Dr. Thomas Hutson on Long-Term Durable Response After 4 Years Follow-Up in the CLEAR Study

Thomas Hutson, DO, PharmD, FACP, Baylor University Medical Center, details the recent CLEAR study data on the long-term survival after 4 years of follow-up for patients who received first-line lenvatinib plus pembrolizumab for advanced renal cell carcinoma.

Your 2023 ASCO Annual Meeting presentation on the CLEAR study highlighted the long-term survival data after 4 years of follow-up. Does lenvatinib plus pembrolizumab continue to show durable responses in these patients?

Dr. Hutson: Patients in our trial continue to benefit from the treatment, and you can observe that some patients derive benefits for over 4 years. However, it is unfortunate that patients eventually progress and succumb to the illness, leading to a decline in survival curves.

In our specific trial, we noticed a phenomenon at the far right of the Kaplan-Meier survival curve, where the 2 curves converged. We conducted an extensive evaluation within the limitations of our data and found that a significant factor contributing to this convergence was patients in the comparator arm (sunitinib) progressing earlier and switching to other active therapies. There are other therapies available that impact survival in this cancer, providing the opportunity to rescue patients with later lines of therapy.

Although we did not present the analysis, we examined PFS2, which evaluates the impact of subsequent lines of therapy. The data on PFS2 looks positive, and a publication will be released with that information.

Furthermore, by employing a statistical maneuver of censoring and replacing patients, we observed that when we excluded the influence of second-line and later therapies, the survival curves remained separated throughout the entire duration. Thus, there is a sustained survival benefit even when considering the impact of post-progression therapy.

I want to make a provocative statement regarding IO/TKIs. People often say that the curves for IO/TKIs do not appear as favorable as those for ipi/nivo in the intermediate and poor-risk patient population. However, we must remember that the approval of ipi/nivo in the United States is specifically for the intermediate and poor-risk patients, and they rightfully present their survival curve, which demonstrates maintained separation and a notable tail.

In our intent-to-treat analysis, we show the survival curves for all 3 prognostic risk groups: favorable, intermediate, and poor. Due to the favorable risk group, the curves may not look as attractive. However, if we focus on the intermediate and poor-risk survival curves alone, they appear just as attractive, if not more so, than ipi/nivo. Unfortunately, this aspect is often overlooked in discussions, as we present data for all 3 risk groups. Incorporating the unfavorable risk group of the original ipi/nivo trial would yield comparable results.

We need to approach this topic with more sophistication. During the meeting, there was a back-and-forth discussion among colleagues with differing opinions on the best long-term treatment for patients.

Personally, I support the use of IO/TKIs. In select cases with low volume disease, I may choose IO/IO therapy, but the majority of patients with more significant disease and a need for a response would benefit from an IO/TKI regimen. Specifically, I would select lenvatinib/pembrolizumab as it offers the highest likelihood of benefit compared to ipi/nivo, which incurs a 10%-20% loss in efficacy.

Comparing IO/TKIs among themselves becomes more challenging due to the differences in trial populations. Len/pembro has shown the strongest data and should be acknowledged for that. However, it’s important to consider that trial populations may account for differences in performance. Nevertheless, the data speaks for itself, and it demonstrates strong and robust activity.

In our report with an additional 23 months of follow-up, the data remains robust. Patients and doctors can be confident that the early data was not an illusion and that len/pembro should be a preferred choice. We did not identify any new safety concerns, solidifying len/pembro as the regimen to surpass when comparing against an IO/TKI.

View Dr. Hutson’s previous comments on Conventional and Novel Combination Therapies for First-Line Advanced RCC.