ASCO GU 2021: Phase II Trial of Lenvatinib at Two Starting Doses plus Everolimus in Patients with RCC: Results by Independent Imaging Review and Prior Immune Checkpoint Inhibition

( Lenvatinib is a multi-targeted TKI that is approved in combination with everolimus to treat patients with advanced renal cell carcinoma (RCC), following one prior antiangiogenic therapy. While the combination therapy regimen resulted in improvements in progression-free survival, patients treated with the regimen experience adverse events that often lead to dose reductions and interruptions.1 Study 218 was a phase II study evaluating lenvatinib 14 mg versus lenvatinib 18 mg, both in combination with everolimus 5 mg, for the treatment of clear cell RCC following treatment with a VEGF-targeted therapy. The primary endpoint for this study was previously presented, noting that the lenvatinib 14 mg arm did not demonstrate noninferiority versus the lenvatinib 18 mg arm for objective response rate as of week 24 by investigator assessment (OR 0.88, 90% CI 0.59-1.32). At the 2021 GU ASCO annual meeting, Dr. Sumanta Pal and colleagues presented results of an exploratory analysis of Study 218, evaluating the efficacy of lenvatinib 14 mg versus lenvatinib 18 mg, both in combination with everolimus 5 mg, per independent imaging review assessment and by prior immune checkpoint inhibitor status per investigator assessment.

In this trial, patients with measurable clear cell RCC (1 prior VEGF-targeted therapy; prior PD-1/PD-L1 therapy permitted) were randomly assigned 1:1 to lenvatinib 14 mg or 18 mg (starting dose) plus everolimus 5 mg daily. The trial schema is as follows:


There were 115 patients in the lenvatinib 14 mg arm that were titrated to lenvatinib 18 mg at cycle 2 as they did not experience intolerable grade 2 or any grade ≥3 treatment-related adverse events requiring dose reduction within cycle 1. This analysis assessed objective response rate and progression-free survival by independent imaging review per RECIST v1.1. Additionally, efficacy endpoints (objective response rate, progression-free survival, and overall survival) were analyzed by investigator assessment per RECIST v1.1 by prior immune checkpoint inhibitor status.

There were 311 patients (lenvatinib 14 mg arm, n=156; lenvatinib 18 mg arm, n=155) included in the efficacy analysis and 341 patients (lenvatinib 14 mg arm, n=173; lenvatinib 18 mg arm, n=168) included in the summary safety analysis. Objective response rate by independent imaging review (lenvatinib 14 mg arm: 39.7%, 95% CI 32.1–47.4; lenvatinib 18 mg arm: 38.7%, 95% CI 31.0–46.4) was similar between treatment arms. Progression free survival by independent imaging review was numerically longer in the lenvatinib 18 mg arm (median 12.9 months, 95% CI 9.2–17.1) versus the lenvatinib 14 mg arm (median 11.0 months, 95% CI 9.3–12.9). In 82 patients with prior immune checkpoint inhibitor therapy, for the lenvatinib 14 mg (n=43) versus 18 mg (n=39) arms (95% CI):

  • Objective response rate was 30.2% (17.2–46.1) versus 51.3% (34.8–67.6) by investigator assessment
  • Median progression-free survival was 12.0 months (8.9–16.7) versus 12.9 months (8.4–NE) by investigator assessment, HR 1.27, 90% CI 0.74-2.20
  • Median overall survival was 17.1 months (10.6–NE) versus 18.0 months (13.1–NE), HR 1.28, 90% CI 0.75-2.18

As previously reported, the safety profile was similar in both treatment arms: 71.7% of patients in the lenvatinib 14 mg arm and 76.8% of patients in the lenvatinib 18 mg arm had grade 3/4 treatment-related adverse events.

Dr. Pal concluded this presentation with the following summary points:

  • The objective response rate was similar between treatment arms and progression-free survival was numerically longer in the lenvatinib 18 mg arm per independent imaging review
  • Efficacy outcomes were generally numerically improved for the lenvatinib 18 mg arm compared with the lenvatinib 14 mg arm, regardless of prior immune checkpoint inhibitor therapy
  • As previously reported, safety was similar in both treatment arms
  • These results further support starting patients with RCC at the higher 18 mg dose of lenvatinib plus everolimus 5 mg
Presented by: Sumanta K. Pal, MD, Department of Medical Oncology & Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021


  1. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomized, phase 2, open-label, multi-centre trial. Lancet Oncol 2015;16(15):1473-1482.
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