CLEAR trial analyses reaffirm benefit of lenvatinib/pembrolizumab in aRCC

In this interview, Thomas E. Hutson, DO, PharmD, shares in-depth insights into the study, “Analyses on impact of tumor burden at progression and changes in IMDC from baseline in patients (pts) with advanced renal cell carcinoma (aRCC) treated with lenvatinib + pembrolizumab (L+P) in the phase 3 CLEAR trial (NCT02811861).” These data were recently presented at the 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium in San Francisco, California.

Hutson is a professor of medicine and the director of the University Medical Center at Texas Tech University Health Science Center College of Medicine in Lubbock, Texas.

Thomas E. Hutson, DO, PharmD

This transcript was AI generated and edited by human editors for clarity.

Could you describe the background/rationale for this trial?

What was presented at the meeting is updated results of the phase 3 CLEAR study, which is an international randomized trial looking at treatment with lenvatinib combined with pembrolizumab vs sunitinib in patients with advanced renal cell carcinoma. This regimen has been FDA approved in the United States, and it's approved in many countries around the world. Based upon the original results that have previously been presented and published in the New England Journal of Medicine, lenvatinib plus pembrolizumab has been given a category 1 recommendation for use as initial therapy for this disease. That was based on superior efficacy end points [of] response rate, progression-free survival, and overall survival when compared to sunitinib, which is an oral VEGF-TKI that had been the international standard of care for approximately 14 years. This IO-plus-TKI regimen joins several other regimens that are potential choices for someone to use as first-line therapy.

The phase 3 CLEAR trial demonstrated a superior efficacy with tolerability, and the efficacy end points were quite robust. We saw [that] 95% of patients enrolled in the trial who received the regimen had at least stable disease. Roughly 70% of patients had what would be considered a partial response with greater than 30% tumor shrinkage. We saw complete response rates of 17%. Those numbers by themselves are very robust, and it fares very favorably against similar regimens that one could utilize. Unfortunately, there are no head-to-head trials comparing these other regimens with lenvatinib/pembro, so the clinician has to choose.

What were the key findings from the CLEAR trial?

With the CLEAR trial, we have gone on and updated results. I was able to present them orally at the ASCO meeting in 2023 where we [reported] greater than 4-year survival results. [In that analysis,] we saw a maintained level of efficacy, meaning that as time went on, we didn't lose control of the cancer. The efficacy was as robust as it was at the beginning. More importantly, we also saw that the [adverse] effects that we initially reported were the same. We weren't accumulating [adverse] effects with long-term use.

We have gone on with subsequent updates from the CLEAR trial to try to further unpack the benefits of the of the combination, trying to determine, is there a group of patients that do better or worse? Can we predict survival based on the amount of tumor shrinkage a person is achieving? This most recent update is an analysis of the impact of tumor burden at progression, as well as changes of the international IMDC risk factor score from baseline in patients on this trial. It makes sense, but we're able to show with data that patients who have more tumor shrinkage on therapy are going to have a better outcome when it comes to progression-free survival and overall survival. Also, patients who have better shrinkage of tumor are going to be patients who have improvement in their IMDC risk score. For instance, if someone was a risk score of 3, 4, or 5, they can improve by 1 or 2 points. The average person improved by a point. [Among] people that were responding, their disease—based on risk characteristics, which we've used historically to prognosticate how people would do—improves with therapy. It makes sense. Your tumor is shrinking, so you expect to do better. We were able to show that in our trial, both looking at the hard end points of progression-free survival and overall survival and the Kaplan Meier curves, and also using the prognostic model of the IMDC risk score.

In the trial, we broke this down into thirds. We have a T1 group, which is people who had a 61% change from baseline in the sum of target lesions, a T2 group, which was between the 61% the 34% change, and a T3 group, which was the 34% change from baseline. That shows us the greater the amount of shrinkage from baseline, the better the outcome. That all makes sense; the more shrinkage you get, the better you get.

The conclusions of the trial were that patients with lower disease burden at the time of progression, meaning they had the greatest shrinkage of tumor from therapy with lenvatinib plus pembrolizumab, had an improved prognosis in that the 6-month IMDC risk scores were typically constant or improved in patients who had received [this regimen]. These patients had either maintained or improved their risk score with therapy; they didn't worsen. That means they can move into second-line therapy at a better spot than where they started off their first-line therapy. It's a continuation of the patterns of benefit that we've seen from this regimen, and it's our attempt, myself and my coauthors, of trying to further unpack this and describe this for practical use.

How should urologists interpret these findings in the context of real-world decision making?

The updated results from CLEAR trial confirming that the amount of tumor shrinkage correlates with prognosis through overall survival, PFS, as well as through IMDC prognostic scoring should add further weight to lenvatinib and pembrolizumab being a go-to standard of care in this setting. We have clear evidence that this is a very robust treatment. There is no other available therapy that seems to produce benefit better than it, although we lack a head-to-head comparative trial. The long-term follow-up data support this therapy, and all of the correlative studies that we've updated support the benefit that the patients receive long term. As they enter into their next line of therapy, since most patients are not going to be cured of this cancer, they're going to do so at a better spot than when they started. This should give great peace and comfort to clinicians—urologists and medical oncologists—in prescribing this medication for their patients.

Do you think IMDC risk remains a valuable prognostic tool for combination therapy, or should we consider new biomarkers?

The easy answer to that is we need new biomarkers. They've been very elusive to us in kidney cancer. [There’s been] great work from my colleagues, scientists throughout the world, who have studied biomarkers, and we've identified certain characteristics of tumors that we can establish either through next-generation sequencing of the tumor or biomarkers or categories. We just haven't been able to validate that yet for use in the clinical setting. There seem to be patients who do better with immune-based therapy and some who will do better with VEGF targeted therapies. The current combination of lenvatinib/pembrolizumab and the other IO/TKIs are so potent that they work in most patients. That's certainly encouraging. They work irrespective of the IMDC class of the patient.

So, is it absolutely important that I know when I'm going to use lenvatinib and pembrolizumab, whether they're favorable-, intermediate-, or poor-risk? The answer is no. I don't need to know that. Based on the data that we've reported, this regimen is active, irrespective of what class they're in. You don’t need to know in order to select therapy with the IO/TKIs. They all have shown benefit. That's reflected in, for instance, the United States NCCN [National Comprehensive Cancer Network] guidelines, which have given these regimens as category 1 for favorable, intermediate, and poor prognosis patients. [IMDC risk group] does not influence my choice of therapy because it works in all of them.

In the future, maybe an IMDC-like prognostic factor, incorporating biomarkers or next-gen sequencing, may be of value if we're able to show that by doing so, we can predict better outcome with 1 type of therapy or another. We're just not quite there yet. For real term use it doesn't. I think it does have value, though, when we're trying to make sure our randomized trials have similar types of patients in them. That’s always the challenge in a randomized trial, especially when we do cross trial comparisons, which are already fraught with statistical problems. When we try to compare 1 study to the next study, having a way to make sure that it was a similar patient population is useful. If you had a trial that had a disproportionate number of, for instance, favorable patients on it, and you were trying to make assumptions and comparisons with another trial that didn't have that, you would say that it would be fraught with error. There’s use in that. For practical, day-to-day use for urologists and medical oncologists, it's becoming less needed because these drugs work so well in all the types.

What are the next steps planned based on this study?

Lenvatinib/pembrolizumab has shown us now, with repeated analysis and long-term use and follow-up, that it is a potent and robust [combination]. You get what you're bargained for when you start the regimen, and it correlates with outcome. Therefore, this is a regimen [we] want to take forward in combination strategies with novel agents. There are trials being done [already]. There's a trial being done in combination with the HIF-2α inhibitor belzutifan. This trial will be reading out soon, which is [exploring the] triplet therapy. Then, other molecules—what I'll call third generation, new-mechanism-of-action molecules—we would want to combine to this backbone, since lenvatinib and pembrolizumab is, without a doubt, one of our most potent [options]. It’s one of those backbones that we want to move forward, combining with new agents.