Key Efficacy and Safety Findings from the CLEAR Trial

EP: 1.Current Therapies for Advanced RCC: Options and Challenges

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EP: 2.Key Efficacy and Safety Findings from the CLEAR Trial

EP: 3.Impact of the CLEAR Trial on Clinical Practice

EP: 4.Updates on CLEAR from ASCO 2021

EP: 5.The Future of Therapy for Advanced RCC

Robert J. Motzer, MD: Today, we’re going to focus on the CLEAR trial which is the most recent report, and it is characterized by striking efficacy data compared to sunitinib. This trial compared lenvatinib plus pembrolizumab to sunitinib. Lenvatinib is a multi-targeted tyrosine kinase inhibitor that targets VEGF [vascular endothelial growth factor] receptors as well as a number of other kinase including fibroblast growth factor receptors, which may play a role in resistance for RCC to anti-angiogenesis therapies. It is also very active in augmenting immunity within tumor cells. There have been studies that have looked at lenvatinib plus IO [immuno-oncology] therapy that showed that it augments the effect of checkpoint inhibitors within tumors by changing the microenvironment. Pembrolizumab is a well-established checkpoint inhibitor; it inhibits PD-1 [programmed cell death protein 1] and it is widely used in multiple malignancies. It did show single agent activity in clear cell carcinoma of the kidney, and lenvatinib has shown activity in kidney cancer and has been approved by regulatory authorities in second-line therapy in combination with everolimus. The lenvatinib and everolimus made up the 3rd arm of the trial and this was a 3-arm phase 3 trial in which both of the lenvatinib arms were compared to sunitinib. The study design for the CLEAR trial stipulated that the patients had to have a clear cell RCC or that with a predominant clear cell component. The patients had to be treatment naïve, have measurable disease, and have adequate performance status and blood work. The population was comprised of global recruitment from many centers around the world. The key end points of the trial were progression-free survival as the primary end point by independent review for both lenvatinib and pembrolizumab compared to sunitinib and lenvatinib and everolimus compared to sunitinib. The key secondary end points included overall survival, adverse events, and safety, and there were number of exploratory end points as well including health-related patient-reported outcomes or quality of life studies. This trial met the primary end point for both of the lenvatinib containing arms compared to sunitinib. In the lenvatinib-pembrolizumab arm there were 355 patients that were enrolled. In that study, median progression-free survival was 23.9 months compared to 9.2 months with sunitinib. The hazard ratio was 0.39, and the p-value was statistically significant at less than .001. For lenvatinib plus pembrolizumab, there was also a benefit in overall survival that was established with the hazard ratio of 0.66 and p-value of .005. There was also a strikingly high objective response rate of 71% with 16% complete responses compared to a 36% objective response rate, and 4.2% complete responses by independent review with sunitinib. There was a striking efficacy of benefit for lenvatinib plus pembrolizumab versus sunitinib. In that trial lenvatinib plus everolimus was also compared to sunitinib, and the study met its primary end point for that arm as well with the median PFS [progression-free survival] of 14.7 months with lenvatinib plus everolimus and a hazard ratio of 0.65. There was a higher response rate for lenvatinib plus everolimus compared to sunitinib, but there wasn’t a benefit in overall survival. The takeaway from that trial was that there was a benefit in progression-free survival in response rate and overall survival for lenvatinib plus pembrolizumab compared to sunitinib while with lenvatinib plus everolimus there was a more modest benefit, although meeting the primary endpoint with no benefit and survival. The safety was assessed for those 2 combinations compared to sunitinib, and in that sense of the 2 lenvatinib combinations, the lenvatinib plus pembrolizumab appeared to be the winner as well. The treatment plan is to start with a high dose of lenvatinib, a 20 mg daily dose with a standard dose of pembrolizumab and then dose reduce as needed. In point of fact, about 60% of patients required a dose reduction, some to as low as 10 mg, but over time people appeared to tolerate this regimen really quite well.

This transcript has been edited for clarity.