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Rana McKay: Hi, my name is Rana McKay. I'm a Medical Oncologist at the University of California in San Diego. I lead our Genitourinary Oncology team here. It's a pleasure to be with you today.

Bradley McGregor: I'm Brad McGregor. I'm a Medical Oncologist and a Clinical Director for the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts.

Rana McKay: It's exciting to be with you today. We're going to be reviewing several abstracts that were presented at the virtual 2021 ASCO meeting. And hopefully, the next one will be in person. But a lot of exciting data coming out in genitourinary malignancies, and specifically in renal cell carcinoma. And we will kick off our discussion by talking about the CLEAR trial that was presented by Dr. Motzer, updated analyses from CLEAR, and really the quality of life data.

Bradley McGregor: CLEAR was a great trial. This is a large randomized Phase 3 trial comparing lenvatinib in combination with pembrolizumab versus lenvatinib with everolimus versus sunitinib. And we saw the data presented earlier this year for the primary analysis, showing that lenvatinib plus pembrolizumab had a marked improvement in overall survival with an improvement in response rate. The response rate was 70%, the CR rate was over 15%, really impressed with that, with the PFS over 24 months. So great, great data. There was some concern at the presentation with toxicity profile and how it is tolerated by the patients with close to 70% requiring some sort of dose reduction of lenvatinib. This was really an interesting companion to that trial after one of the key secondary endpoints for which was the quality of life analysis.

Rana McKay: I always find the quality of life data to be... It's, very important because I think how the patient is feeling and what they go through while they're on therapy is critically important and one of the things that play into a decision around treatment. But, I also think it's one of the toughest to interpret, and how do you make sense of the quality of life data? Especially, not to say that we're going to compare across trials, but what are the instruments that were used? What are the nuances of the questions that were asked? And what do they actually mean? What's statistically significant versus what's clinically meaningful?

And then who's filling out the questionnaire? If you're sick in the hospital, you're probably not going to say, "Yeah, I'm going to log on and fill out my questionnaire," but if I'm feeling great, "Yeah, sure. I'll fill out the questionnaire for the study that's making me feel great." So, I think there is tremendous bias too, that kind of gets introduced. And so, I think it's important to understand that as we talk about quality of life.

Bradley McGregor: Yeah. You can see that even when you look at any of the sunitinib quality of life data, you had that sawtooth pattern, right? Because they answered at three weeks, they feel bad. But then they answer at six weeks, they're on like [inaudible 00:02:58] ...two weeks off, and they feel better. And you can see this variation just in the overall, just in the same arm, just from when they're answering the questionnaire and how they feel in terms of where they are in their treatment cycle.

Rana McKay: And that's interesting too as we interpret the LEN/PEM data with the degree of people that had dose modifications, dose interruptions. Who's to know what the state of their lenvatinib dosing was at the time that they filled out the questionnaire. Usually, patients will fill out their questionnaires while they're in the waiting room, see the doc, and then a decision is made about resuming their therapy. Do you know what I mean, or something? So, it will be interesting to see. It's interesting how that plays in.

But I have to say, it was reassuring at least to see that for some domains, patients did a little bit better than [inaudible 00:03:49]  For most domains, they did about the same as the [inaudible] patients did with Len-Pem. I think probably of all of the regimens, it seems to be the one that's associated with a little bit worse toxicity. But to see that quality of life data I think was reassuring.

Bradley McGregor: No, I 100% agree. At the end of the day, when you look at the instruments they use, they are actually similar to what they used in KEYNOTE-426. And there really was no deterioration in the quality of life between sunitinib or the IOTI combination in either trial using the instruments they've looked at. So, it does offer some reassurance that these agent combinations are not only effective for controlling cancer, and helping patients to live longer but seem to be associated with not a detriment in quality of life.

Rana McKay: Yeah and I know that they didn't go into too many details regarding the len-ev data. What's unique about the CLEAR trial is this trial had three arms as opposed to two arms like the other studies and did include the combination of len-ev. I think we all scratch our heads as to which front-line patient would ever get len-ev, but it was nice to see that data get presented too. And in that scenario, we did see at least on par or decrements. So it gives a point of reference that the len-pem combo was equivalent, if not a little bit better, the len-ev equivalent, if not a little bit worse, and then the sut-ev was sort [inaudible 00:05:20] of your control. So, it kind of gave a little bit more contextualization for the quality of life data.

Bradley McGregor: 100% agree. That actually pairs well with the data presented for Len-Ev in its second line looking at different dosing strategies and trying to muse[inaudible 00:05:35] out if a lower dose lenvatinib and everolimus was the higher dose. And in that analysis, the higher dose lenvatinib, the standard 18-5 actually showed a better quality of life than starting at a lower dose. So to your point, these instruments, are great tools and they provide us some insight, but they're not going to be the be-all-end-all as we look at these different regimens.

Rana McKay: Yeah. I think it's, and you brought, you bring up a good point about dosing because I think we still haven't figured out dosing because on the trial it was 18 milligrams when paired with everolimus. It's 20 milligrams when paired with pembrolizumab. When it's single-agent Len, which we don't really use in kidney cancer was 24 milligrams. I think the dosing strategy with CLEAR is a little bit different where it's more starting higher in dose reducing, then maybe the dosing strategy that was utilized in CheckMate 9ER, which was starting in the middle of the road and trying to maintain and adjust if needed, but different dosing strategies between these regimens. Same with Pem-axi, you're starting in the middle of the road with an opportunity to escalate deescalate dosing.

Bradley McGregor: Absolutely. From my standpoint, I think it's really important to note that despite the fact that patients have 70% dose reductions, [inaudible 00:06:50] nine or maybe six vendor reductions, you still have this marked improvement in outcomes. So as you're looking at this, take the quality of life data, take the fact that patients can get dose reductions and still have these outcomes as you counsel your patients, and not step away from dose reductions or be worried about them because this was the way the trials were designed and patients got dose reductions and still did really well with the quality of life metrics showing that they felt well too.

Rana McKay: Yeah. I think that is the big take-home, sort of getting familiar with using these regimens on a regular basis, and kind of honing in everybody on the care team, nurses, physicians, mid-level or advanced practice providers, I should say, really about toxicity management is the key to maintaining a good quality of life.

Bradley McGregor: Absolutely. Because at the end of the day, I think the quality of life really matters to these patients. And so while there may be some nuances, these different tools, I think they do offer some importance that into how the patient is feeling on a given therapy. And so it's really, the patient trying to tell us how he feels. I think it is important to add and to look at and talk about with the patients.

Rana McKay: Absolutely. I know when you've got a PFS of two years, you don't want to be feeling crummy for two years. So I think it's... you're absolutely right. Our patients are living longer and because they are living longer, I think we need to ensure that they're actually living better. And I think paying attention to that is key, right?

Bradley McGregor: Because grade one and two toxicities can still be pretty miserable for our patients. And so [crosstalk 00:08:29]

Rana McKay: No one wants, nobody wants grade II diarrhea.

Bradley McGregor: Exactly.

Rana McKay: Yeah. So excited to see that data, and I'm sure that in future meetings we will continue to see data cuts of different subset analyses and additional longer-term follow-up from CLEAR. And it's exciting that we now have four regimens that have demonstrated improvements in overall survival and frontline space for advanced renal cell carcinoma. So great progress for the field.

Bradley McGregor: Absolutely.