The CLEAR Trial: Lenvatinib Plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma - Episode 2

Combining I/O and TKI in Frontline mRCC

The rationale for investigating the combinations of lenvatinib plus pembrolizumab and lenvatinib plus everolimus as frontline therapy for metastatic renal cell carcinoma.

Chung-Han Lee, MD, PhD: Lenvatinib plus pembrolizumab was a very interesting combination to use together. As you all know, lenvatinib is a multi–tyrosine kinase inhibitor targeting the VEGF signaling pathway. So it inhibits VEGFR receptor 1-3 and also FGF receptor 1-4. Along with some other more minor tyrosine kinases.

This was originally studied in combination with everolimus and is FDA approved for metastatic kidney cancer in patients who have progressed on at least 1 prior VEGF-targeted therapy. Pembrolizumab is a very well-known PD-1 inhibitor that works by inactivating 1 of the key immune checkpoints. Pembrolizumab has been studied in multiple malignancies and demonstrated all levels of clinical efficacy. There are some preclinical data that demonstrated that the combination of VEGF-targeted signaling plus immune checkpoint inhibitor leads to enhanced immune responses. It was hypothesized that the combination of these 2 compounds would lead to at least a positive interaction to see whether this could be translated clinically. This combination was originally studied in RCC [renal cell carcinoma] in HOPE–Study 111, which was the phase 1B/2 study of lenvatinib plus pembrolizumab, originally in multiple diseases and then in a separate analysis. There were subcohorts of diseases, including bladder, endometrial, lung, and kidney. In that study, they showed very high levels of efficacy for the patients. That study was later expanded to study patients who right previously progressing immune checkpoint inhibitors and formed the key data that was used for the design of the CLEAR study.

Transcript edited for clarity.