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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today, Dr. Wenxin Xu, who is a GU Medical Oncologist and a researcher at the Dana-Farber Cancer Institute in Boston, Massachusetts. Thank you so much for being here with me today Dr. Xu.

Wenxin Xu: Thanks for inviting me. It's great fun to be here.

Alicia Morgans: Wonderful. So I wanted to speak with you a little bit, Wenxin, about some updates from GU ASCO 2021, specifically focusing on some of the exciting developments for kidney cancer. And I'd love to hear us kind of start off with you talking a little bit about the CLEAR Trial. Can you tell us a little bit about that study?

Wenxin Xu: Yes, absolutely. This was a very exciting presentation and one that I think will immediately inform what we do in our clinical practice. The CLEAR Trial is a phase III trial in first-line clear cell metastatic kidney cancer which compared lenvatinib and pembrolizumab combination against sunitinib. And there was another competitor arm of lenvatinib and everolimus against sunitinib. The primary endpoint for this trial was progression-free survival and the secondary endpoints included overall survival, overall response rate, safety, and health-related quality of life. In this trial, it was very, very impressive in the lenvatinib and pembrolizumab arm with a significant improvement in progression-free survival and a hazard ratio of 0.39 versus sunitinib. So highly significant results with a median progression-free survival that was also very impressive at about two years.

There was an overall response rate with this combination of lenvatinib and pembrolizumab of 71% and a complete response rate of over 16%, numerically the highest that we've seen in this kind of IO/TKI combination, though of course, we can't compare directly across trials. These improvements were seen across all subgroups and did translate into an overall survival benefit with a hazard ratio of 0.66 for lenvatinib and pembrolizumab over sunitinib. I think similarly, we did also see a progression-free survival benefit for the other active arm of lenvatinib and everolimus, but unfortunately, the overall survival data was less clear for this lenvatinib and everolimus arm. Whereas there was a significant PFS benefit with a hazard ratio of 0.65, the OS was not significant and actually trended in the wrong direction numerically favoring sunitinib with a hazard ratio of 1.15.

I think looking at how patients did on all three arms, the toxicity was kind of more or less what we've expected from prior IO/TKI trials. Nearly all patients experienced some treatment-related toxicity and patients in the pembrolizumab and lenvatinib arm were more likely to have dose reductions with 18.5% of patients discontinuing lenvatinib in the IO/TKI arm. I think when I look at all this together, it certainly adds another compelling frontline IO/TKI regimen in relation to our existing data that supports cabozantinib and nivolumab, axitinib with pembrolizumab, and also axitinib with nivolumab.

Alicia Morgans: So now, and if it wasn't uncrowded before, but now we have an even more crowded first-line space potentially with this extremely compelling data. It sounds like it was relatively well-tolerated, the lenvatinib and pembrolizumab arm. Have you a sense of whether this is as well-tolerated as maybe like pembrolizumab and axitinib or other combinations that are available to patients in this setting? They weren't obviously compared head to head in this trial, but what is your sense?

Wenxin Xu: Right. I think toxicity is going to be a key question and we are probably going to learn more as this becomes more widely used. I think one important point to know is that lenvatinib in this CLEAR trial was dosed at a starting dose of 20 milligrams, which is significantly higher than some prior lenvatinib trials, which for example, in the previous FDA approved setting was started at 18 milligrams for kidney cancer. I think just at the face of it, the rate of phase III toxicity, it's hard to say if it is higher or lower than other IO/TKI trials because obviously, they are not the same patients being randomized. But I think just knowing that we are starting the 20-milligram dose, there certainly is concern that this may be a tough regimen for patients who already have significant symptoms coming into the trial. We are probably going to learn more about the health-related quality of life outcomes from the CLEAR Trial as time goes on, and I think that will much better inform how well patients can do on this higher dose.

Alicia Morgans: Absolutely. It's just so interesting. These are the kinds of studies that may be set up perfectly within a cooperative group setting or in settings where large groups of investigators could even do a registry and just collect patient-reported quality of life on these different regimens as they are receiving them in the real world to help us understand, are their characteristics of certain patient populations that might be associated with better or poor quality of life as we have so many regimens as options in this setting, but also just really exciting for the patients to have choices and to have those discussions with their physicians. So thank you. And I'm excited to see where this CLEAR trial ultimately leads us in terms of affecting that frontline space in RCC. But this was certainly not the only study that was presented at GU ASCO 2021 in kidney cancer. There was also the PAPMET trial, which I know is also a really important but different patient population that we want to ensure that we have options for. Can you tell us a little bit about that?

Wenxin Xu: Yes, absolutely. This was also very exciting data to hear. And I think the context is that within kidney cancer, we've had a lot of very strong improvement in our management based on solid clinical evidence for clear cell kidney cancer, but the evidence for non-clear cell kidney cancer has always been a lot more limited. And so the PAPMET trial was a phase II randomized trial where patients with metastatic papillary RCC with a zero to one prior line of therapy were randomized to sunitinib, cabozantinib, crizotinib, or savolitinib. Importantly, both the savolitinib and crizotinib arms were actually closed early due to an interim analysis of futility. Nonetheless, the results of this trial were presented at GU ASCO with cabozantinib meeting its primary endpoint of progression-free survival superiority over sunitinib.

And I think this is the first real randomized phase II [inaudible] evidence showing that we have a superior regimen for papillary kidney cancers. The hazard ratio was 0.6 favoring cabozantinib with an impressive higher overall response rate of 23% versus only 4% for sunitinib. So for this trial, there was a trend towards overall survival which appears to favor cabozantinib, but that data is still maturing and we'll find out more probably in the months to come. But I do think that this randomized evidence supports cabozantinib as now a first-line regimen for papillary kidney cancer.

Alicia Morgans: That's so important because as you've said, there have not been many studies that have really focused on this group. And because so many trials have really been designed for the clear cell population, this population has certainly been in dire need of options. Can you remind us what percentage of patients essentially make up this patient population of these papillary renal cell carcinomas? And in terms of their prognosis, what does that look like, and how meaningful is this kind of development for those patients?

Wenxin Xu: Right. So I think part of this and part of the challenge is that the classification of papillary cancers has been changing over time. We know that among all comers in kidney cancer, about 70% have clear cell pathology, and the rest are spread towards the less common pathologies with papillary being the most common out of the less common non-clear cell kidney cancers with the rest being comprised of chromophobe, translocation, modularity, and others. So I would estimate probably around 10% to 15% of what we see are papillary kidney cancers, and even that classification has been changing over time.

Another update we got at GU ASCO was an update to the classification of papillary kidney cancers. We are now moving away from the old type one, type two papillary classification towards the sort of a unified classification. And what will probably emerge in the next couple of years is a better understanding of the molecular subtypes of papillary cancer in particular as it relates to this trial, knowing which patients really should be given the MET-targeted agents such as savolitinib and crizotinib, which have been so disappointing at the PAPMET trial, but have previously shown promise in selected patient groups, such as the prior [inaudible] trial.

Alicia Morgans: So I think that's really fantastic and so important as we continue to treat kidney cancers and are able to classify them and target the right treatment to the right alteration and doing that by molecular classification makes the most sense. And I'm so excited that we are moving in this direction in the future. And thinking about another population that needs to have certainly some targeted therapies, the VHL population, and some recent developments in the HIF-2 alpha inhibitors space I think were made at GU ASCO 2021. I'd love to hear your thoughts on some of the progress made in this area from this meeting.

Wenxin Xu: Absolutely. I think among those of us who treat kidney cancer and all the drugs that are coming down the pipeline, the HIF-2 alpha inhibitors are probably the class that has generated the most excitement in the last few months. These are medications that target HIF-2 alpha, which is a pathway that is amplified in kidney cancer, and especially in clear cell kidney cancers through the VHL gene. And this was the same pathway that led to the 2019 Nobel Prize by William Kaelin and has now translated into orally available medications that are promising for the treatment of kidney cancer.

So at GU ASCO, we saw two interesting abstracts in this space, one was an updated follow-up from a phase I, II study of belzutifan. In this trial with a heavily pretreated population of predominantly third-line clear cell kidney cancer patients, belzutifan achieved a 25% overall response rate, which was quite impressive with an equally impressive 14.5 months median progression-free survival, again, in this heavily pretreated patient population.

I think the second abstract to point out is a phase II trial of belzutifan in combination with cabozantinib, which of course is a well-established VEGFR TKI, currently, FDA approved for clear cell kidney cancer. Within cohort two of this trial, patients with prior immunotherapy were treated with belzutifan and cabozantinib in the second and third-line setting achieving an overall response rate of 22% with a 34% overall response rate when unconfirmed responses were included. Among these patients, 88% had a reduction in target lesion size with only 1% out of 41 experiencing the progressive disease. Again, in a pretreated patient population, very impressive results, but of course, still early with relatively small numbers of patients. This points to a lot of anticipation for the ongoing phase III trials of belzutifan in kidney cancer.

Alicia Morgans: Well, it sounds like so much progress has been made and I sincerely appreciate you sharing these updates with us, but certainly a long way to go. I look forward to continued conversations with you as we hear updates over time and continue to try to put the abstracts that we hear at these meetings into the context of our clinical practice on a day-to-day basis. Thank you so much for taking the time to go through all of this with us and for sharing your expertise,

Wenxin Xu: Thank you, Dr. Morgans. I was so glad to be here.