ASCO GU 2021: Phase 3 Trial of Lenvatinib plus Pembrolizumab or Everolimus Versus Sunitinib Monotherapy as a First-Line Treatment for Patients with Advanced Renal Cell Carcinoma (CLEAR Study)

( The treatment landscape for first-line therapy among patients with metastatic renal cell carcinoma (mRCC) has changed dramatically over the past 2 years. In 2018, the publication of the CheckMate214 data demonstrated a survival benefit for patients treated with nivolumab and ipilimumab compared with sunitinib in intermediate and poor-risk mRCC, ushering in the immunotherapy era for mRCC. The subsequent publication of the JAVELIN Renal 101, KEYNOTE-426, and CheckMate-9ER studies demonstrated the superiority of avelumab and axitinib, pembrolizumab, and axitinib, and nivolumab and cabozantinib compared to sunitinib in this disease space. Recently, lenvatinib and everolimus demonstrated prolonged progression-free survival, compared to everolimus, in the second-line setting, and lenvatinib and pembrolizumab have shown promise in a phase I/II setting. In a plenary abstract presentation in the Oral Abstract Session: Renal Cell Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Robert Motzer and colleagues describe the results of the CLEAR study examining first-line lenvatinib and everolimus or lenvatinib and pembrolizumab versus sunitinib in patients with advanced RCC. Concurrent with the presentation, CLEAR was published in the New England Journal of Medicine.1

The authors recruited patients with advanced RCC who had not received prior systemic therapy. These patients were then randomized (1:1:1) to receive lenvatinib 20 mg orally once daily + pembrolizumab 200 mg IV every 3 weeks (weeks); or lenvatinib 18 mg + everolimus 5 mg orally once daily; or sunitinib 50 mg orally once daily (4 weeks on/2 weeks off in 6-weekly cycles). Randomization was stratified by geographic region and MSKCC prognostic group.


The authors assessed the primary endpoint of progression-free survival (PFS) by Independent Review Committee per RECIST v1.1 with key secondary endpoints including overall survival (OS), objective response rate (ORR) and safety. A sequential approach was used to test PFS first, then OS and ORR. PFS and OS were compared across arms by a stratified log-rank test; hazard ratios (HRs) were estimated by a stratified Cox regression model.

The authors randomized 1069 patients, 355 who received lenvatinib and pembrolizumab, 357 who received lenvatinib and everolimus, and 357 who received sunitinib. The baseline characteristics of the study population were in keeping with those observed in other first-line mRCC trials. Notably, intermediate and poor-risk disease comprised just over 70% of the cohort.

As of a data-cut off of August 28, 2020, the median follow-up was 27 months. At this time,

PFS was significantly improved among patients receiving lenvatinib and pembrolizumab (median 24 months) vs sunitinib (median 9 months; HR 0.39, 95% CI 0.32–0.49) and among patients receiving lenvatinib and everolimus (median 15 months) vs sunitinib (HR 0.65, 95% CI 0.53–0.80).


The benefit of lenvatinib and pembrolizumb versus sunitinib with respect to progression-free survival was consistent across many subgroups, comprising age, sex, geographic region, PD-L1 expression, IMDC risk group, prior nephrectomy, and sarcomatoid features.


Similar consistency of findings was observed for lenvatinib and everolimus versus sunitinib.

Further, OS was significantly longer among patients who received lenvatinib and pembrolizumab compared to sunitinib (HR 0.66, 95% CI 0.49–0.88), whereas there was no significant difference in OS for patients receiving lenvatinib and everolimus compared to sunitinib (HR 1.15, 95% CI 0.88–1.50).


As with progression-free survival, these findings were consistent across all relevant tested subgroups for the comparison of lenvatinib and pembrolizumab, except patients with favourable risk group.


ORR was significantly greater with lenvatinib and pembrolizumab (ORR 71%; complete response [CR] 16%) vs sunitinib (ORR 36%; CR 4%; odds ratio 4.35, 95% CI 3.16–5.97) and lenvatinib and everolimus (ORR 54%; CR 10%) vs sunitinib (odds ratio 2.15, 95% CI 1.57–2.93).


Grade ≥3 treatment-related adverse events occurred in 72% of patients (pts) in the lenvatinib and pembrolizumab arm and 73% of pts in the lenvatinib and everolimus arm compared with 59% of pts in the sunitinib arm.


A relatively similar profile was identified in the lenvatinib and everolimus versus sunitinib comparison.

In conclusion, Dr. Motzer concluded that lenvatinib and pembrolizumab demonstrated significant improvements in PFS, OS, and ORR compared to sunitinib while lenvatinib and everolimus demonstrated improvements in PFS and ORR, but not ORR.

Presented by: Robert J. Motzer, MD, Memorial Sloane Kettering Cancer Center, New York, NY

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021


  1. Motzer R, Alekseev B, Rha SY et al. "Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma." The New England Journal of Medicine. 2021. 10.1056/NEJMoa2035716.