Pedro Barata: Hi, my name is Pedro Barata. I'm a GU medical oncologist at Case Western Seidman Cancer Center in Cleveland, Ohio. And I'm so, so happy to be joined today by friend, colleague, Dr. Mehmet Asim Bilen. He's an Associate Professor, Department of Hematology Oncology, and the Director of, actually, the GU Medical Oncology Program at the Winship Cancer Institute at Emory University.

Asim, pleasure to have you here today.

Mehmet Asim Bilen: Thank you so much, Pedro. It's my honor and privilege to be here with you today and looking forward to our discussion.

Pedro Barata: Absolutely. And I have to congratulate you for your investigator-initiated study. Neoadjuvant cabozantinib in patients with renal cell carcinoma. Very, very important study. It's been a while since I've seen data with other TKIs in that space, so I was really happy when you present that data recently, IKCS and KCRS, and it's fantastic to see that data, and I think there are good news for patients as well.

So maybe first things first, I know the design, but some people that might be listening to us might not be as familiar with the design. So can you tell us, how did you come up with the idea of exploring cabozantinib in this setting? Tell us a little bit about the rationale, and then maybe if you want to walk through us the design and the endpoint, that'll be great.

Mehmet Asim Bilen: No, thank you so much, Pedro. And again, thank you so much for highlighting our work, because we are all working for our patient with kidney cancer and hopefully in the near future we can cure this deadly disease.

Actually, we ask the question first. What is the utility of presurgical therapy in renal cell carcinoma? And, as you know, for patients with localized kidney cancers, neoadjuvant therapy can help to facilitate partial nephrectomy. And for patients with local advanced or unresectable, and we see this kind of patients a lot in our academic institution, neoadjuvant therapy can make the surgery easier, or even sometimes can make the surgery feasible, and we also can achieve organ sparing. And also, depends on treatment, we can understand the biology of disease. We can also achieve some systemic effects such as immune induction. Because of this reason, there is multiple role for pre-surgical therapy.

I think all great ideas coming from patient. We had a patient, very young, very healthy man, and very large left-sided mass. It was very large, close to 20 centimeters. We have a fantastic surgeon, Dr. Viraj Master, and he felt it's unresectable. And when he tell me it's unresectable, it's really unresectable. And because of this reason we need to give pre-surgical therapy. And again, this patient didn't have any metastatic disease. We chose cabozantinib based on the data we have at that time for first line MRCC, and he had a fantastic response. And because of that response, he become surgically eligible, underwent nephrectomy, and two years out he's still alive. And that patient really gave us the idea, can we try cabozantinib in the presurgical setting?

Pedro Barata: What a powerful story, Asim. That's wonderful. And we all have those patients, exactly your point, some of that surgical teams we work with, some are more avant-garde than others, but we all have those situations at a tumor board when we look at the pictures and say, boy, surgery is just not feasible. So the fact that you are looking for response of the primary tumor is actually quite good.

Going back to this trial, it's a proof of concept trial, as I call it, because it's a relatively small number of patients, although enough for you to see a signal. And I think one of the important aspects of it is, can you tell us about ... Because one of the things happens in clinic is patients want the cancer out and they want the surgery happen right away, and when you're introducing a concept of the induction with treatment before surgery, you've got to explain to patients what that means, and that means surgery will happen later on.

So walk us through how much time did you design for the pre-ap for the neoadjuvant or the induction period of cabozantinib? And then tell us a little bit the results including, which I think is important, the number of patients where you actually ... Did you lose the window of opportunity for cure in any of them? In other words, the fact that patients went on cabo instead of getting surgery, if that was feasible elsewhere, what happened to those patients while on study? I think those are important pieces of data for us to know.

Mehmet Asim Bilen: No, Pedro, those are excellent questions. This is a Phase II study. If you look at the design, patients with biopsy proven clear cell RCC eligible, because we know all those drugs are much more effective in clear cell population and we want to pick those patients to enroll in the trial, because we don't want to lose the cure, as you said earlier. And we only enroll patients clinical stage T3 or more, or NEN, or deem unresectable by our expert surgeon. And after then patients receive 12 weeks of cabozantinib with the studying dose of 60 milligram daily, which is our standard single agent dose. And cabozantinib has a long health life because of this reason, after 12 weeks patients stay on washout period for four weeks and then underwent nephrectomy. And based on our Simon two-stage design, we enroll 17 patients and our primary endpoint was objective response rate at 12 weeks.

And then we have multiple secondary endpoints, including safety, tolerability, longer term clinical outcomes, such as DFSOS, and surgical outcome, quality of life data. And also we have a number of exploratory endpoints, including correlatives. And I think this is very important for those kind of trials. And we able to open and enroll this trial during COVID, and I think we able to do that because surgery, urology, and medical oncology, you need to have a fantastic team to able to do those kind of trials, because, as you said, why we are doing this trial, what is our aim, what we try to achieve from this trial, need to be explained to our patients very well, and patients see the team approach and then if they see the team approach I think will be much easier to conduct this kind of trial, because again, those studies are giving some clinical data, but at the same time some biological data which will help us down the road what we're going to do.

Again, we enroll 17 patients like male dominant as we all see on clear cell or kidney cancer, and the median baseline tumor size was around 10 centimeters. And in terms of our primary endpoint, we see close to 30% response rate, which is five patients. And then because of this reason we call this trial is positive and all the remaining patients are stable disease, and our disease controlled rate is 100%. And when we look at the median reduction of primary renal tumor size was around 23%, and this is between 6% to 45% reduction.

As you asked earlier, everybody completed 12 weeks of therapy and 16 of them underwent surgery as planned without any additional delay. One patient refused to go surgery, he really didn't want to go surgery, and because of this reason he want to stay on systemic therapy.

Gladly, we didn't have any patient progress during this treatment and couldn't able to go to the next step, which is surgical removal. And the other important thing is one patient was deemed to be unresectable, become resectable, and then two patients were converted from radical to partial nephrectomy, and we are still following those patients in terms of longer term follow up. So far, the medium follow up is 25 months. We only have one patient have recurrence and unfortunately die because of kidney cancer. And overall this is still very important piece of data we are going to follow in terms of additional longer term follow up, what is the DFS rate and OS rate and all of those going to be very important for our future questions.

Pedro Barata: Very important results, Asim. I'm really glad for the patients we enroll in that study, because sounds like there was not even one who missed the window of opportunity for surgery later on, which is great.

I guess one hot topic right now, as you know, of course, is the emergence of these combination regimens. We're basically trying to include immunotherapy in all the combos that we can think of. And of course I'm referring to these metastatic setting and we also have some concepts about the bulk nephrectomy for patients with stage four, which I think is not that different from this neoadjuvant concept in the sense that you do a trial of induction systemic therapy, you select the good actors from the bad actors, and then you do local approach later on.

So with that in mind, obviously IO based combo, especially IO/TKIs, have been offering very high response rates, and that seems to be true in the metastatic sites that are responses perhaps in a lesser degree in the primary tumor that nonetheless real. And we just saw recent data with a combination with axi/avelumab in the neoadjuvant space.

So I guess my question to you, the natural question, is, now that you are done with this monotherapy TKI in the neoadjuvant space, what are the plans to actually taking the next step in going to an IO/TKI approach, perhaps, in that space? Do you think that makes sense? Are you exploring that? Can you tell us a little bit about that and how you see that playing a role in the future management of localized RCC?

Mehmet Asim Bilen: Yeah, Pedro, fantastic question. I think we discuss this all the time. The kidney cancer space is rapidly evolving. I think this is great for us as an oncologist. I think this is great for us for our patients, because every year we have a different menu for them. But for clinical trial design, I think it's also very exciting and some somewhat challenging because the question keep evolving based on all these important data come to our doorsteps every year.

I 100% agree with you. I think the IO/TKI combinations are very appealing. We have very good options for first line, like IO/IO or IO/TKI. And one of the beauty of IO/TKI is early and deep responses that we see in our patients with MRCC. Because of this reason, we are very much interested into exploring IO/TKI for our next trial, and also our adjuvant space change after the approval of pembro.

When we design and enroll our neoadjuvant cabo trial, our first line was cabo, based on cabozan trial, and we didn't have any adjuvant trial or adjuvant approval. But now we have all these combinations, and plus we have pembro as an adjuvant therapy. We are also currently enrolling another investigator initiated trial, Pedro. For that study we are combining pembrolizumab plus lapatinib. As you know, this trial give us the highest response rate based on clear trial and we are giving three months of therapy, and then after then patients undergo one week of washout, because the Lenvima half life is short.

And then after surgical resection, patients will receive additional nine months of pembro as an adjuvant therapy. We are very much interested in this trial. We are almost halfway through. We passed the first stage and now we are on the second stage, and hopefully in the near future we can share our results with all the stakeholders in the field and we can ask the question, what is utility of IO/TKI and IO adjuvant in this patient population?

Pedro Barata: That's amazing. That's great news, actually. And very, very neat and smart concept, Asim. Congratulations for that. I'm happy to hear that is enrolling quite well, and I'm also looking forward to those results for sure.

So listen, I think we could spend a long time here chatting. I want to congratulate you. Very important work. I'm looking forward to the manuscript to get for the details on the data that you mentioned to us, also on correlatives. Really, really important as we try to help these patients. So thank you so much for taking the time, sitting down with us, and I'll see you soon.

Mehmet Asim Bilen: Oh, thank you so much, Pedro. Again, thank you for having me. It's really my pleasure to discuss with you. As you said, the manuscript is cooking. Stay tuned. We are waiting couple additional correlative data to include it and hopefully after holidays, new year, we'll be able to publish this data. And looking forward our future discussions for other data in the field. Thank you.

Pedro Barata: Awesome, thanks.

Mehmet Asim Bilen: Bye-Bye.