Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago, Illinois. I am so excited to have here with me today, a friend and colleague who is here to highlight some of the abstracts that were presented at ASCO 2020. Thank you so much for being here with us today, Dr. Choueiri, to talk about the kidney cancer abstracts that we really wanted to dig into a little bit more, particularly because several of them are yours. It's great to talk to the lead author.

Toni Choueiri: Thank you.

Alicia Morgans: Wonderful. So some of the abstracts, including SAVOIR, there was the OMNIVORE study, can you highlight some of the abstracts that we've discussed related to ASCO 2020 this year and help us think through them in terms of putting them all in context?

Toni Choueiri: Yeah, no, I'll be happy to. I think one thing I want to highlight because it encompasses multiple presentations and an important question in the field of renal cell cancer, is we have a very important standard first line, which is nivolumab, ipilimumab too, immune checkpoint blocker, a PD-1 and a CTLA-4 inhibitor. And that combination is approved frontline in advanced, intermediate, and poor-risk clear cell renal cell cancer. A complete response rate 11%, an overall response rate of 42%, the survival benefit over in old standard sunitinib. But the question started many years ago, even before that combination got approved, is can we sequence these drugs and perhaps keep the same efficacy and lower toxicity. As we know, nivo and ipi have more immune-related adverse events that could be serious compared to each drug alone.

So a lot of studies were launched. At ESMO 2019 there was an oral presentation by Dr. Grimm that showed that if you start by nivolumab and ipilimumab, if you actually don't have a response from four doses, your complete responses are low. The salvage rate is less than 20%, in the range of less than 15%. And probably you'll have a high attrition rate. Some patients just can't stay on study and get ipilimumab. And here we had two studies somewhat similar in design, one from Dr. Atkins, the HCRN study that came to the same conclusion starting by nivolumab. And if you do not have a response, you add four doses of ipilimumab. And the salvage rate was in the 12, 13% without any complete responses within an attrition rate. In a smaller study by Dr. McKay, 83 patients came to the same conclusion and in this, the salvage rate was even less than 5%.

So in my opinion, if you want to get the maximum benefit from nivolumab, ipilimumab, give it in untreated patients, give it together. Nivolumab, then maintenance, and ipilimumab, the four doses. That's where you start seeing the CR, you start seeing the higher responses. And give it in untreated patients, because there's another study I've been involved with a collaboration that looks at nivolumab and ipilimumab as part of a large program called FRACTION-RCC, which is a very interesting program that evaluates actually new assets in immuno-oncology from BMS and has two tracks, I-O untreated and I-O experience. So we reported on 46 patients that were I-O experience that get nivolumab, ipilimumab after progressing on prior I-O, nivolumab, pembrolizumab, atezolizumab, you name it. And we saw, again, a response rate 15%. That's great, fine. There are responses, no CRs, low progression-free survival. Yes, some of these patients couldn't be salvaged by nivolumab, ipilimumab. We saw an introspective study from, at that time, Cleveland Clinic, from Dr. Rini. But again, we're not reaching the 42% response rate and the 11% CR. Important studies suggesting, again, start by a strategy of nivolumab, ipilimumab together, combination in untreated patients.

Alicia Morgans: Absolutely. I think that's a really powerful message to everyone practicing in the community too, and of course, academic centers as well. That sometimes we think about starting easy on a patient and if that patient can tolerate or seems to have progression, then we think about adding something more intense like ipilimumab or a different combination, just as you have tested. And it just doesn't seem like that approach is really the one that's going to get us where we need to go. If you're going to commit, commit to both drugs upfront or choose an alternate regimen is what I think these studies are showing. Is that what you're getting at?

Toni Choueiri: All right. That's correct, although, I would say one caveat. We haven't looked at Dr. McKay's study, but in the study of Dr. Atkins, the HCRN. Interesting enough, if you look at the INBC favorable risk, these are not more than 20% of all-comers. The response rate is 50%, the PFS near 20 months. That mirrors the experience of Dr. McDermott whose KEYNOTE-427 with a single agent pembrolizumab in untreated patients where the responses were higher in INBC favorable risk. And then we start seeing, when you give a combination, let's say pembrolizumab, axitinib, with more follow up, the overall survival has a ratio versus sunitinib, which is not standard anymore, it was above 1. So you ask yourself in INBC favorable risk, do you need two drugs? Could you get away with one TKI or one I-O checkpoint inhibitor-based on just overall survival? And this is really, really intriguing. And I think hopefully people could invest in the INBC favorable risk group to see what is a minimal strategy of less. Because less could be more and certainly less toxic.

Alicia Morgans: I think in kidney cancer, we have that unique opportunity. Certainly, we have a way to understand these risk groups. We've been using that for years. We understand how that seems to really be tightly associated with prognosis. And it also seems, as you've just mentioned, that that is associated with our responses to these different approaches. So I know that you have been involved in a lot of the thought around de-escalation, perhaps, in patients who don't need more to save them from the toxicity and save them from going through something. But then they end up stopping therapy because they've had some major complication. But of course, to apply the necessary disease control using all the guns that we have that are available in those patients with higher risk. So I have a feeling we'll see more studies from you that really look at this escalation/de-escalation strategy. And I look forward to that. I'm sure some are in the works.

Toni Choueiri: We are having some of these and actually very proud of the kidney cancer trialist communities worldwide, how we come together. We really consider ourselves a family overall. And we're able to answer very important questions for our patients who accept to continue being part of clinical trials.

Alicia Morgans: Absolutely. And you actually presented another trial looking at sunitinib versus savolitinib, and this was the SAVOIR trial. And I'd love to hear your thoughts on that.

Toni Choueiri: Well, SAVOIR is kind of a labor of love. And SAVOIR, we named that trial, it's a French word meaning knowledge. It was a labor of commitment and love to papillary kidney cancer. It's one of the areas dear to our heart. It's an uncommon kidney cancer, but it's the most common uncommon kidney cancer. And work from the TCGA we had was, at that time, Marston Linehan. And then at the same time, the French Group with Dr. Albiges, who was one of our DFCI fellows, in parallel converged on the fact that there's a subset in these papillary renal cell cancer that are MET, I would say, dependent. MET is a tyrosine kinase that involves, I would say, 30 to 40% of renal cells have alteration in MET. And by that I mean, a chromosome 7 duplication and MET reside on chromosome 7. They could have a mutation in the MET domain, whether in the tumor somatic or in the germline, we have some hereditary form of kidney cancer. And actually the ligand, the hepatocyte growth spectrum could be amplified. So maybe 30% overall.

Now we conducted a Phase II study with savolitinib, which is a pure MET inhibitor, an international study. And we saw a low response rate, 8%. We published that in the Journal of Clinical Oncology. However, when you go retrospectively and look at the 30, 40% subgroup that is what we call MET dependent, knowing for each alteration, we don't know how much it's going to drive the tumor in that patient, but it does make sense. We saw a response rate of 18% in PFS over six months. And if you're MET independent, your response rate is 0 and your PFS is near 0, your first scan. So based on that, we took this to a Phase III trial of controlled sunitinib, average control in all renal cell trials, versus savolitinib. The good thing about savolitinib where we focused on it, since it's a pure MET tyrosine kinase inhibitor, it doesn't have the VEGF target therapy toxicity. So we don't see hypertension, we don't see fatigue, the reaction is a well-tolerated drug. There are some LFT changes and some edema, but actually it's overall well tolerated.

So we took this story Phase III trial, we start enrolling in MET dependent. So patients had to be screened. Unfortunately, we had to stop the trial after 60 patients. We envisioned enrolling 180. We stopped after 60 because, in parallel, we ran a study with Dr. Albiges and Dr. Heng, my close colleagues. It was a retrospective epidemiological study that wanted to see what is the progression-free survival of sunitinib if you have MET altered papillary RCC. And the whole idea around putting statistics and designing SAVOIR was the fact that we assume, like in other tumors, MET-driven tumors in papillary or metastatic papillary RCC, we'd have a shorter progression-free survival and a worse outcome.

The epidemiological studies, which patient from Dana-Farber, the INDC, France, and Korean group showing that actually, no, this is not prognostic. MET alternations are not prognostic in papillary RC. Now in retrospect, it doesn't mean that MET altered papillary RC would not respond to MET inhibitor. So I think we had some discussion then, but the bottom line, the study stopped after 60 patients.

When the study results were analyzed, we saw actually that the response rates were tripled with savolitinib. The PFS hazard ratio to primary endpoint was 0.7, the OS has a ratio 0.5, and the safety favored largely savolitinib over sunitinib. So this was a moment of, ah, what have we done? So we went back to the drawing board here, and hopefully, we will bring savolitinib in MET dependent papillary RC, in another trial as a single agent with checkpoint inhibitors. So we have a working group working on this. And yes, in retrospect we should have continued. But you cannot build a trial, think about the epidemiologic study, have results, and go in retrospect.

So I cannot claim savolitinib is superior to sunitinib. We have a concomitant publication in JAMA Oncology. This is a severely underpowered study, but actually, at the same time, there are some very intriguing results.

Alicia Morgans: Absolutely. And at least it did what a Phase II we hope will do, which is to profile more clearly, there's definitely a signal or at least there's a hint at a signal. And so moving it into another trial actually makes a lot of sense. And if you design it, you may not put it versus sunitinib. There are lots of things that you can do. And this is a population that really needs that attention. It's also really important to, while you're running a clinical trial as new data comes out, to be able to recognize that data and integrate that knowledge into the trial. And if you have to stop the trial because of assumptions that may or may not be true, you have to do that.

So you definitely did that and still accomplished what we need to understand from a Phase II sufficiently. And so I still think that's an exciting result, and as you said, maybe moving forward into future studies. So as you think about the SAVOIR trial, OMNIVORE, all of the trials that we've discussed today, what would your take-home message be from ASCO 2020 from a kidney cancer perspective?

Toni Choueiri: I think there's always room. I see when I was a fellow in Cleveland. And at that time, my mentor, Ron Bukowski, who's retired, we're working on sorafenib and how we went and how we have new targets, new ways focused on rare variant histologies, two major grant, SPOREs, a Department of Defense focused on kidney cancer. I think kidney cancer is more and more exciting, more junior colleagues joining the battle against kidney cancer, more postdocs.

This is still a disease, Dr. Morgans, that kills 15,000 people in the United States alone. So we have to do better. I think they will be more focused on early-stage disease, but as we've seen in ASCO 2020, it's still very, very vibrant. I think we have an update on major Phase III trials. We have questions about sequences that they didn't pan out like we wanted, but we have answers now.

And I think I like the focus. I didn't bring it up in it, about non-clear cell and rare variant histology. We brought it with SAVOIR, but there are a couple of abstracts with other combinations. And with the new drug, which is a HEF-2 inhibitor work in part based on the Nobel Prize in October, 2019, that showed that inhibiting HEF-2 is a small molecule, not just in clear cell RCC, which was what's reported at the previous ASCO meeting, but also in VHL syndrome with clear cell RCC is a powerful strategy that results in responses and alters the natural history of the disease. A very exciting time for kidney cancer, and GU cancers, in general, obviously I'm very biased to think it's the best field go to, but it is. And thank you, UroToday, for always providing some of the best updates in the field.

Alicia Morgans: Wonderful. Well, thank you for your compliments. Thank you for sharing your insights and we'll have to focus, I think, in another recording on the non-clear cell rare variants. Because I agree with you, they were highlighted at ASCO this year and really do deserve attention as we're putting these patients into buckets and really trying to address them by risk strategy and also by their histology. So thank you so much for your time. Thank you to all the patients who, as you mentioned, have participated in these trials. And thank you again.

Toni Choueiri: Thank you, Alicia. Take care. Bye.