Lenvatinib Combo Shows Promising Findings in Phase 2 Study of Non-Clear Cell Renal Cell Carcinoma

Lenvatinib (Lenvima) in combination with everolimus demonstrated anti-tumor activity as treatment of patients with advanced non-clear cell renal cell carcinoma (nccRCC) in the frontline setting, according to findings from a phase 2 clinical trial presented in a poster during the 2020 International Kidney Cancer Symposium (IKCS).¹

Lenvatinib, the multitargeted tyrosine kinase inhibitor, in combination with the mTOR inhibitor everolimus is currently 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 nccRCC.¹

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

The single-arm 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 nccRCC with measurable disease per RECIST v1.1. Patients had to have 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%).

A total of 31 patients enrolled in the study, 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 objective response rate (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.

By Investigator Assessment, the ORR was 25.8% (95% CI, 11.9%-44.6%), and all responses were partial responses (PRs). Of the 8 patients who achieved a PR, 3 were from the papillary group, 4 from the chromophobe group, and 1 from the unclassified, with ORRs of 15.0%, 44.0%, and 50.0% in these groups, 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.

The clinical benefit rate in the overall population was 61.3% (95% CI, 42.2-78.2), and the disease control rate 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% (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. The ORR by Independent Imaging Review (IIR), in which the outcomes were similar to the Investigator Assessment. The ORR with this combination of lenvatinib and everolimus was 25.8% (95% CI, 11.9-44.6), which included 8 partial responses, 14 cases of stable disease, and 6 progressive disease. The clinical benefit rate was 51.6% (95% CI, 33.1-69.8), and the disease control rate 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).

_References

_{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 IKCS; November 6-7, 2020. Virtual.}

_{2. Lenvatinib in combination with everolimus. News Release. FDA. May 16, 2016. Accessed November 6, 2020. https://bit.ly/3p5igss​}