ASCO 2021: Post Hoc Analysis of the CLEAR Study in Advanced Renal Cell Carcinoma (RCC): Effect of Subsequent Therapy on Survival Outcomes in the Lenvatinib (LEN) + Everolimus (EVE) Versus Sunitinib (SUN) Treatment Arms

( There have been transformational changes in first-line therapy for patients with metastatic renal cell carcinoma (RCC) in the past three years. Foremost among these is the move from monotherapy to combination approaches. While CheckMate 214 first brought combination therapy with dual checkpoint inhibition (nivolumab and ipilimumab) to the forefront, subsequent studies have examined combinations of immune checkpoint inhibitors and tyrosine-kinase inhibitors in the first-line setting. One such combination is lenvatinib and pembrolizumab which, in the CLEAR trial (NCT02811861), was found to significantly improve progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) as first-line therapy for patients with advanced RCC. In the clear trial, the combination of lenvatinib and everolimus improved PFS but not overall survival. In the Kidney and Bladder Poster session at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Thomas Hutson presented results of post hoc analyses of the CLEAR trial to understand the effect of subsequent therapy on overall survival.

While the CLEAR trial has been previously presented and published, to briefly summarize, this multicenter, open-label, randomized, phase randomly assigned patients with advanced RCC who had not previously received systemic therapy in a 1:1:1 fashion to 1 of 3 treatment arms: lenvatinib 20 mg orally QD + pembrolizumab 200 mg IV Q3W; lenvatinib 18 mg + everolimus 5 mg orally QD; or sunitinib 50 mg orally QD (4 weeks on/2 weeks off).


In this analysis, the authors examined overall survival by subsequent systemic anticancer medication among patients who received lenvatinib + everolimus or sunitinib. Hazard ratios (HR) comparing lenvatinib + everolimus to suntinib were derived from stratified (geographic region and MSKCC prognostic risk groups) Cox proportional hazards model.

Among 1069 patients with advanced RCC randomized in the CLEAR study, 357 patients were randomly assigned to each of the lenvatinib + everolimus and SUN arms. The median duration of survival follow-up was 27 months for patients randomized to lenvatinib + everolimus and 26 months for those randomized to sunitinib.

Given the shorter median duration of on-protocol study treatment for patients randomized to sunitinib (7.8 months) compared to those receiving lenvatinib + everolimus (11.0 months), a greater proportion of patients in the sunitinib arm received subsequent anticancer therapy during survival follow-up (lenvatinib + everolimus n=167 compared to sunitinib n=206). Among those who received subsequent therapy, patients randomized to lenvatinib + everolimus had a longer median time from randomization to initiation of subsequent therapy compared to those randomized to sunitinib (8.0 vs 6.6 months, respectively).


There were no statistically significant differences in overall survival between patients initially randomized to lenvatinib + everolimus compared to sunitinib in the overall population, among those who received no subsequent anti-cancer treatments, and among those with no subsequent immunotherapy.

In a subset of patients treated in the United States (including 62 patients randomized to lenvatinib + everolimus and 61 patients randomized to sunitinib) with similar utilization of subsequent anti-cancer therapies (62.9% for those randomized to lenvatinib + everolimus vs 65.6% for those randomized to sunitinib), overall survival was comparable (HR 0.95, 95% CI 0.51-1.76).


Further survival analysis of adjusted OS account for switching to any subsequent anticancer medication by a two-stage estimation method demonstrated comparable results (HR 0.84, 95% CI 0.64-1.12).

In terms of adverse events, updated analyses were consistent with the initial report of the CLEAR trial. Thus, the authors conclude that lenvatinib + everolimus met the primary endpoint of the CLEAR trial with significant benefits in progression-free survival compared to sunitinib but no difference in overall survival. This post hoc analysis provided evidence that subsequent systemic anticancer therapy affected these results. However, when accounting for the confounding effects of secondary anticancer therapies, OS was comparable for the two treatment arms.

Presented by: Thomas E. Hutson, DO, PharmD, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021