Upfront lenvatinib plus everolimus active in advanced non-clear cell renal cell carcinoma

"There is unmet medical need in trying to determine if there is a differential benefit to using one therapy over another in the non-clear cell setting," Thomas E. Hutson, DO, PharmD.

Combination therapy with lenvatinib (Lenvima) and everolimus (Afinitor) showed promising clinical activity in the frontline setting for patients with advanced non-clear cell renal cell carcinoma (nccRCC), according to findings presented during the 2020 International Kidney Cancer Symposium.1

The objective response rate (ORR) was 25.8% with the combination, comprising all partial responses. An additional 58.1% of patients reached stable disease (SD), for a disease control rate of 83.9%.

While plenty of research is available in the much more common clear cell RCC setting, there is limited available prospective data for patients with non-clear cell histology, explained lead study author Thomas E. Hutson, DO, PharmD.

“The regulatory authorities in both the United States and Europe have given the oral TKIs and other therapies for RCC very broad labels, so that they can be utilized in both the clear cell and non-clear cell settings. But there is unmet medical need in trying to determine if there is a differential benefit to using one therapy over another in the non-clear cell setting,” said Hutson, of Texas Oncology‐Baylor Charles A. Sammons Cancer Center.

The study included 31 patients with nccRCC who had not received chemotherapy for advanced disease. The median age was 64 years (range, 38-85), 64.5% of patients were male, and 35.5% were female. Overall, 87.1% of patients were White, 74.2% had an ECOG performance status of 0, and 35.5% had prior nephrectomy. About two-thirds (64.5%) of patients had papillary disease, with 29% having chromophobe and the remainder having unclassified histology.

All patients had metastatic disease, with over 60% of patients having at least 2 sites of metastases. Additionally, over two-thirds of patients had intermediate or poor-risk disease.

All patients received lenvatinib at 18 mg orally once daily combined with everolimus at 5 mg orally once daily. ORR per investigator assessment was the primary outcome measure. Secondary outcome measures included progression-free survival (PFS) and overall survival (OS).

Among patients with papillary histology, the ORR was 15% and the SD rate was 70% for a disease control rate of 85%. In the subgroup of patients with chromophobe histology, the rates were 44.4%, 33.3%, and 77.8%, respectively.

Across all patients, the median PFS was 9.23 months by investigator assessment and 5.62 months by independent review. The median OS was 15.64 months.

“The safety profile observed in this study was similar to the established profile of the study drug combination, with no new safety signals,” said Hutson.

The most common treatment-emergent adverse events (TEAEs) occurring across all grades included fatigue (71%), diarrhea (58.1%), decreased appetite (54.8%), nausea (54.8%), vomiting (51.6%), stomatitis (38.7%), decreased weight (38.7%), hypertension (32.3%), abdominal pain (29%), dyspnea (25.8%), epistaxis (25.8%), headache (25.8%), insomnia (25.8%), proteinuria (25.8%), arthralgia (22.6%), back pain (22.6%), and dysphonia (22.6%).

Overall, 67.7% of patients had grade ≥3 TEAEs. The most frequently occurring grade ≥3 AEs included hypertension (16.1%), malignant neoplasm progression (12.9%), diarrhea (9.7%), fatigue (6.5%), nausea (6.5%), vomiting (6.5%), proteinuria (6.5%), decreased platelet count (6.5%), abdominal pain (3.2%), back pain (3.2%), fall (3.2%), hyperglycemia (3.2%), and peripheral edema (3.2%).

Treatment discontinuation, dose reductions, and dose interruptions related to study treatment occurred in 32.3%, 45.2%, and 67.7% of patients, respectively. Serious TEAEs were experienced by 35.5% of patients. There were no treatment-related deaths.

The combination of lenvatinib and everolimus is approved by the FDA for the treatment of patients with advanced RCC following one prior antiangiogenic therapy. Everolimus is also approved by the FDA for single-agent use as a treatment for patients with advanced RCC after failure of treatment with sunitinib (Sutent) or sorafenib (Nexavar).


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. Abstract 1.