Sumanta Kumar Pal, MD: I'm going to ask Bob to discuss the CLEAR trial with us. Can you give us a general overview of CLEAR? We've already touched on some of the key results. Can you give us a bird's-eye view of what the study demonstrated?

Robert S. Alter, MD: Sure. I'll give you the broad 90-second approach. This was based upon a phase 1b/2 study that showed the activity of lenvatinib-pembrolizumab in patients with renal cell carcinoma. This was a multicenter, open-label phase 3 trial with a treatment-naïve patient population. Good performance status is measurable disease in a 1:1:1 randomization of lenvatinib 20 mg and pembrolizumab 200 mg every 3 weeks. Lenvatinib-everolimus was usually 18 mg of lenvatinib and 5 mg of everolimus. Sunitinib was at 50 mg with a schedule of 4 weeks on and 2 weeks off. The primary end point was progression-free survival, while the secondary end points were OS [overall survival] response rate and safety as well as health-related issues.

This was a 27-month analysis for PFS [progression-free survival] and interim analysis for OS. The numbers were astronomical. We were teased earlier when we looked at lenvatinib-everolimus for second-line therapy. Here we are now for first line therapy. The PFS of lenvatinib-pembrolizumab was 23.9 months. This was a lenvatinib-pembrolizumab vs sunitinib and lenvatinib-everolimus vs sunitinib. The median PFS was 23.9 months for lenvatinib-pembrolizumab and 9.2 months for sunitinib with a hazard ratio of 0.39. Lenvatinib-everolimus had a median progression-free survival of 14.7 months, compared to sunitinib at 9.2 months with a hazard ratio of 0.65.

Both the lenvatinib arms did meet the primary end point when compared to sunitinib. There significant benefits of lenvatinib-pembrolizumab in all categories including all IMDC [international metastatic renal cell carcinoma database consortium] subgroups. Lenvatinib-everolimus did not meet it for the poor IMDCs, but maybe for sarcomatoid. It was a significantly longer overall survival in patients getting lenvatinib-pembrolizumab compared with sunitinib with a hazard ratio of 0.66. Again, this is just 27 months. The analysis for survival is much less. The numbers were not as successful when it came to lenvatinib-everolimus compared with sunitinib for OS. I think the hazard ratio was 1.15.

There was a 71% response rate for lenvatinib-pembrolizumab, 54% response rate for lenvatinib-everolimus, and 36% response rate for sunitinib. What really caught everyone's eyes was the 16.1% CR [complete response] rate on patients who got lenvatinib-pembrolizumab. Those are the best numbers we've seen. We then have to talk about progression of disease being the best response. That number for lenvatinib-pembrolizumab is 5.4%. Sunitinib was 14%. Here we are at the trifecta all over again. Now it has spread to other drugs. We're getting to be teased that we have 2 very good I/O [immuno-oncology]-TKI [tyrosine kinase inhibitor] therapies that can really displace how we take care of our patients, some of the patients with aggressive disease who we feel we have to add a TKI to in first-line therapy.

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