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Pedro Barata: Hi, I'm Pedro Barata. I'm a GU medical oncologist at Tulane Medical School in New Orleans, Louisiana. I have the pleasure to be joined by Dr. Christopher Ryan. Dr. Ryan is a professor of medicine at Oregon Health and Science University, Knight Cancer Institute. He also serves as the executive officer for the SWOG Cancer Research Network. Thank you, Dr. Ryan, for joining us today.

Christopher Ryan: Thanks Pedro.

Pedro Barata: First of all, congratulations on your very elegant presentation on EVEREST. Large effort from the cooperative group led by SWOG, and it's a great effort investigating the role of Everolimus in the adjuvant setting. So, very elegant presentation out of ASCO in Chicago. And there's a lot of thoughts about it, and insights on that particular data, and also, kind of next step. So, hopefully we'll cover all that. But I perhaps would start by asking you, as the PI, please, can you summarize for us what would be, I guess, the highlights from the efficacy point of view, but also from the tolerability of Everolimus.

Christopher Ryan: Right. Yeah, thank you. I can do for us. So, to briefly summarize, SWOG SO931, and I mention that because S09 means the year it was just developed. This study we designed beginning back in 2009 when EVEREST had just been approved for metastatic disease. And there was really nothing, no positive data in the adjuvant landscape. And we fast forward now, Everolimus, to put it in context, is to my knowledge, the only study of adjuvant mTOR use in renal cell carcinoma. And in the metastatic setting, obviously the field has changed. Checkpoint immunotherapies have really come to the forefront. And Everolimus mTOR pathways, I don't want to say been forgotten, but it's kind of fallen to the bottom of the list.

So, when we did this placebo control trial, over 1500 patients randomized to up to a year postoperative. Everolimus, we saw an improvement in recurrence free survival, with patients who received Everolimus. For the overall study population, the hazard ratio was 0.85. The issue is that we just missed statistical significance with the one sided P value of 0.025. And because of the interim analyses and spending alpha, the threshold for significance was 0.022. So, just missed that by 0.03. When we looked at subgroups, however, the thing about EVEREST, it included a wide range of risk, based on staging. All patients, from T1B high grade, T1B, all the way up to node positive disease went, and we stratified by a group of patients we called very high risk, which was T3A high grade up through node positive disease. And patients were stratified along those lines. And in that group, the very high risk group, the hazard ratio was 0.79. And the one sided P value was 0.011.

And when you looked at the rest of the patients, what we call the intermediate risk, or really the lower risk group patients, there was no difference at all. The curves were completely superimposed. So, this benefit seems to be restricted to these high risk patients. And so, we're obviously very excited by those results. The issue about side effects, I think the side effects of Everolimus are well known. We saw nothing surprising in terms of the side effect profile, probably mucositis was the most bothersome side effect to patients. And 14% of patients had grade three or higher mucositis, I'll point out that we did not do any kind of prophylactic dexamethasone washes, like what's done these days. So, there wasn't kind of a prophylactic strategy that might help mitigate that.

But there was a fairly high dropout rate because of sought side effects. About 37% of patients discontinued the Everolimus early due to adverse events, and only 45% overall in that arm completed all adjuvant therapy. And this is something we see across, certainly the TKI studies, with relatively high dropout rates due to adverse events in the adjuvant population. And I'll point out, we see it across oral cancer adjuvant therapies in general. In general, if you look at breast cancer, chest tumors, lung cancer, kind of the tolerability of patients in the adjuvant setting seems to be less. So again, no surprises in terms of side effects, but as we see with other, especially oral adjuvant agents, kind of a lower acceptance rate among patients. And I think we could potentially do better with that with a very intense side effect monitoring and management in clinical practice.

Pedro Barata: Those are great, great, great points. Thank you for breaking it down for us. That's very helpful. And I mean, I couldn't agree more. That's kind of what caught my attention as well, from your presentation. I also know that you did a great job, as usually SWOG in a cooperative groups do, right? As far as correlatives. I mean, you did get tissue available, and you got samples. And so, the question that I have for you is, down those lines of, with a different mechanism of action, it is true that the mTOR inhibitors in general lost traction, right? Perhaps the exception in the metastatic setting might be the combination with Lenvatinib. But they were moved later in the course of the disease, so it's kind of provocative, I think, that we see data from EVEREST, actually in the high risk population as you pointed out. So, I guess the question I have for you is, what can we do on the biomarker perspective to understand a little bit better, who are the patients who might benefit from it? And thinking of tissue and perhaps blood samples, if you will, what is the work that you and others are kind of planning on doing to help us understand a little bit better the place and role of these mTOR inhibitors?

Christopher Ryan: Yeah. Well, excellent question. And this is something that's kind of baffled us in renal carcinoma for many years now with our targeted agents. We've had targeted agents for years, but kind of really inability to predict response based on any biomarker. With the VEGF and with mTOR as well, and to some degree as well, with the checkpoint immunotherapies. In my mind, it still raises the question, why does mTOR exactly work in renal cell cancer and other cancers as well? We always talk about, is it have to do with mTOR regulation of [inaudible 00:07:16], but it's a very central pathway. The mTOR pathway, lots of growth factors that can signal through the pathway, and senses nutritional signaling for the cell, and as well as potential immune effects as well.

So, I think it remains somewhat unknown why mTOR really works in renal cell carcin, and why it might work in the adjuvant setting. So, to that end, we are going to explore this more and start looking for potential. Well, I'll be honest, we did not know this was going to be a positive or near positive study, because there was some pessimism about mTOR inhibitors. So, we had been talking now for the last few years, about looking at prognostic markers from these samples. But now, we have the opportunity really to look for predictive markers, especially in this high risk patient population. So, this is being planned. We hope to interrogate the tissue. And I can't go into too many details yet, but various molecular profiling platforms to see if we can elucidate a subgroup that may benefit.

And as well as focusing on the mTOR pathway, as well as some other kind of generic signature pathways, kind of talking about how it works. In the mTOR pathway, just looking at the data, we thought, "Well, maybe this positive signal is being driven by known alterations that may make mTOR an important target, such as PTEN and chromophobe tumors." But actually, when we looked at kind of chromophobes, not that many patients, but still a sizeable minority of patients, or non-clear cells, we didn't necessarily see a signal in that group. So, it remains to be seen what is driving the activity. And we're going to be looking at that, especially honing in on the mTOR pathway itself.

Pedro Barata: No, that's great. Thank you for those insights, they are very helpful. And I guess, a follow up question on that. So, we have the biomarker where we can perhaps understand a bit better. The other piece of the story is obviously when we put Everolimus in the context of everything else out there, right? We had a number, as you elegantly show, by the way, one of your slides actually is great, because it puts everything together. So, I definitely recommend everybody to look at those slides, because they're very helpful for us to study. And of course, for target therapy, you show elegantly all the studies that have been done with different target therapies. And as you pointed out, they've all been negative except, abstract for Sunitinib. I mean, of course, more recently, we've been kind of living around the promise around checkpoint inhibition.

We have the adjuvant Pembrolizumab being now FDA approved. And yes, we got some news around Nivolumab, and we are expecting other news regarding combination regimens. And that's already in the works, and we're going to find out what's the exact role of checkpoints beyond Pembrolizumab in that setting. And then, we can also add that, as you know, there's a number of studies being prepared or being designed as we speak, exploring different combination approaches, right? Whereas IO plus TKI or IO different strategies. So, with all that said, this seems to be becoming a very busy place and setting for these patients. And mainly clear cell, but not all of these studies are addressing those questions in the clear cell histology and go beyond that to non clear cell. So I guess, the broader question that I have for you is, knowing the perhaps immunosuppressive properties of Everolimus among other characteristics, how do you see we can leverage EVEREST data into the next steps? Would you rather focus on the high risk population where the signal seems to be the cleanest, I guess? Or do you think there are out there some interesting combination approaches that one could explore, whether it's through a cooperative group mechanism, or a different mechanism? What are your thoughts as you see this field moving forward?

Christopher Ryan: Well, I think we can't ignore Everolimus based on these data. We have to bring it kind of back into the fold, and think of how we move things forward. I mean, basically we have, thus far, one positive study out of each of these therapeutic categories. VEGF, four negative, one positive. PD1, the story's evolving, one positive study, and some other studies forthcoming that may not be positive. And one study, and one study only, of Everolimus mTOR pathway. So, how we figure all this out is a good question, but I think I would certainly advocate for Everolimus playing a role in future adjuvant studies. I think as far as the risk grouping, obviously this signal was really only seen in these very high risk patients, that kind of really overlaps with what we've seen more or less with the other positive studies. The S-TRAC trial, and the Pembrolizumab trial, which really focused on higher risk patients. So, that certainly should be our effort, I think in future studies, that we really focus on that group.

And then, what role could Everolimus play in future studies? Does it have a role to be a single agent? I think, as a comparator in trials, I think so. I think it warrants a seat at the table. And then, interesting combinations as well, and this is where it's mostly conjecture. I think that it's actually interesting, again, going back to how Everolimus actually works in kidney cancer, remains somewhat of a little bit of a mystery, because it has so many different effects. On one hand, it's an immunosuppressive. On the other hand, I've found some preclinical data actually suggesting that it actually may have some immune stimulating properties, in conjunction with checkpoint inhibitors in frequent clinical models, which is intriguing in and of itself.

And the other thing about the Rapamycin analogs is, I'm not familiar with this whole body of research, but actually in the anti-aging research community, there's ongoing interest in studies of Rapa logs as kind of fountain of youth drugs. Including studies of Everolimus in patients over 65, actually showed that it can actually boost immunity in conjunction with vaccination. Again, I'm not totally familiar with that data, but there's all this potentially immunostimulatory effects of it as well, that I think we need to think carefully about in potentially designing rational combinations for a next generation of studies.

Pedro Barata: Well, that's indeed really, really interesting. Those are priceless insights and thoughts. Dr. Ryan, I really appreciate you sitting down with us today and walk us through the EVEREST. Again, congratulations for a very nice presentation in Chicago, and the future is bright. Thank you for your work. Also, thank you for leading the efforts of an important cooperative group, as SWOG is and represents for researchers around the world. So, thank you for that. And I hope to see you soon.

Christopher Ryan: Thank you, Dr. Barata. Enjoyed the conversation.