ASCO GU 2018: The CLEAR study: A Phase 3 Trial to Compare Efficacy and Safety of Lenvatinib in Combination with Everolimus or Pembrolizumab Versus Sunitinib Alone in First-line Treatment of Patients with Metastatic Renal Cell Carcinoma

San Francisco, CA (UroToday.com) Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor alpha, and RET and KIT. Based on a phase 2 study,1 LEN was approved in combination with everolimus (EVE) for the treatment of metastatic renal cell carcinoma (RCC) following 1 prior VEGF-targeted therapy. A phase 1b/2 study of LEN in combination with pembrolizumab (PEM) in patients (pts) with RCC is also underway.

In this Trials in Progress abstract, the authors report the design of a multicenter, open-label, phase 3 trial of LEN plus EVE or PEM vs sunitinib (SUN; a standard therapy for RCC) as first-line treatment for advanced RCC.

Inclusion criteria:
Pts aged ≥ 18 years with confirmed advanced RCC diagnosis, ≥ 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Karnofsky Performance Status ≥ 70, controlled blood pressure, and adequate blood coagulation, renal, hepatic, and bone marrow function are eligible. Histology must be clear cell RCC.

Study design:
Patients will be randomized 1:1:1 to receive LEN 18 mg/d + EVE 5 mg/d, LEN 20 mg/d + PEM 200 mg every 3 weeks, or SUN 50 mg/d (on a schedule of 4 weeks on treatment followed by 2 weeks off) until disease progression, unacceptable toxicity, withdrawal of consent, or study end.

Outcomes:
The primary endpoint: superiority of LEN+EVE or LEN+PEM over single-agent SUN as first-line treatment for advanced RCC in improving progression-free survival (PFS)
Secondary endpoints: comparison of objective response rate (ORR), overall survival, PFS on next-line therapy, health-related quality of life, and safety and tolerability in pts receiving LEN+EVE or LEN+PEM vs SUN
Exploratory endpoints: PFS in the LEN+PEM arm using immune-related RECIST, comparison of duration of response, disease control rate, and clinical benefit rate in pts treated with LEN+EVE or LEN+PEM vs SUN, and analysis of the relationship between blood biomarkers and outcome.

Interestingly, no interim analysis is planned for efficacy or futility.

Enrollment of 735 pts is planned to achieve 90% power at 2-sided α = 0.05 to detect a difference in ≥ 1 of the primary comparisons.

For more information, look up the clinical trial: NCT02811861

Speaker: Robert Motzer, MD

Co-Authors: Viktor Grünwald, Thomas E. Hutson, Camillo Porta, Thomas Powles, Masatoshi Eto, Corina E. Dutcus, Mahadi Ali Baig, Lea Dutta, Di Li, Toni K. Choueiri; Memorial Sloan Kettering Cancer Center, New York, NY; Hannover Medical School, Niedersachsen, Germany; Baylor University Medical Center, Dallas, TX

Institution(s): Memorial Sloan Kettering Cancer Center, New York, NY; Hannover Medical School, Niedersachsen, Germany; Baylor University Medical Center, Dallas, TX; IRCCS San Matteo University Hospital Foundation, Pavia, Italy; Barts Health NHS Trust – St Bartholomew’s Hospital, London, United Kingdom; Kyushu University, Fukuoka, Japan; Eisai Inc., Woodcliff Lake, NJ; Dana-Farber Cancer Institute/ Brigham and Women’s Hospital/ Harvard Medical School, Boston, MA

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA
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