The Phase 3 CLEAR Trial: Lenvatinib Plus Pembrolizumab or Everolimus for Advanced RCC - Episode 1

Frontline Therapy Options for Advanced RCC and Combining IO and TKI in the First-line Setting in mRCC

A summary of frontline treatment options for metastatic renal cell carcinoma and the rationale for the combination of lenvatinib plus pembrolizumab.

Transcript:

Moshe Ornstein, MD, MA: Hello. My name is Dr Moshe Ornstein. I’m a GU [genitourinary] medical oncologist at the Cleveland Clinic Taussig Cancer Institute in Ohio, where I focus on kidney cancer research and the clinical care of patients with renal cell carcinoma. Today, this Targeted Oncology program is going to provide investigator perspectives on the phase 3 CLEAR trial, which is lenvatinib [Lenvima] plus pembrolizumab [Keytruda] or everolimus [Afinitor] for advanced renal cell carcinoma.

Prior to the publication of the CLEAR trial, which compared pembrolizumab and lenvatinib versus sunitinib [Sutent] in treatment-naïve renal cell carcinoma, there were 2 main categories of IO [immuno-oncology]-based regimens for the treatment of patients in frontline metastatic RCC [renal cell carcinoma]. Broadly, they could be broken down to IO/IO, which is a doublet immunotherapy which is ipilimumab [Yervoy] and nivolumab [Opdivo]. On the other side is the general category of IO/TKI [tyrosine kinase inhibitor] immunotherapy with tyrosine kinase inhibitors, which prior to pembrolizumab and lenvatinib being approved, included cabozantinib [Cabometyx] and nivolumab, axitinib [Inlyta] and pembrolizumab, and axitinib and avelumab [Bavencio]. With those combinations having been published and approved by the FDA [Food and Drug Administration] for their efficacy, the combination of lenvatinib and pembrolizumab was the last piece of the puzzle to have these doublet therapies to be able to decide what the optimal frontline regimen is for patients with treatment-naïve RCC.

Prior to discussing the trial design and the general outcomes for the CLEAR trial, it’s important to understand the mechanisms of actions of these drugs and why they were put together in the first place. Pembrolizumab is a well-known PD-1 [programmed cell death protein 1] inhibitor that has some single-agent efficacy with metastatic renal cell carcinoma and has also been paired with axitinib as part of the axitinib and pembrolizumab combination for treatment-naïve RCC. Lenvatinib, the VEGFR [vascular endothelial growth factor receptor], is really a multikinase inhibitor, but primarily it’s a VEGFR TKI. The rationale for combining them is that there was prior data for this combination in a phase 1b/2 trial and there are also a host of other trials combining VEGFR inhibition with immunotherapy. The thought is—and this has been proven by the multiple positive trials in this setting—that not only is there an additive effect, but there’s likely a synergistic effect as well.

Transcript edited for clarity.