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Petros Grivas: Hello, I'm Dr. Petros Grivas. I'm an associate professor at the University of Washington and Fred Hutchinson Cancer Research Center, and an Oncologist at Seattle Cancer Care Alliance.

I'm very excited and thrilled today to host two of the most prominent figures in GU oncology. Professor Dr. Toni Choueiri, he's a true professional at The Harvard Medical School, and he is the Director of the Lank Center of GU Oncology at The Dana-Farber Cancer Institute. As well as Dr. Monty Pal, Sumanta Pal, the famous Monty, who is a professor at the City of Hope Comprehensive Cancer Center.

Guys, thank you so much for joining today, both of you.

Sumanta (Monty) Pal: Thanks, Petros. When you said two prominent figures in GU oncology, I was thinking, well, you've got Toni here, and then who else? But thank you for including me in that.

Toni Choueiri: Oh, he's so humble.

Petros Grivas: So guys, we experienced a fantastic ASCO GU 2021 symposium and both of you had some really, really practice exchanging data, as you usually do.

So, Monty, we will start with you. I met you about 10 years ago, when you were starting to put together a PAPMET trial, and working very hard to generate preclinical data. Can you walk us through this experience? The energy that it took you to get a study through the cooperative groups, the SWOG 1500, that actually resulted in practice-changing data that was just presented at ASCO GU.

Sumanta (Monty) Pal: What's so crazy is that I have told bits and pieces of this story on Twitter, and I think you may have seen some of that. But I was actually at an airport in Seattle. I think it was when we were hanging out. Maybe it was actually at the SWOG Young Investigator Training Course. But I was chatting with Toni Choueiri and he was giving me some advice on how to structure a trial in papillary. And I remember on the back of a napkin, or a piece of paper, I'd written down this concept for sunitinib versus cabozantinib in papillary kidney cancer.

And as the cooperative groups go, the study expanded, but at one point it was a six-arm study. It got narrowed down as certain companies participated and chose not to participate, but ultimately this turned out to be a four-arm trial, looking at sunitinib as a control arm, versus cabozantinib, and two MET inhibitors, savolitinib, and crizotinib.

Petros Grivas: Over the years, you pretty much narrowed down this study into a two-arm trial. Do you want to talk a little bit about the results at ASCO GU?

Sumanta (Monty) Pal: Yeah. Yeah, sure. Just as you alluded to, the study ultimately whittled down, ironically, to what Toni and I discussed a decade ago, sunitinib versus cabozantinib in these patients. And it very much mirrored in fact the results that Toni got from his CABOSUN clinical trial, looking at the same randomization in clear cell kidney cancer. The savolitinib and crizotinib arms dropped out very early, after a futility analysis that was designed to look at outcomes after 15 progression-free survival events. And we had the two lasting arms, sunitinib and cabozantinib, ultimately report out with a PFS of 5 1/2 months with sunitinib, above nine months with cabozantinib. So, cabozantinib ultimately won out there. The response rate with cabozantinib was much higher, 23% versus 4%. So really a strong signal for cabozantinib in unselected patients with papillary kidney cancer.

Petros Grivas: That was some amazing effort and took so much energy over the years, and it's great to see the finish line here. And the paper in Lancet, a fantastic publication. Congrats Monty, and the whole team. Toni, would you agree that this is practice-changing, establishing this cabo standard of care in papillary metastatic RCC?

Toni Choueiri: I do. If you look at the progression-free survival response rate, there is no doubt that this study met strongly its primary endpoint. I would love also to see the effect of cabozantinib in MET-dependent patients, which is probably around 30% to 40%, and that work is ongoing. My understanding with Brian Shuch, who's the [inaudible 00:03:55] lead. It brings back memories of hard work, I think Monty and I were on the phone, he was in Seattle. I don't know what airport I was in but I remember that I was in an airport also, but not the same one. So it tells you that for all our, the young investigators of that, it takes a lot of work initially, and a lot of perseverance and sticking with the idea and I'm happy that Monty was able here to change the standard of care with the SWOG team, Dr. Lara and others. And I think it should not come as a surprise overall, but I think this is an important strategy now in papillary kidney cancer.

Petros Grivas: And don't you have data working on metastatic kidney cancer, amazing practice-changing work, but you also presented the data in the SAVOIR trial, I think last year. Any comments on that, in terms of the context of Monty's PAPMET trial?

Toni Choueiri: Yeah. We took a bit of a similar approach, but a bit more different, in terms of drugs and target. We said to ourselves since 30% to 50%, maybe, of papillary RCC do have some serious alterations in MET where that receptor is mutated, amplified, the ligand sublimes are amplified, you have chromosome seven duplication if you group all those patients, 30% to 50%.

We've done preliminary work with savolitinib, and actually, Monty was involved, with this in Phase I and Phase II studies, and showed that their responses when they happen with savolitinib, which is a pure MET inhibitor, happened in patients that have MET alterations. And the side effect profile of this drug, you take away all the VEGF-targeted side effects, are actually quite good, and it is quite tolerable.

So we launched a trial against sunitinib, a Phase III, in the MET altered patient. The trial, unfortunately, had to stop because the accrual wasn't going well. But most importantly, we had a molecular epidemiology study that showed that MET-altered patients receiving sunitinib do the same as MET independent patients. So then when you look at SAVOIR, with the control arm being sunitinib, you have to readjust all the statistics, increase the size of the trial. So it wasn't really possible to continue.

So we enrolled out of 180, [inaudible] and interesting enough the results came. The PFS hazard ratio was 0.70. The OS hazard ratio was 0.5. The response rate was three times more. None of them were significant just because of this power, but certainly, the efficacy favors and the toxicity favors, largely savolitinib. And so we did not, were not able to close on the study. But nevertheless, it's a good proof of concept, and hopefully, we will build on that with immune checkpoint inhibitor combination in a MET-dependent population in the future.

Petros Grivas: Thank you, Toni. These are excellent points and as we think about combinations, Monty, I know you have been mentoring so many people in the field, like you and Toni, do you want to talk a little bit about the next steps after PAPMET and the practice-changing data? Are you already thinking about the next step in this papillary RCC?

Sumanta (Monty) Pal: SWOG has had a long history of papillary kidney cancer. It actually dates back to some studies of erlotinib monotherapy, which obviously didn't turn out very well.

There was a second look at erlotinib with a compound that was a putative MET inhibitor called ARQ197, then PAPMET, of course. So we are hoping to really continue the momentum with the study that Ben Maughan is proposing through the cooperative groups called PAPMET-2. The concept is really simple, cabozantinib with, or without immunotherapy. So we are hoping to build on the success of PAPMET one in an unselected population.

I think there's so much room for other studies in non-clear cell disease. I think Toni has really taught me that there is probably room also for studies that really look at MET-driven tumors specifically. So I'm hoping that we see more of that over the course of time as well, but there is just still a lot of work to do. I think PAPMET was helpful in establishing a standard of care for papillary kidney cancer; but my hope is that it is temporary, that we get even better drugs for these patients.

Petros Grivas: And the last quick question, guys, for both of you before we finish this wonderful discussion. Do you see the need for germline testing in patients with papillary RCC? I know there is MET type one and MET type two papillary RCC. Do you do that routinely, or is it based on family history, age of diagnosis? How do you approach that with the patients and families?

Sumanta (Monty) Pal: Yeah. I can tell you just in my clinical practice, I sequence all my patients with non-clear cell kidney cancer, and you just never know what you are going to get in that population. Everyone is biased by their own experiences, but I had a hit rate that was considered for ALK alterations in my population, so we actually treated some of these papillary patients with alectinib, the drug that we would apply for that 4% of patients without translocated lung cancer, got some really great results. So, I definitely think there is a role for it.

Now that's referring to somatic sequencing. When it comes to germline sequencing, I also feel that there's a call to probably refer most of these patients for counseling, especially if there are questions around family history and so forth. We are lucky in Los Angeles to have Brian Shuch, who Toni alluded to, right across the town, who is a real expert when it comes to hereditary disorders. I think he advocates for a lot of these patients receiving some form of genetic counseling that may ultimately evolve into the genetic assessment.

Petros Grivas: Thank you, Monty, I appreciate your comments. Toni?

Toni Choueiri: Yeah, no, I think that's sensible. No doubt. Not every patient, I think family history and age bring really, to me are very important in selecting patients, but also the stage of the patient, for a small stage, one tumor in an elderly gentleman without any family history or personal history of cancer. I am really not sure here. But then, you have the younger patient with a locally advanced or advanced tumor, whether it's a clear cell or rare variant histology that probably should get both somatic and germline testing, and anyone in the middle.

There have been studies now in renal cell cancer that showed that systematic germline testing can yield more information and more insight than relying on triggered testing by family history and age.

The problem also, even if you find something, yes, there could be the implication, but sometimes you wouldn't know what to do with that information, and that also can happen. So I do get it, like Monty, almost on all the patients, certainly the metastatic one. Sometimes though, I have to admit, I don't know what to do with the information. But maybe I'll know in the future, and the biology becomes much more clear.

Petros Grivas: Again, with you guys. I think we need to do more work with genomic sequencing, both on the somatic side and target validation, as well as on the germline side. I think genetic counseling is definitely a career on the rise, and I advise younger folks who want to pursue a career in genetic counseling, that it definitely has a significant future, and type one, type two RCC are just examples, but there are many more.

I would like to thank both of you for your insightful comments here. Again, congratulations, Monty for PAPMET with your team, and looking forward to discussing more with both of you.

Toni Choueiri: Thank you.

Sumanta (Monty) Pal: Thanks, Petros.