The Phase 3 CLEAR Trial: Lenvatinib Plus Pembrolizumab or Everolimus for Advanced RCC - Episode 2

Design and Key Takeaways of the CLEAR Study in Metastatic RCC

Results of the efficacy and safety data demonstrated by the CLEAR study of lenvatinib plus pembrolizumab or everolimus as first-line treatment for metastatic renal cell carcinoma.


Moshe Ornstein, MD, MA: The CLEAR trial is a phase 3 trial that included patients with advanced clear cell RCC [renal cell carcinoma] who had not yet received treatment for their advanced RCC, had a good performance status, measurable disease, and they were randomized into 3 different arms. For the purposes of this presentation, we’re going to focus on 2 of the arms, but for completion’s sake, we’ll list all 3 arms. Arm A was lenvatinib [Lenvima] plus pembrolizumab [Keytruda]. Lenvatinib at 20 mg once a day and pembrolizumab at the usual standard IV [intravenous] infusion of 200 mg once every 3 weeks. Arm B was lenvatinib at 20 mg once a day combined with the mTOR [mammalian target of rapamycin] inhibitor everolimus [Afinitor] at 5 mg PO [by mouth] once a day. The control arm, much like the control arm in the other IO [immuno-oncology]-based combinations, was sunitinib [Sutent] at 50 mg once a day, 4 weeks on and 2 weeks off as per the standard schedule. For the purposes of this discussion, we’re going to focus on the combination of lenvatinib and pembrolizumab versus sunitinib. The primary end point of the trial was progression-free survival and secondary end points included overall survival, objective response rate, safety, and quality of life.

Let’s talk about the big picture efficacy data, the primary end point being PFS [progression-free survival]. The median progression-free survival for lenvatinib and pembrolizumab was 23.9 months versus 9.2 months for sunitinib and a hazard ratio of 0.39. This is a really impressive risk reduction for PFS. When looking at overall survival, there’s no median for the lenvatinib and pembrolizumab arm or for the sunitinib arm. For overall survival, we’re just going to look at the hazard ratio, which is risk reduction for death of 0.66. In terms of objective responses, we’re looking at a 71% objective response rate for the combination of lenvatinib and pembrolizumab. That’s compared to a 36.1% response rate for sunitinib. Importantly, the complete response rate was 16% for patients receiving lenvatinib and pembrolizumab and only 4% for patients receiving sunitinib. Across all 3 primary efficacy end points of PFS of close to 2 years, of a hazard ratio for survival of 0.66, and an objective response rate of 71% with a CR [complete response] rate of 16%, it was clearly superior to sunitinib. In a further section, we’ll get into where we put this in the context of the other IO/TKI [tyrosine kinase inhibitor] combinations, but strictly for this trial, it was wildly positive across the primary end points and the secondary end points.

We previously reviewed the superior efficacy of lenvatinib and pembrolizumab versus sunitinib across PFS response rate, overall survival, and complete response rates, but when using such a combination it’s really important to consider what the toxicity is as well. Within the clinical trial, the majority of patients had some form of toxicity, both in the lenvatinib and pembrolizumab arm as well as in the sunitinib arm. That’s to be expected. We understand the toxicity of TKIs. We understand the toxicity of immunotherapy agents. I want to point out a couple of things about toxicity. First of all, there are different kinds of toxicity. There’s toxicity that relates to lab values, which are generally asymptomatic. For instance, most patients who have an elevated AST [aspartate aminotransferase] and ALT [alanine transaminase] don’t really feel that. Then there are toxicities that are symptomatic in nature, and it’s important to keep that in mind as we manage toxicities. Some of the general paradigms that I keep in mind when I think about toxicities in IO/TKI combinations in general, as well as lenvatinib and pembrolizumab in particular, is keeping an eye on LFTs, liver function tests, and making sure we’re managing a patient’s blood pressure. I ask my patients to monitor their blood pressures at home. I ask them to let me know of any symptoms that might be related to cardiac dysfunction, whether it’s low extremity edema, whether it’s shortness of breath, or whether it’s lightheadedness. That goes to the differences between the lab-based monitoring. For instance, we treat with liver function tests every 3 weeks when they come in for the pembrolizumab and then some of their general symptomatic monitoring of symptoms, which they can do at home, and we can check in with them as a clinical team.

Transcript edited for clarity.