Efficacy of Lenvatinib + Pembrolizumab Versus Sunitinib in Patients with Advanced Renal Cell Carcinoma in the CLEAR Trial - Camillo Porta

June 28, 2023

Camillo Porta provides a comprehensive overview of the CLEAR trial, an impactful research investigation into lenvatinib/pembrolizumab (lenv/pembro) as a first-line treatment for patients with advanced clear cell kidney cancer. The study showed significant survival benefits in favor of the combination treatment compared to sunitinib, a previous standard treatment for the disease. The conversation also explores the implications of stopping immunotherapy after two years, noting that this doesn't seem to affect survival rates, with patients still benefitting from the treatment combination. The discussion concludes with the hope for potential biomarkers and a more refined treatment algorithm, promising further insights from future updates of the CLEAR trial.


Camillo Porta, MD, Professor of Medical Oncology, A. Moro University of Bari, Head of the Division of Medical Oncology Group (GION), Bari, Italy

Pedro C. Barata, MD, MSc, Leader of the Clinical GU Medical Oncology Research Program, University Hospitals Seidman Cancer Center, Associate Professor of Medicine, Case Western University, Cleveland, OH

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Pedro Barata: Hello, everyone, and welcome. My name is Pedro Barata. I'm a GU Medical Oncologist at Case West University Seidman Cancer Center in Cleveland, Ohio. Today I'm very, very happy to be joined by Dr. Camillo Porta. Dr. Porta is a full Professor of Medical Oncology at Moro University of Bari in Italy. He's a key opinion leader, and he was heavily involved in the CLEAR study. Dr. Porta, welcome, and thank you for taking the time today.

Camillo Porta: Absolutely. My pleasure to be with you, Pedro. Thank you.

Pedro Barata: Absolutely. So thanks first of all for joining us, and then also great job with your presentation of this updated analysis for the CLEAR study investigating lenv/pembro. This is a very, very important study, as you highlighted, and I think this data is particularly important, because we start to have some good insights about what's going on for these patients with a longer follow up. So maybe for those, I'm sure a lot of people are already familiar with this design, but can you just remind us briefly the design of the CLEAR study and the endpoint for this work?

Camillo Porta: Absolutely. The CLEAR study is a randomized controlled phase III trial that enrolled patient with advanced clear cell kidney cancer, treatment naive. This is a first line set of treatment. Patients were randomized in a 1:1:1 fashion to receive lenvatinib plus pembro, typical schedule. Lenvatinib plus everolimus or sunitinib as the control arm, since at that time, at the time of study design sunitinib was still the standard treatment for the diease. The primary clinical study was progression to survival and secondary endpoints included overall survival, responses, safety, quality of life and so on.

So a very important study that established one of the novel treatment standards for metastatic kidney cancer. The original data, the original data from the study were published, if I do remember well, in April 2021, on the New England Journal Medicine and showed a benefit in favor of the pembro and everolimus, and I had the opportunity of [inaudible 00:02:21] this results and a small in meta-TCA this year with a longer follow-up of more than 30 months. And basically what we were able to show is that the progression free survival continued to be superior for the experimental arm, pembro/lenv, compared to sunitinib with a median progression free survival that was about 23 months for lenv/pembro as compared to 90 months, 9.2 months for sunitinib This is a very important thing in my opinion, because 9.2 for sunitinib is absolutely in line with the PFS results achieved by sunitinib in almost every phase III trial conducted today. And this, in my opinion, strengthens the relevance of the results and the benefit achieved by the use of the combination.

Pedro Barata: That's great. Great point. And I agree completely. I mean those numbers are definitely remarkable. As you said, I mean basically two years median PFS compared with ceritinib. I don't think sunitinib seem like the underperformed, right, which is also not important point. The combo was shown completely superior. And also what was quite remarkable in my opinion, but I'll ask you what your thoughts about that, is with this median follow up of 33 or so months, you actually allow us to know more about patients who completed two years of pembro, because we have that question in clinical practice. What we do once we achieve, when we get patients on two years of pembro, do we stop? We don't stop? What do we do? Do we continue TKI? So can you comment a little bit for us, what were your findings for that particular group of patients? Did that happen a lot? And then, what was the findings for those patients who end up completing two years of pembro?

Camillo Porta: This is a very important point in my opinion, because even the benefit we can achieve nowadays with this combination, a key point is what can we expect when patients stop immunotherapy, even though they continue usually lenvatinib, or the other TKI associated with immunotherapy, and the make up of the design presented clearly show that there is no detrimental effect of stopping immunotherapy. Although there are a lot of patients still censored, in terms of survival, we know that the overall survival rate at 36 months exceeds 94%.

This means that the benefit of immunotherapy is maintained, the benefit of the combination as a whole, is maintained also when immunotherapy is stopped. And the key point now will be to check if restarting immunotherapy in case of progression, would eventually benefit more of the patient, but this is a total different story. What we can say now is that stopping immunotherapy is safe and allows a continuous control of chemotherapy. This is quite important, in my opinion.

Pedro Barata: Got it. No, I agree with you completely. And I guess the hot topic here, or the hot question is, as we get longer follow up for these IO TKIs for lenv/pem, the question really is, in your opinion, until when or when can we start looking at those survival curves and start commenting about, do we see a plateau of those curves suggesting a percentage of these durable responders or patients in remission? Obviously we have over five years of median follow up for IO-IO with ipi-nivo, with the IO TKIs have shorter follow up, because they were done afterwards and they read out later. So I guess my question to you is, when do you think we're going to be able to start saying, you know what? We are expecting X percent of patients 20%, maybe more, that actually when they start on these a combination, we're able to see durable persistent remissions over time. When do you think we can start talking like that?

Camillo Porta: This is a very good question and it is also a very difficult one. Because for example, if you take a look at the more recent updates of the CheckMate-14 study of ipi-nivo, it is clear that after the initial evaluation of the results we study, a plateau was evident. But the latest update of survival results is that there is a drop in the survival of those patients.

So it is clear, in my opinion, that the kidney cancer is not melanoma and it would be more difficult, in my opinion, to see a real plateau as in melanoma and kidney cancer. For sure, the survival curve of the CLEAR study are very promising, because there is a plateau that starts at around 40 months of follow up and persists towards even more than 50 months of follow up. Although, a lot of pain patients are censored here, because the follow-up is still too short. So, it is definitely too early to hypothesize the relevance of such a plateau. I think that we should wait at least five years of follow up before really saying that there is some long survival, and I wouldn't be keen to speak about a cure in kidney cancer, although this is clearly our ultimate goal.

Pedro Barata: For sure. That's really well said. Yeah. I was going to ask you, cure is a strong word and I don't know if you used that word in clinical practice. I personally talk about long remissions and no evidence of disease, but to challenge that concept of the no evidence of disease, it looks like also from CLEAR, and you were part of that with a different subgroup analysis, that seems like patients also with a very deep partial response, not just those where we don't see disease anymore, known as complete response, which by the way, you reported 17% in this updated follow-up analysis for lenv/pem. Those patients with very deep partial response seem to do almost as well as the CRs. So I guess my final question to you is, how do you see that depth of response, and how do you take response as a surrogate for those durable and persistent remissions, and perhaps some of them might be cured, is that you feel strongly about that? Do you want to wait longer to see what happens? What are your insights about that?

Camillo Porta: Well, a first consideration is that 70.2% complete response rate is something totally unprecedented in clear cell kidney cancer. It is really striking, and this is clearly the most active combination we have in our hands for treatment of these patients. If these complete inhibitions will translate into a really long survival, I wouldn't use the term cure, although we should start thinking about that. It's probably too early. We do not have a clear-cut evidence of a relationship between complete responses and survivor in kidney cancer, but it's something that it is highly likely. So, I would expect a longer follow up before speaking about this issue. But for sure the possibility in using such huge responses is something that I'd like to see, I'd like to explain to the patient, and basically I really would expect this could translate in a long survival.

Pedro Barata: Got it. Final question before I let you go, I mean this is very important data. You presented this data with a follow-up over 33 months. The question is, can you share with us, are any plans defined right now as we move forward for the CLEAR study? Any other subgroup analysis you might be involved with that you want to share with us? What should we expect from CLEAR study in the near future in your opinion?

Camillo Porta: Well, of course from every study that collected the huge amounts of tissue and blood and whatever, we would like to see some biomarker coming out. It'll be extremely difficult, but each time we have to hope for the possibility of finding something that could guide our treatment algorithm in a more rational way. Then, I would really like to take a look at the differential outcome of the patient according to the different MSKCC data, because from the data that I presented seems very, but there is no difference in terms of progression free survival, which is something slightly different from what happened in the other studies on combinations. But we lack an enough number of events, as far as other survivors concerned. And finally, I would really like to take a look at the type of progression in progression patients, in terms especially of site progression, that could be quite important. So we accumulated a huge amount of data, and we're early in the elaboration of this data, and I do expect to provide more interesting and probably practice changing data in the near future with the subsequent updates of the CLEAR study.

Pedro Barata: Well, that's great to hear and I'm looking forward to that. And I'm sure that folks who are listening to us are also going to welcome more important data from the CLEAR study. Dr. Porta, this was amazing. Thank you. Thank you so much. Congratulations. Very, very important data and I'm very happy we had a time to do these behind the scenes, I guess, or beyond your presentation, to share insights with us. So, thank you for taking the time. Congrats and we'll talk soon.

Camillo Porta: Absolutely. Thank you and bye-bye.

Pedro Barata: Thank you. Bye.