The CLEAR Study: Lenvatinib + Pembro vs Sunitinib in Advanced RCC - Camillo Porta

January 25, 2023

In a detailed discussion between Pedro Barata and Camillo Porta, they dissect the findings from the update of the CLEAR study. The study explores the effectiveness of lenvatinib and pembrolizumab versus sunitinib in treating advanced renal cell carcinoma patients. The results revealed significantly higher medium progression-free survival and overall survival rates for the lenvatinib/pembrolizumab combination, with a 17% complete response rate. Safety concerns did not yield new issues, though Dr. Porta mentions the importance of managing side effects such as diarrhea effectively. Additionally, they highlight the success of patients who discontinued immunotherapy per protocol after two years, maintaining an impressive overall survival rate. The interview concludes by acknowledging the necessity for further biomarker research and expressing gratitude to the patients who participated in the study.


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: Hi and welcome. Today, I have the pleasure to be joined by Dr. Porta. Dr. Camillo Porta is a well-known world expert in kidney cancer and the reason why we're going to be chatting with Dr. Porta is about the trial update he presented at ESMO, this last ESMO in Paris, about the updated efficacy of the combination of lenvatinib and pembrolizumab versus sunitinib in patients with advanced renal cell carcinoma, also known by the CLEAR study. My name is Pedro Barata, I'm a GU Medical Oncologist from Tulane University Medical School. So again, Dr. Porta, thank you so much for joining us and congratulations on this great presentation you did in Paris.

Camillo Porta: Thank you, Pedro.

Pedro Barata: This is very interesting data, right? We have a number new of combos, IO/TKI and IO/IO, and we are starting to see longer follow up analysis that seems to be confirming the outstanding results for patients with advanced renal cell carcinoma and the CLEAR study, definitely at the top of those combos, right? You presented data for a medium follow up of 33 months or so, with very, very interesting results. Can you highlight for us the main results of this updated analysis that you just presented?

Camillo Porta: Yes, I had the opportunity, I had the privilege of presenting an update of the results of the CLEAR study. The CLEAR study was a randomized control phase III trial that compared the three treatments, lenvatinib plus pembrolizumab, lenvatinib plus everolimus or sunitinib in patients with advanced clear cell RCC who were treatment naive. The primary results of the study have been already published in the New England Journal Medicine in April 2021, with a median follow up of around 26.5 months. The data I presented were just the efficacy data, so not system data. Also because no unexpected signals were recorded in terms of safety, which is of course important and I provided no novel data on the lenvatinib plus everolimus that was the second of the three arms of the study. What emerged from these longer follow up analysis is where the PFS remained statistically significant in favor of the lenva/pembro combination, which will lead to something like 23 months of medium progression free survival as compared to nine point something for sunitinib, which is absolutely in line with the results so far within different studies for sunitinib.

And notably enough, the advantage for recommendation in terms of progression free survival was maintained across all the prognosis groups, irrespective of the use of the IMDC or VS cases classification. Also, survival was consistent with the results of the primary analysis. The median results of overall survival was not reached in either of the arms, but we have the overall survival rate at 12 and 24 months for both treatments. And in both cases, lenvatinib proved to be superior as compared to sunitinib. The overall survival rate, 24 months was 80% for lenva/pembro versus less than 70% for Sunitinib monotherapy. In this case, the advantage in terms of overall survival was observed just in intermediate poor patients because the number of patients in the favorable risk who had an event were quite low. And this means also that we are still waiting for final overall survival data, although it is clear that all in this analysis, the combination could be clearly superior as compared to the V GFR T monotherapy.

I updated also the results in terms of anti-tumor activity and what is really striking to me is that the number of complete responses observed in the lenva plus pembro  arm increased from 16% of the primary to 17%, which is definitely and by far the higher percentage of complete response ever observed in the field of metastatic kidney cancer. Something really unexpected. I had the opportunity fortunate I would say, to start working on kidney cancer from the era of cytokines based immunotherapy and also with the cabozantinib inhibitors we were able to report one, two, 3% complete responses and having 17% of complete responses really, really something. And also because we know that these complete responses translates into a long, long survival, which is the most important part of it. But I want to also to highlight another point, which is key in my opinion, the key is the lenva/pembro not only induce so many complete responses, but also induce the lower percentage of progressive disease at the best response to treatment with just 5% of the patients experiencing progression, first disease evaluation as a whole, their rate of complete responses in the rate of progressive diseases, it is clearly showing my opinion, how important this combination is.

Pedro Barata: I agree with you and I mean when I saw the results from your presentation, I was going to say the exact same thing, very low numbers of pd, right? In the four, 5%. 17% complete responses on the other hand and meeting overall survival, right? So exactly, I mean very, very good news for patients and that's very encouraging. But go ahead, please.

Camillo Porta: No, no, no. You highlighted the key points of this presentation. I think that it is really important to confirm on a longer follow up of the results achieved in the primary analysis because we know that sometimes in many randomized control phase III trials, the survival curve tend to decrease over time and although of course the follow up is not so long as compared to for example, ipi/nivo for obvious reasons. Still these data really support the extreme activity and efficacy of this combination. And the last important figure that I presented was the outcome of those patients who stopped pembro per protocol after two years of treatment and continued lenvatinib immunotherapy. And the striking part of it is that despite stopping immunotherapy, the overall survival rate at 36 months for these patients is extremely exciting but under 95%.

Pedro Barata: So tell us a little bit more, who are those patients?

Camillo Porta: At the very beginning of a story of a combination of immunotherapy plus antigens, we used to continue the two treatments indefinitely and more recently we started to stop immunotherapy because from an immunological viewpoint we know that once activated, the immune system maintains this activation over time and therefore there is not such a huge need to continue treatment independently also because you risk to the exhaustion of immune system. So presently, the vast majority of studies are designed to stop immunotherapy after two years while continuing the antiangiogenic, which makes sense because from the early days of the antiangiogenic treatment, we know that as soon as we stop antiangiogenic treatment, then there is a regrowth of the vessels which fill with tumor and the results are of a tumor. In this study, we stopped, we were able to pembrolizumab in one third of a patient's enrolled. And despite this, the over survival rate is that I did report and we know that these patients are mainly from the intermediate according to the IDC or MSKCC classification. So we are trying to understand a little bit better who are the patients who can benefit more from these treatments. Although it is clear for all of us that we better need biomarkers which are presently totally lacking in this field.

Pedro Barata: That's great. And I mean we've touched on very, very important points and I'm thinking as you're talking about efficacy, I'm thinking if you guys were able to dive into the tolerability and safety as, I guess as providers become more familiar with this combination, perhaps we're better equipped to handle the adverse events that can occur with this combo in this particular trial with longer follow up. Did mention the safety profile was similar to what was reported previously. Is there any adverse events or safety signals you want to highlight for us with these longer follow up on a good or not so good way?

Camillo Porta: Well, this update analysis didn't comprise safety, but again because no particularly unknown effects emerged for sure with this treatment. We may have on one hand the EGRF TKI related toxicity such as palpitation, high fatigue, dermatitis and so on and on the other end of it, typically mirror related adverse events, colitis, pneumonitis, hypophysitis and so on. Basically nothing that is not known for worse, at least work with immunotherapeutic agents and with targeted agents. I want to highlight diarrhea because it is one of the most common adverse events which has been recorded in into the study and I want to highlight it because diarrhea sometimes creates some issue relative to the identification of a real cause because it can be due to both treatments, to antiangiogenic and also to immunotherapy. And making a correct differential diagnosis is key in order to find the ideal treatment that on one end they could be related to those reduction in the case of antiangiogenics. And of course in the case of an immune related adverse event, we use corticosteroids despite the activity of corticosteroids as immunosuppressant. So diarrhea is key and sometimes is really troublesome to manage, especially for non-experienced physicians. But again, more than all, the most important part is to try to understand which of the two agents can cause really adverse event in order to perform the more adequate treatment.

Pedro Barata: Dr. Porta, thank you so much. There has been a comprehensive overview, not only on the efficacy side but also on the safety side. I think this is a very helpful, enlighting conversation about the CLEAR study. I really appreciate you taking the time to sit down with us and give a little bit beyond the presentation, I guess, discussion with us today here for the audience. So thank you so much for taking the time. Congratulations again for your outstanding presentation on ESMO and I hope to see you soon. Thank you.

Camillo Porta: Thank you to you, Pedro, and thank you to all the attendees of this meeting, of this webinar, whatever. And thank you also to all the patients and their relatives of the patients enroll into the study because if I may present this data is because a lot of patients are accepted to be randomized within a randomized trial, which is really something important for all the community of kidney cancer.