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Pedro Barata: Hi, I'm Pedro Barata. I'm a GU Oncologist at University Hospital, Seidman Cancer Center, Case Western University in Cleveland, Ohio. It's my true pleasure to be joined today by my colleague and friend, Dr. Lee, from Memorial Sloan Kettering in New York. Welcome.

Chung-Han Lee: Thank you, Pedro. Glad to be here. Thank you for having me.

Pedro Barata: Absolutely. Listen, I have to congratulate you again because you keep conducting very practice-changing, in my opinion, studies, particularly in kidney cancer, and this year is no exception. We just came out of ASCO where you presented very elegant work, or an important update on your elegant work clinical trial, focusing on patients with non-clear cell renal cell carcinoma. And we both know those are patients that definitely need better therapies.

So we all know that IO based approaches have emerged as the better way to treat patients with advanced clear cell, and you're really kind of paving the way, I guess, for in the non-clear cell, showing us what the activity of IO TKIs is for those particular patients. So maybe instead of me summarizing your trial, can you please remind us the concept of this, the trial concept you put together a couple of years ago regarding for patients with advanced non clear cell RCC?

Chung-Han Lee: Yeah, no, thank you Pedro. You're way too kind and generous with your compliments. So as you know, and the rest of everyone else, that non-clear cell is a very rare type of histology. Kidney cancer is made of multiple different malignancies, with the most common histologic subtype being clear cell, and kind of more collectively, everything else has been grouped into this category of non-clear cell type kidney cancer.

Historically speaking, with most of our clinical trials kind of optimized for clear cell, there's been a great unmet need for developing therapies for the non-clear cell space. And historically speaking, the efficacy that we saw in non-clear cell was probably not what we saw within the clear cell space.

For B-61, we basically designed a single arm multicenter international phase two clinical trial looking at the combination of lenvatinib plus pembrolizumab. So lenvatinib was given at the 20 milligram daily dose, in addition to pembrolizumab at 400 milligrams every six weeks. We essentially treated people until treatment progression or unacceptable toxicity, with kind of key endpoints looking really at both the objective response rates and PFS within this fairly large cohort of patients.

Pedro Barata: Great. So that's such an important study, because the standard of care has been, for many, many years, TKI is monotherapy, right?

Chung-Han Lee: Yeah.

Pedro Barata: Initially, I think a lot of us were doing sunitinib, and then with data from PubMed supported the use of Cabozantinib. So it's really, you're building upon what we knew about the activity of TKI. To your point, that seems to be less evident or less strong than perhaps a combination. But you build on that and you bring an immunotherapy combo, which is very effective for patients with clear cell.

So, I'm very impressed with the results. You presented last year ESMO, and then you give us an important update. So please remind, us how many patients were enrolled in this study in the different subtypes, and what the main findings that you observed?

Chung-Han Lee: Yeah, so as you know, per NCCN guidelines right now, the preferred regimen listed there is of course clinical trial, and also sunitinib as a preferred regimen, and also Cabozantinib as a preferred regimen. And then there's been a little bit more limited data for the TKI IO sort of space. So in this protocol, what we end up doing is we enrolled a total of 158 patients across all clear cell... non-clear cell histologies, kind of excluding the ones that we kind of knew were not be TKI responsive, the collecting ducts, the medullaries. And we saw on an overall cohort sort of standpoint, a fairly robust objective response rate of about 49%, so nearly half of the patients.

Very interestingly within that cohort, if we actually broke it down by subgroups, if we look only at patients with papillary type kidney cancer, then we now see it north of 50%, almost to 57%. Really, the subgroup that probably dragged down the cohort a little bit was the chromophobe, which historically has been not as high of responsive. It's certainly very exciting types of findings from a direct response rate standpoint. Also thinking about from a PFS sort of standpoint, nearly 18 months progression-free survival, which is pretty unexpected and probably unprecedented in terms of outcomes, in terms of the longevity of the patients.

Pedro Barata: I mean, those results are quite remarkable, right? Because we say it all the time, we don't compare data, we don't compare trials, but it's hard not to look at your numbers, right? How people did, a year and a half until progression, or half of them, looking at medians. Response rates over 50%, to your point, in some cases, but let's just say 50%, and not compare with where we would expect thinking of clear cell.

Do you think those results are because of this particular combo? We have no doubt this combo is very active, but are you convinced this is a specific regarding lenvatinib pembrolizumab, or do you think it might be the combo of IO TKI, it's a smarter way to treat those patients?

Chung-Han Lee: So I actually do think that there's a certain contribution of the combo. If we really think back, I remember several years ago, based off of the results of atezo bev, granted atezo bev was also less active for clear cell. I think that we were here at ASCO and people were saying that maybe this is just the wrong thing, like a VEGF IO sort of treatment for non-clear cell is not the direction that we should be going. I remember people on stage making that argument. But I think that we're starting to see that it probably is more than just VEGF and there's probably something very special about the mix, and I think that there's probably the need to hit some of the other kinases in addition to just VEGFR signaling.

Pedro Barata: Right. No, that's a fantastic point. Let me just look at your data from a different angle, and that has to do with tolerability, because when we are in clinical practice, I mean we would argue not all patients are fit to enroll in a clinical trial. They have comorbidities, they have other limitations, and as we know, the tolerability is, it goes side by side with the amount of therapy we provide. So it's dose dependent, right? Specifically the TKI. And lenvatinib of 20 milligrams is higher than what we've used when we combine with everolimus, right?

Chung-Han Lee: Yes.

Pedro Barata: So how do patients do on this trial with the standard combination of 20 milligrams of lenvatinib with a standard dose of pembrolizumab?

Chung-Han Lee: So I think the tolerability of the regimen still remains good. I think that when we talk about tolerability, there's two aspects of that. So from a tolerability standpoint is obviously incredibly important, but it's important to know that the ability to dose reduce is possible. And some of that tolerability, in terms of your grade three, grade four adverse events won't be reflected on how the patients feel after the dose reductions happen. There are a fairly significant number of patients that do require dose reduction, but as soon as you titrate to the dose which you expect, then at that point people are able to be maintained on that type of dosing.

And I think that it's also important to, there have been studies, granted in the clear cell space, that we probably don't want to get too creative about how we do the lenvatinib dosing, trying to start at a lower dose and up titrate certainly, compromise some efficacy. And I think it's probably more important to remember to start with that initial dose, and if you run into issues to drop it down quickly, of course, maximizing the supportive medications that you can give.

Pedro Barata: Yeah, no, that's a very important tip for the treating providers, right, is start with the dose that was studied, investigate it, and then adapt according to how the patient is doing. I think that's a very pragmatic and straightforward tip. Thank you for that. So let me ask you, in the absence of level one data, there's always the question about next week in clinic. Do you think this is enough to change practice, or should we be still thinking about and advocating for TKI monotherapy? What are your thoughts?

Chung-Han Lee: So I think that the data is certainly very, very compelling. I think that there's a strong push to implement this in clinical practice. I think that having randomized data is always still critically important. There's some ongoing studies that provides that randomized data. It's perhaps even more important, especially in non-clear cell, to have those studies because of the histologic diversity within the cohorts. So that really makes sometimes the comparisons very, very challenging. However, in the absence of a trial that's really truly investigating that, I think that it is reasonable to really consider, with these types of results, to at least discuss with the patients, with the caveats that this is certainly a single arm protocol.

Pedro Barata: Yeah, no, I agree with you. And I guess my final question for you is, we kind of try to do that with NIOIO. The results are different from an IO TKI. Are you convinced that we really need the TKI anti-VF integrated as part of the treatment regimen, whatever combo we choose for patient with non-clear cell histology?

Chung-Han Lee: I really do think that that part is really important. I mean, I think that the results that we saw with a pure IO based therapy within non-clear cell was a little bit more lackluster than we would've hoped, and I think that the TKI really does add a component. I think that it remains an unanswered question whether or not the addition that the TKI provided was strictly a stromal sort of modulation of angiogenesis sort of effect, or there's a lot of preclinical data indicating that the TKIs do have some immune modulatory effects. Whether or not those effects are strong enough to lead to a change in the clinical outcomes, it still remains to be seen and debated based off what the downstream portal of analysis that can be done.

Pedro Barata: Right. Great. Final question before I let you go. Where do you think the field is going? Now, I mean, it's likely that a lot of us, we're going to start to strongly consider an IO based approach, likely an IO TKI, whether there's lymph or even other ones, like we've seen data, very compelling data, also with CaboNivo. And so the question is, where do you think the field is going for these different subtypes?

Chung-Han Lee: Yeah. I think that one of the things that the field needs to go is probably a better stratification of patients. Certainly with two different IO TKIs that have shown activity, there's not reason to believe that the responders would be fully overlapping. Trying to tease out a little bit more kind of predictors that correlate with each will be critically important. I still do think that there's a lot of value in terms of the randomized protocol demonstrating activity beyond what we see with single agent TKI. I think that that's an important study that certainly does need to be done. And then afterwards, I think that what we really need to do is kind of break apart some of these histologies and have slightly more tailored approaches to see whether or not we can more rationally subdivide this, so the treatments are going to be paired with underlying biology.

Pedro Barata: Right. Really well said. This was great. Thank you so much. Congratulations. Very important data for patients, and I really think this is, again, the lack of level one data, which is very difficult to do, right? And the lack of randomized studies. We will have them. I think your data is one of the most important data to help us make decisions in clinical practice with patients with unclear cells. So for that, congratulations.

Chung-Han Lee: Yeah, thank you.

Pedro Barata: And thank you for putting together and leading the efforts of an international effort to be able to treat these patients in this way, and I'm happy these patients did better than what would be the expectation. So congrats. Thank you for taking the time, and I know we'll be chatting again soon.

Chung-Han Lee: Yeah. Thank you so much.