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Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We are live in Chicago at ASCO 2024 and I'm delighted to be joined by Dr. Talal El Zarif, who is an internal medicine resident at Yale University, and Dr. Karl Semaan, who is a medical oncology research fellow at DNA Pharma Institute. Gentlemen, thank you both for joining us today.

Karl Semaan: Thank you for the intro.

Talal El Zarif: Thank you for the invitation.

Zach Klaassen: So you guys have some really interesting data. We've had all this excitement about KEYNOTE-564, overall survival recently published. So I want you guys just to give us a high-level overview of that trial, but really, a little background on what do we do with these patients after they receive adjuvant IO. What's the treatment pattern after that? So maybe if somebody wants to take that first question on the landscape of KEYNOTE-564.

Talal El Zarif: Karl, go ahead.

Karl Semaan: Yeah, so as you may know, pembrolizumab has been recently approved as an adjuvant IO therapy in the setting of RCC, early stage RCC. And so there is a lot of question about the patient that we cure on adjuvant IO or maybe later, in later stages, what do we give to these patients in systemic therapy settings? So it's an unmet need until now. So do you want to add anything?

Talal El Zarif: Sure. So I think the KEYNOTE-564 was one of the very new trials in the RCC world where adjuvant therapy was successful. And I think our mentor, Dr. Toni Choueiri, presented that at ASCO-GU and he really nicely highlighted how it's 50 years or so, there was no adjuvant systemic therapy in RCC. So this is a major breakthrough, but the question now is, what do we do next? If somebody gets the adjuvant therapy and they relapse after that, what's the next step? We have a lot of options like VEGF target therapy or IO-VEGF combinations or IO-IO combinations and it's unclear who benefits from what. So that's what prompted the study.

Zach Klaassen: And I like it too because obviously, there's going to be trial design answering those questions, but until those trials read out, we have these patients sitting in our clinic today. So take a step back in terms of the context of the study that you guys designed.

Talal El Zarif: Sure. I think what we essentially did is this is like a multi-institutional international cohort similar to prior efforts that we have done. Obviously, there's not a lot of these patients, this practice is still being newly incorporated and we reached out to multiple centers and we asked which patients got adjuvant immunotherapy and relapsed or had a recurrence actually, and can you give us more information about their survival, the type of medications they received and what were the recurrence patterns? We're interested in the sites of metastasis and different, the other outcomes that we outlaid. That's where we are.

Zach Klaassen: And is it all US population or is it international? How did you guys look at the centers that you chose?

Karl Semaan: It was an effort across the world. So we have a certain country from, it was 30 institutions and it was a big effort, multidisciplinary effort. We had to contact urologists and oncologists and combine forces together, this small but a good cohort to start with, at least for now. And as you highlighted, clinical trials should base their efforts on this concept, this study, to go from there and...

Zach Klaassen: Absolutely. And you guys are the workhorses, you're the ones contacting them. Dr. Choueiri's got all the contacts, but you're the ones making the phone calls, sending the emails.

Talal El Zarif: It's a lot of emails, especially as we mentioned, it's international. So there are people from Europe, people from Australia, New Zealand, and then you will get emails at 2:00 AM, 3:00 AM, 4:00 AM, 5:00 AM, there's no limit because of time zone differences.

Zach Klaassen: That's right.

Talal El Zarif: But it was very interesting to see the shared interest and the shared enthusiasm for the study which led this study to fruition.

Zach Klaassen: That's great. So I want you to take some time to break down the results, not just the outcomes, but as you mentioned, patterns of recurrence based on baseline characteristics and then what your ultimate findings were from the study.

Karl Semaan: So the main highlight of the study, so first we found that patients that had bone metastasis recurrence, this number was higher in the early recurrence setting. The second point is that we observed a good response of patients to either VEGF-targeted therapy or even immunotherapy-based therapy. And the final point and interesting finding, is that the IMDC risk group still was predictive-

Zach Klaassen: Interesting.

Karl Semaan: Yeah, as a prognostic factor even after adjuvant IO.

Zach Klaassen: And how many patients in the study and what was the time from the time of second treatment, I guess, to recurrence?

Talal El Zarif: Sure. So I think the study included 94 patients, 76 of which received systemic therapy following adjuvant IO. The rest received either surgery or radiotherapy. In terms of time to recurrence, I don't have the number on top of my head, but it was around, I think, a year and a half or so. That was the number.

Zach Klaassen: And you're right, because this is only recently approved, we're only going to start seeing more events as we keep following these patients up further.

Talal El Zarif: I think, taking into consideration the median follow-up with this study was about 16 months. So that hinders the generalization of the time of recurrence. And again, this is a very biased cohort, in a way. Everybody received systemic therapy. So is this real-time to recurrence or is it just enriched... or it's maybe shorter in this population as they presented.

Zach Klaassen: Did you guys get any sense from looking at the data, patients that subsequently had surgery or had additional therapy or was there any sort of pattern in those findings?

Talal El Zarif: Yeah, so what we ended up doing, so initially, we were not expecting to see a lot of patients with surgery because we're used to focusing a lot on systemic therapy, just the nature of our database. So we didn't end up capturing outcomes on the 18 or so patients who had actually received surgery or radiotherapy. And the outcomes focused mostly on the systemic therapy. And the reason for that also, to make the study easier because survival was determined from the time of receiving first-line therapy until the end. But in surgery, it would be like they got surgery and then they got maybe something else. So it would be a little bit hard to-

Zach Klaassen: A little bit different to tease out. I would imagine it would be probably small recurrences, metastasectomy and trying to keep them on therapy. So you guys did a great job putting this together. You're seeing a patient tomorrow, there may be a candidate for KEYNOTE-564 pembro, how are you counseling the patients? Obviously, with the side effects of pembro and then we know the DFS and the OS numbers are both statistically significant. How are you then counseling them with the possibility of needing treatment afterwards?

Talal El Zarif: It's so important. So there are different approaches in the clinic. Some patients come in and they know about the study, they propose it, and sometimes you propose the study and it's really important to present the data in its entirety and just mention that adjuvant pembro showed improved OS. We should also show them the data from the other adjuvant IO trials because it's important for them to see the bigger picture here. And then, as you mentioned, immune adverse events are very important to highlight in adjuvant therapy. And then a study like ours, and we hope to see more of these efforts, can give them a sense of where we're heading if recurrence happens, which is an option.

Zach Klaassen: It seems like TKIs and VEGFs both work in this disease space, right afterward.

Talal El Zarif: So we saw there were radiographic responses for both VEGF or target therapy, VEGF with IO or IO IO, which was kind of interesting for us. But again, it's not a straightforward group.

Zach Klaassen: Yeah.

Talal El Zarif: Some people recurred while on adjuvant pembro, some people recurred after that. Some people stopped adjuvant pembro because of toxicity. And then there's a lot of variability in comparing, and the small numbers really limited going down to all the details. But a higher level is that there is a response with different therapies. And this was not very surprising because we saw that also in melanoma where adjuvant immunotherapy was used. And then, the patients should know that basically, a lot of options are going to be based... And so the data that's going to come up in the next few years is going to guide us, but the present data suggests that there are outcomes. And we can talk more about the IMDC and how we test that.

Zach Klaassen: Yeah, absolutely. Tell us about that. That'd be great.

Talal El Zarif: Yeah. Karl, would you like to?

Zach Klaassen: Go for it, Karl.

Karl Semaan: So as you also know, it was very interesting that most of the patients recurred as favorable after a single adjuvant IO, a good proportion of these. So it's still interesting that these favorable patients still benefit from VEGF-targeted therapy like monotherapy without IO-IO. Giving maybe immunotherapy for this patient, even though it was a small cohort, it looked like they were less responsive to immunotherapy. So this is in concordance with the IMDC risk group. Some urologists and oncologists prefer to give just the VEGF monotherapy for a favorable patient. In the setting of some patients recurred and were high risk, intermediate or poor. These patients seemed to still benefit more from immunotherapy-based adjuvant.

Zach Klaassen: Excellent. Excellent. Congratulations on this work. It's very timely as we wait for additional trials to be designed and those trials to accrue and then have outcomes, this is great timely data and congrats on all the hard work and the multi-collaboration together as well. So I'll give you guys each a couple of minutes to maybe have some take-home messages for our listeners. I'll start with Talal.

Talal El Zarif: Sure. I think the take-home messages, first of all, patterns of recurrence were important. We saw maybe more patients had bone metastasis with early recurrence. That tells us that we need to be very diligent and very cautious in screening these patients. What if they had occult metastatic disease? And that is going to prompt us in two directions, either improving the currently available radiologic techniques or relying on other techniques of detecting cancer like liquid biopsies, which is-

Zach Klaassen: Sure, great point.

Talal El Zarif: What we, me and Karl, we work in the lab on. That's what prompted us to pursue this study and we hope we can pursue something more
translational.

Zach Klaassen: Absolutely.

Talal El Zarif: I think that's the big take-home message. And the other take-home message is, once these patients have a recurrence, we kind of go back to the drawing board. So is this oligometastatic disease? Is this local recurrence or is this widespread metastatic disease? If it's oligo or local, maybe surgery or radiotherapy, there's room for that. That's what we saw in our cohort. And if it's widespread metastatic disease, we go back to, it's metastatic RCC, similar to what we do, IMDC, MSKCC risk criteria. And as Karl mentioned, the favorable risk group, there's a lot of questions about whether these patients should get VEGF-targeted therapy, not IO therapy 'cause we know we can save that for a later point in time. I think that's how we should approach these patients when they recur.

Zach Klaassen: Yeah, absolutely.

Talal El Zarif: I'll pause here. See if Karl...

Zach Klaassen: Yeah. Karl, thoughts?

Karl Semaan: Yeah, I would like to highlight the urgent need for a biomarker that could be through liquid biopsy, circulating tumor DNA, this is, it's a booming field-

Zach Klaassen: Artificial intelligence, maybe as well?

Karl Semaan: Even, yeah. Through imaging and everything because we really need to know which patient will recur or which patient might take longer time to recur, some patient can be just totally cured. So we need a closer way to follow up the patients and detect maybe this occult metastasis that maybe were not detected at the start of the patient assessment.

Zach Klaassen: Absolutely.

Talal El Zarif: And I think this also may be a reason why we saw a lot of differences in the adjuvant IO trials in RCC.

Zach Klaassen: Absolutely, yeah.

Talal El Zarif: So this is interesting and we look forward to seeing more data from the clinical trials and from our cohort if it expands further.

Zach Klaassen: Awesome. Great job and thank you so much both of you for your time and expertise today.

Talal El Zarif: Thank you so much.

Karl Semaan: Thank you.

Talal El Zarif: Appreciate it.