ASCO 2021: Analysis of the CLEAR Study in Patients with Advanced Renal Cell Carcinoma (RCC): Depth of Response and Efficacy for Selected Subgroups in the Lenvatinib (LEN) + Pembrolizumab (PEMBRO) and 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 Kidney and Bladder Poster session at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Viktor Grunwald presented a secondary analysis of the CLEAR trial examining treatment effect in various subgroups.

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 efficacy outcomes including PFS, OS, and ORR stratified by IMDC risk group (favorable and intermediate/poor) and the presence of a target kidney lesion at baseline (post hoc analysis). Further, post hoc 6-month landmark analyses examined the association between tumor shrinkage during this time and OS. Tumor assessments were performed by independent review committee per RECIST v1.1.

The CLEAR trial included 1069 patients of whom 355 were assigned to lenvatinib + pembrolizumab and 357 to sunitinib. The median follow-up was 27 months for patients randomized to lenvatinib + pembrolizumab group and 26 months for those randomized to sunitinib.

Progression-free survival was longer for those who were randomized to lenvatinib + pembrolizumab (median 22.1 months, n=243) than sunitinib (median 5.9 months, n=229) in both the IMDC-intermediate/poor subgroup (HR 0.36 [95% CI 0.28-0.47]) and in the IMDC-favorable subgroup (median 28.1 months, n=110 vs median 12.9 months, n=124; HR 0.41 [95% CI 0.28-0.62]). While OS similarly favored lenvatinib + pembrolizumab compared to sunitinib in the IMDC-intermediate/poor subgroup (HR 0.58 [95% CI 0.42-0.80]), there were too few events in the IMDC-favorable to provide an adequate analysis (HR 1.15, 95% CI 0.55-2.40). Assessing ORR, the authors similarly found a benefit to lenvatinib + pembrolizumab compared to sunitinib in both the IMDC-intermediate/poor subgroup (72.4% vs 28.8%; odds ratio 6.60 [95% CI 4.39-9.90]) and the IMDC-favorable subgroup (68.2% vs 50.8%; odds ratio 2.00 [95% CI 1.17-3.42]).

Among those with target kidney lesions, PFS, OS, and ORR were improved with lenvatinib + pembrolizumab vs sunitinib. Further complete responses were durable with 7.3% of patients treated with lenvatinib + pembrolizumab who achieved CR maintaining this response at 24 months and 74.3% maintaining it at 36 months.


The 6-month landmark analysis in the lenvatinib + pembrolizumab group showed that the OS rate at 24 months was 100% (95% CI not estimable [NE]-NE) for those patients with confirmed CR per RECIST v1.1 and 91.7% (95% CI 53.9-98.8) both for patients with either 100% or 75-100% target-lesion reduction.


The authors conclude that lenvatinib + pembrolizumab conferred a consistent survival benefit, compared to sunitinib, across IMDC risk groups and in patients with or without target kidney lesions. Further, among those with target kidney lesions, response in these lesions at 6 months was associated with long-term overall survival with similar benefits for those with >75% reduction in target lesion size.

Presented by: Viktor Gr├╝nwald, MD, PhD, University Hospital Essen, Essen, Germany.

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
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