A Single-arm, Multicenter, Phase 2 Study of Lenvatinib Plus Everolimus in Patients with Advanced Non-Clear Cell Renal Cell Carcinoma

Abstract

Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy.

Objective: To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC.

Design, setting, and participants: This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease.

Intervention: Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily.

Outcome measurements and statistical analysis: The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method.

Results and limitations: The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12-45). Median PFS was 9.2 mo (95% CI 5.5-not estimable), and median OS was 15.6 mo (95% CI 9.2-not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design.

Conclusions: Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination.

Patient summary: We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects.

Clinical registration: This trial is registered at ClinicalTrials.Gov as NCT02915783.

Keywords: Chromophobe; Everolimus; First-line treatment; Lenvatinib; Non-clear cell renal cell carcinoma; Papillary.

Fig. 1 –. Duration of treatment and tumor response by investigator assessment according to Response Evaluation Criteria in Solid Tumors version1.1.^a

BOR = best overall response; CR = complete response; PD = progressive disease; PR = partial response; NE = not evaluable; SD = stable disease. ^a The figure indicates the outcome at a patient’s first tumor assessment and then any subsequent change in tumor response status. ^b These patients had durable stable disease. ^c This patient had a complete response, but this response was not confirmed by the time of data cut-off, so the BOR for this patient is a partial response. ^d This patient had stable disease at first assessment and a subsequent partial response; since the partial response was not confirmed because of treatment discontinuation (patient’s choice), the BOR for this patient is stable disease.

Fig. 2 –. Percentage change in total sum of target lesion diameters from baseline to postbaseline nadir by investigator assessment according to Response Evaluation Criteria in Solid Tumors version 1.1. The analysis included patients with both baseline and at least one postbaseline target lesion assessment.

Fig. 3 –. Kaplan-Meier estimates of (A) PFS and (B) OS by investigator assessment according to Response Evaluation Criteria in Solid Tumors version 1.1. The survival estimates were truncated when fewer than five patients at risk remained.

CI = confidence interval; NE = not estimable; OS = overall survival; PFS = progression-free survival.