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Christopher Wallis: Hello and welcome to this UroToday Journal Club. Today we are discussing the recently published CLEAR trial examining lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. I'm Chris Wallis, a fellow in urologic oncology at Vanderbilt. And with me is Zach Klaassen, assistant professor in the division of urology at the Medical College of Georgia.

Here is the publication citation for the CLEAR trial led by Dr. Motzer and published this past week in the New England Journal of Medicine.

By way of background, most UroToday readers and viewers will know that the treatment landscape for metastatic RCC has changed dramatically over the last 10 and 15 years. In particular, we've now enjoyed a clear immunotherapy combination era led first by CheckMate 214 with nivolumab and ipilimumab and subsequently with both the KEYNOTE and JAVELIN studies.

Why the combination we are discussing today? Well, there is a couple of important studies here. First, we have randomized phase II data-led also by Dr. Motzer looking at lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma. And this showed promise for the combination approach. However, we also need to look at work from Dr. Taylor, which was published in JCO in a phase 1b/2 trial, looking at the combination of lenvatinib plus pembrolizumab. And this study, while including advanced kidney cancer, also looked at other solid tumors. And so on the basis of these phase II data, the rationale for the phase III CLEAR study was formed.

And so CLEAR included patients age 18 years and greater with previously untreated advanced renal cell carcinoma who had at least some clear cell component. Patients had to have measurable disease per RECIST criteria, an adequate performance score, as well as blood pressure control and end-organ function.

The others then, performed a randomized open-label phase III trial with a one-to-one-to-one randomization to three arms, including lenvatinib plus pembrolizumab, lenvatinib plus everolimus, or the standard of care sunitinib. And stratification of this randomization was performed according to MSKCC risk group, as well as geographic region. And the treatment was administered in a relatively standard fashion, although it is worth noting that lenvatinib was given at a slightly higher dose in the combination with pembrolizumab than it was in the combination with everolimus. Sunitinib was given in the standard six-week fashion.

The primary outcome of this study was progression-free survival, according to independent review, and key secondary endpoints included overall survival, objective response rate, safety, and progression-free survival according to individual investigator assessment. There are further exploratory endpoints, including the duration of response and objective response rate by the investigator. An assessment for these endpoints was performed with CT and MRI at baseline and every eight weeks thereafter. Progression was assessed using the RECIST criteria and adverse events were assessed by the standard means.

This is a schematic of what we've just discussed, highlighting the three-arm design of the CLEAR study.

And so the authors designed and powered their study based on an assumption of a median progression-free survival in the control arm of 12 months, as well as a hazard ratio of 0.714 for either drug combination. And so focusing primarily on lenvatinib and pembrolizumab, this gave a 90% power with an alpha 0.045, once 388 progression-free survival events had occurred. And this then corresponded with a power of 70% for an alpha 0.0049 in the lenvatinib and everolimus arm given an alpha reallocation that was used. And the authors used a sequential approach for multiple comparisons and performed standard efficacy and safety analysis in the ITT and ever-exposed arms.

And now I will pass it over to Dr. Klaassen to talk us through the results of this study.

Zachary Klaassen: Thanks Chris.

You can see here, this is a demographic and baseline characteristics table for this study. You can see that there were 255 patients in the lenvatinib pembrolizumab arm, 257 in the lenvatinib everolimus arm, and 357 in the sunitinib arm. And this is pretty standard for advanced metastatic renal cell carcinoma in terms of the median age being in the low to mid-sixties.  The predominance of male patients at about three-quarters of the patients, majority of these patients having an excellent performance status with more than 80% of a Karnofsky performance status of 90 to a 100. And then you can look at in the middle of the table, the MSKCC and IMDC prognostic risk groups. About one-quarter of these patients, MSKCC favorable risk, about two-thirds intermediate-risk, and about 9% poor risk. Looking halfway down the table as well, looking at sarcomatoid features in about five to 8%, a number of metastatic organs, more than two metastatic organs in about two-thirds of the patients with the predominance of metastatic sites in the lung and in the lymph nodes. About three-quarters of the patients in each arm had a previous nephrectomy.

These are the results looking at progression-free survival. You can see the lenvatinib plus pembrolizumab arm in red, the lenvatinib plus everolimus arm in blue, and the sunitinib arm in black. And a very clean and beautiful looking diversion of the curves in the progression-free survival favoring lenvatinib plus pembrolizumab, which had a median progression-free survival of 23.9 months. Lenvatinib plus everolimus at 14.7 months and sunitinib at 9.2 months. And so the hazard ratio for the comparison between lenvatinib plus pembrolizumab versus sunitinib was at 0.39, the 95% confidence interval of 0.32 to 0.49. And the hazard ratio for lenvatinib plus everolimus versus sunitinib was 0.65 with a 95% confidence interval of 0.53 to 0.80.

This is a subgroup analysis for progression-free survival, specifically comparing lenvatinib plus pembrolizumab versus sunitinib. And it doesn't take a strong statistician to realize that this all favored the lenvatinib plus pembrolizumab arm with all of the hazard ratios to the left of this curve. And so across the board, across all subgroups, a very strong progression-free survival benefit for those patients receiving lenvatinib plus pembrolizumab.

This is a subgroup analysis for lenvatinib plus everolimus. Also a pretty good response. Several notes here, in terms of what did not favor lenvatinib plus everolimus, including those in the MSKCC risk group poor as well as in the IMDC poor-risk group, as well as those patients with not as strong of performance status and as well as patients with only one organ metastasis.

This is the Kaplan-Meier curve for overall survival. You can see here that in all three of these arms, the median overall survival was not reached. However, the hazard ratio for death comparing lenvatinib plus pembrolizumab versus sunitinib was 0.66 with a statistically significant confidence interval of 0.49 to 0.88. However, in the lenvatinib plus everolimus versus sunitinib arm, the hazard ratio was 1.15, and the 95% confidence interval was 0.88 to 1.50. There is a survival benefit for lenvatinib plus pembrolizumab, but not for lenvatinib plus everolimus versus sunitinib.

This is the results of the subgroup analysis for overall survival in the lenvatinib plus pembrolizumab versus sunitinib. And we can see here a lot of these subgroups favoring lenvatinib plus pembrolizumab. Several that did not were in the MSKCC and IMDC favorable risk group, as well as patients with one organ of metastasis, as well as the patients with a PDL1, combined positive score of greater than one.

This is the Kaplan-Meier curve for response duration. Once again, these favor the lenvatinib plus pembrolizumab arm with a median duration of response of 25.8 months. Lenvatinib plus everolimus had a median duration of response of 16.6 months and sunitinib 14.6 months.

This table looks at confirmed tumor response across the three arms and several important points to highlight here. You can see that lenvatinib plus pembrolizumab had an objective response rate of 71%, which is the highest we've seen in the first-line treatment arms to date. Also a very impressive 16.1% complete response rate for lenvatinib plus pembrolizumab and only 5.4 patients had the progressive disease in this arm compared to 7.3 in the lenvatinib plus everolimus arm and 14% in the sunitinib arm. You can see here that the median time to response was pretty equal across all three arms.

This is the adverse events table for this trial. Lenvatinib plus pembrolizumab on the left, lenvatinib plus everolimus in the middle, and sunitinib on the right. And we will focus briefly on the grade three or greater adverse events. You can see that for lenvatinib plus pembrolizumab, this rate was 82.4%, for lenvatinib plus everolimus was 83.1% and for sunitinib was 71.8%. In terms of common adverse events for lenvatinib plus pembrolizumab, hypertension at 27.6% of patients, as well as a weight decrease in 8% of patients and diarrhea in 9.7% of patients. And this was comparable with lenvatinib plus everolimus.

Several discussion points from the CLEAR trial. In the lenvatinib plus pembrolizumab arm, there was a median progression-free survival of 23.9 months. 71% of patients had an objective response and 16.1% had a complete response. And these are notable findings relative to other first-line trials in this disease space. Importantly, only lenvatinib plus pembrolizumab had an overall survival benefit versus sunitinib as lenvatinib plus everolimus did not. And this confirms that immune checkpoint inhibitor combination with kinase inhibitor therapy is important in first-line advanced renal cell carcinoma treatment. The safety profile for each of these combinations was consistent with these agents as is with single agents, as well as previously reported outcomes for the combination of these treatment arms.

In conclusion, the combination therapy with lenvatinib plus pembrolizumab provided significantly greater benefit versus sunitinib for progression-free survival and overall survival in the treatment of first-line advanced renal cell carcinoma. The grade three or higher adverse events occurring in more than 10% of patients included hypertension and diarrhea. And the safety profile of lenvatinib plus pembrolizumab was consistent with the known profile of each drug. Based on the results of the CLEAR trial, lenvatinib plus pembrolizumab should be considered as an option for the first-line treatment of advanced renal cell carcinoma.

Thank you for your attention and we hope you enjoyed this discussion of the CLEAR trial, first presented at GU ASCO 2021.