifically, data showed that the investigator-assessed objective response rate (ORR) was 25.8% (95% CI, 11.9%-44.6%); all responses were partial responses (PRs). Of the 8 patients who achieved a PR, 3 had papillary RCC, 4 had chromophobe histology, and 1 patient’s disease was unclassified.

Currently, lenvatinib, a multikinase inhibitor, in combination with the mTOR inhibitor everolimus is approved by the FDA for the treatment of patients with advanced RCC following treatment with 1 prior line of antiangiogenic therapy.2 RCC can be divided into 2 larger classifications, including clear cell and non-clear cell histologies, but clear cell is known to comprise of 75% to 80% of all RCC cases, leaving limited data in clinical trials depicting the non-clear cell RCC.

Patients with non-clear cell RCC may fall under multiple other histological subtypes, such as papillary, chromophobe, and unclassified. Among these patients with non-clear cell RCC, VEGF expression appears increased, as well as dysregulation of the mTOR pathway. Prior studies have explored the use of single-agent VEGF and mTOR inhibitors, which demonstrated low response frequency in patients with non-clear cell RCC.

The multicenter study explored the safety and efficacy of the combination, which was given in dosages of 18 mg once daily for lenvatinib and 5 mg once daily for everolimus. The study included patients with a histologically confirmed diagnosis of non-clear cell RCC with measurable disease per RECIST v1.1 criteria. Patients must have had no prior chemotherapy for advanced disease, and their ECOG performance status had to be either 0 or 1.

At baseline, 14 patients (45.2%) were intermediate risk, 7 (22.6%) poor risk, 1 (3.2%) had favorable risk, while 9 (29.0) were missing this information. Prior nephrectomies were experienced by 11 patients (35.5%). The sites of metastases at baseline was lymph node (71.0%), liver (29.0%), lung (25.8%), bone (22.6%), and adrenal (12.9%), or other (35.5%), and the number of metastatic sites was 1 (38.7%), 2 (32.3%), and 3 or more (29.0%).

Thirty-one patients were enrolled, of which 20 had papillary disease, 9 had chromophobe, and 2 were unclassified, and all patients received the combination. The median age was 64 years (range, 38-85), and the majority were male (64.5%), Caucasian (87.1%), and had an ECOG performance status of 0 (74.2%).

The primary end point of the study was ORR by investigator assessment, and secondary end points included progression-free survival (PFS) by investigator assessment, overall survival (OS), and safety and tolerability of the combination.

Most patients experienced a decrease in their tumor size when treatment with the combination of lenvatinib and everolimus, according to analysis of the patients with both baseline and at least 1 post-baseline target lesion assessments, which excluded 3 nonevaluable patients.

Results also showed that the investigator-assessed ORRs in the papillary, chromophone, and unclassified RCC subgroups were 15.0%, 44.0%, and 50.0%, respectively. Stable disease was observed in 18 patients (58.1%), including 14 (70.0%) in the papillary group, 3 (33.3%) in the chromophobe group, and 1 (50%) in the unclassified, while progressive disease was observed in 3 (9.7%) of patients overall, including 2 (10.0%), 1 (11.1%), and 0, respectively

Overall, the clinical benefit rate (CBR) in the overall population was 61.3% (95% CI, 42.2-78.2), and the disease control rate (DCR) was 83.9% (95% CI, 66.3-94.5). These rates were, respectively, 50.0% (95% CI, 27.2-72.8) and 85.0% (95% CI, 62.1-96.8) in the papillary group, 77.8% (95% CI, 40.0-97.2) and 77.8% (95% CI, 40.0-97.2) in the chromophobe group, and 100.0% (95% CI, 15.8-100.0) and 100.0% (95% CI, 15.8-100.0).

Investigators also assessed ORR by Independent Imaging (IIR) as an exploratory end point and found the results to be similar to the Investigator Assessment results. Here, the ORR was 25.8% (95% CI, 11.9-44.6), which included 8 PRs, 14 cases of stable disease, and 6 with progressive disease. The CBR was 51.6% (95% CI, 33.1-69.8), and the DCR was 71.0% (95% CI, 52.0-85.8).

The median PFS was 9.23 months (95% CI, 5.49-not evaluable [NE]) by investigator assessment and 5.62 (95% CI, 3.48-NE) by IIR. The median OS was 15.64 months (95% CI, 9.23-NE).

Treatment-emergent adverse events (TEAS) occurred in 100.0% of the patients, and these were treatment-related in 29 patients (93.5%). TEAEs of grade 3 or higher severity were observed in 21 patients (67.7%), and these were treatment-related in 15 (48.4%). Ten patients (32.2%) with TEAEs withdrew or discontinued treatment, 14 (45.2%) had dose reductions, 21 (67.7%) had an interruption, and 25 (80.6%) had a dose reduction or interruption.

The safety profile for this combination appeared similar to its established profile from prior studies, and no new safety signals were observed.

The most common TEAEs of any grade included fatigue (71.0%), diarrhea (58.1%), decreased appetite (54.8%), nausea (54.8%), and vomiting (51.6%). In terms of grade 3 or higher TEAEs, the most common included hypertension (16.1%), malignant neoplasm progression (12.9%), and diarrhea (9.7%); fatigue, nausea, vomiting, proteinuria, and platelet count decreased (6.5% each); and abdominal pain, back pain, fall, hyperglycemia, and edema (3.2% each).


1. Hutson TE, Michaelson MD, Kuzel TM, et al. A phase 2 study of lenvatinib plus everolimus in patients with advanced non-clear cell renal cell carcinoma. Presented at: 2020 International Kidney Cancer Symposium; November 6-7, 2020; virtual.

2. Lenvatinib in combination with everolimus. News release. FDA. May 16, 2016. Accessed November 6, 2020.

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