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Alicia Morgans: Hi, my name is Alicia Morgans and I am a GU Medical Oncologist at Northwestern University. I am delighted to have with me here today, Dr. Toni Choueiri, who is the Director of the Lang Center for GU Oncology at the Dana Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, and a good friend of mine. Thanks so much for joining us here today, Toni.

Toni Choueiri: Thank you for having me. It's a pleasure to be on UroToday.

Alicia Morgans: One of the things that I wanted to really pick your brain about is kidney cancer in general and really to think through some of the advances in the last year. You've had a hand in some of this with the CABOSUN trial that you reported, maybe about a year ago. I'd love to hear your thoughts on the CABOSUN trial and how it's really changed the landscape of treatment of kidney cancer.

Toni Choueiri: Thank you, Alicia. I think this is a good question. It's one of these more recently approved frontline therapies based on the CABOSUN data. Cabozantinib showed in this trial randomized phase II, superiority over sunitinib. The story with cabozantinib came essentially the approval from a second third line study METEOR where cabozantinib did result in a superior progression-free-survival response rate and overall survival compared to everolimus . But then cabozantinib later on was taken in the front-line setting against sunitinib and that is the CABOSUN, CABO, cabozantinib and SUN, sunitinib. And actually, despite the study being randomized phase two at that time, it was really powered for progression-free-survival. The study was run by Alliance for Clinical Trial with support from the sponsor and here what we focused on is those 70-80% of patients with poor and intermediate IMDC risk group because we do feel that these patients need usually systemic therapy. In general, patients with good risk disease do well from VEGF tyrosine kinase inhibitor and occasionally they don't need to be treated immediately so that's why we focused on the intermediate and poor-risk disease. We published actually our results both in the Journal of Clinical Oncology and earlier this year, the European Journal of Cancer.

First, we looked at the progression free survival by investigator assessment which was the primary endpoint. Cabozantinib was superior to sunitinib and then later on this year we looked at independent review and again the results also remained significant. The hazard ratio actually dropped from .6 to .4. Responses also were significant in favor of cabozantinib. Overall, survival was not different, the study was not powered for survival, unfortunately an area that is of your interest is, quality of life and health reported outcomes. We didn't have that, we had just plain toxicities and the incidence, actually, of grade 3/4 adverse events was not different between sunitinib and cabozantinib. Based on that CABOSUN study, cabozantinib was approved in the front-line setting in the United States and in Europe.

Alicia Morgans: That's great. I also loved that you had the second publication of CABOSUN with this independent radiology review. I'd love to hear your thoughts on the hazard ratio dropping with that independent review and just how important that is, because as investigators we all know that it's actually, at least from my perspective it's kind of challenging to be an investigator and do the RECIST measurements on our own. We do it, we do it all the time, but to have an independent central review doing the RECIST measurements and then to report that out separately and to demonstrate that hazard ratio, I think, is really, really powerful and I'd love to hear your thoughts.

Toni Choueiri: Well, I totally, totally agree because this was, at the end of the day, a smaller study despite cabozantinib established itself as a treatment already in the second line setting, but this was important. It's a smaller study, I think also it's a study that was conducted in multiple centers with multiple investigators, even from each center. Some of the centers enrolled a handful of patients, others enrolled more. So, I think having all the scans converged to one place to be read is very, very important, especially when your primary endpoint is progression-free survival and you have look at RECIST. Of course, this is not a problem when overall survival is the primary endpoint.

There were differences, the PFS, the hazard ratio changed, the responses actually were lower on independent review and our guess here is that there were a lot of responses that we call responses but they're not confirmed so they're not really confirmed responses on investigator assessment. Patients who had the response, it wasn't confirmed because either the patient went off-trial or then the tumor grew a bit so you don't have two scans that have 30% or more shrinkage. Based on that the response went down a bit with the independent review but everything held and when we looked also in the second publication, actually, a sub-group analysis, so intermediate versus poor, patient with bone metastases versus no bone metastases again in adverse prognostic factors, patient with visceral metastasis versus not. And you know you cannot look at millions of prognostic factors here just because it's a smaller study, it's 157 patients, but when you look at the sub group analysis it overall favored cabozantinib over sunitinib. So the results are strong nevertheless.

Alicia Morgans: Yes, and they certainly, I know, have been updated in the NCCN guidelines which is really a huge thing to happen out of a, like you said, a small phase two. So the power of these results and of the independent review, I think, is really clear. And I wonder, as a kidney cancer expert, how do you think through treatment of first line, intermediate, and poor risk RCC because that list continues to grow, and you know, we had the ipi/nivo data come out. I'm just really curious how you think through making these decisions between drugs when you see patients who are in the intermediate and poor risk categories.

Toni Choueiri: Yeah, good question, and you know, I can say in my area, as yours is prostate cancer, and at some point, remember, we had to choose between abi or enza when they were both approved in that same setting at some point, then we had to say, one was steroid, one without steroid, knowing that this is prednisone 5mg bid which we gave right and left. So this is not different in renal cell cancer. I think the difference, though, here, though we will have a problem in the future with the many trials that are going to read, all against sunitinib, and not compared to each other.

But let's live in the moment here, and in the present. We are going to have... the issue here is another trial that showed an overall survival benefit, the combination of immunotherapy with nivolumab/ipilimumab versus sunitinib. And there is an overall survival data that CABOSUN does not have. This is a larger study, drugs with different mechanisms of action, and with some of these responses being long lived and durable. Having said so, nivolumab/ipilimumab despite it's in the same setting of intermediate and poor risk, untreated, clear cell RCC, it's not for everyone treatment.

You know, folks have to be familiar with a new, related adverse events, the patient may not want to come and get intravenous every three weeks, and then most important, cabozantinib is oral, so some patients, especially patients with bone metastases, there is data coming that was actually published in, actually, METEOR, in the second line trial showing that cabozantinib could be of more benefit, perhaps, in patients with bone metastases, which is a really truly unmet need a lot of work from Rana McKay, now that you see at UCSD, so there is a place where cabozantinib in the front line setting.
There's also a place for sunitinib and pazopanib because as you know, going to checkmate 214 the double immunotherapy study, patients with good risk, renal cell cancer, did better in terms of response, in terms of progression free survival, with VEGF TKI sunitinib, so in a lot of situations when patients have good risk and they wish for treatment, despite that nivolumab and ipilimumab is not wrong, the drug leads to responses and some of these responses are durable, but if you look at overall response, at median progression free survival, it favors VEGF TKI with sunitinib, so you could argue that sunitinib is the drug to give there.

It would have been easier if we had biomarker for VEGF tyrosine kinase inhibitor and biomarker for nivolumab or checkpoint blocker, but at this time, we don't have clear biomarkers that can be used in clinical practice.

Alicia Morgans: Thank you for that review and I love how you put it in perspective of prostate cancer for me, very much appreciated, Toni, and you're right. This is not a new concept in GU oncology. That we have had the good fortune of essentially having multiple options and trying to match the right treatment with the right patient and biomarkers are what we are all hoping for I think because that really takes our decision to a new level, a molecular level that might make our decisions more precise. And I'm wondering what your thoughts are on where biomarkers stand now? I know we don't have them at this point, but where do they stand, what work is being done that you're especially interested in and how do you see that part of the field going?

Toni Choueiri: You know, hard to speculate. I'm always interested in, a big part of my research about biomarkers, we have been working really hard on that the past five to ten years, though nothing made it to practice. I think we are close. I think the idea of looking at PD-L1 which has a differential effect on the nivo plus ipi study, is very interesting, and luckily, every study against sunitinib, the combo VEGF and PD1 is looking at that. So that's good for now, remains to be seen what comes of and will there be any compendium test or we will be doing whatever we think at each institution is the right thing to do.

The other area that really should make progress is new targets. So, despite that it's great that we have now the PD1 and PD-L1 to add to VEGF receptor blockade and mTOR inhibitor, I think it's very, very important that we still invest in new targets because even though patients have greater responses on nivo/ipi, they can live longer on drugs, some of the target therapy, but at the end of the day, there's a significant number of patients either do not respond from the get go or progress. So having a new target, whether it's through alternative pathways of angiogenesis or totally new targets or targets that are part of novel immunotherapy that can complement and build on PD1 and PD-L1 inhibition that is not called CTLA-4 inhibition, agonist, antagonist, and other drugs that target the tumor micro environment are very, very important because currently if a patient gets treated with, let's say, a PD1 inhibitor plus a VEGF tyrosine inhibitor, some of these studies going read, I think they are going to be positive, they're going to be superior to sunitinib. Then what do you do second line when you exhaust from the beginning a class like PD1 and VEGF, so I think those are going be the two areas we going go into.

I worry, though, that after, the study's read and positive we're going to have a void of investment in kidney cancer research, and in new drugs and new target. I hope I'm wrong in this perspective.

The other thing I want to mention, which is very important to our multi-disciplinary care that you and I, Alicia, are part of with our urology colleagues is that now there are ongoing studies, none of them read yet, of checkpoint blockers in the high-risk adjuvant setting, or even in M1 and ED. And so far, the results that are coming from the VEGF tyrosine kinase inhibitor trials are largely disappointing and mostly negative except for one trial, and only for recurrence free survival.

So, the trials that use checkpoint blockers are actually accruing, open and accruing. They are a few years away, but I think if we're able, like again with prostate cancer, like you did, giving enzalutamide, giving apalutamide, earlier and earlier and earlier, these drugs that initially enzalutamide for example approved post docetaxel in castrate resistant prostate cancer, they moved earlier. The checkpoint inhibitor drugs are going to be moved earlier and if there is a survival benefit or a significant recurrence free survival benefit in high risk disease, that's also going really alter how we deliver care to these patients.

Alicia Morgans: Absolutely, and one of your colleagues is leading an effort in a perioperative study, I think, looking at nivolumab prior to nephrectomy. Lauren Harshman is working on that and I know you guys work closely together, so that may be something that we ultimately, at least that trial's ongoing, I think it's an ECOG study, but all the cooperative groups are participating if institutions are interested, I believe, right?

Toni Choueiri: Yes, and I think this is one of the most important trials in the field now. Neoadjuvant is very imperative, so checkpoint blocker with single agent nivolumab led by our own, Lauren Harshman, with a lot of correlative actually built around it. Lauren put together a massive huge team of clinicians and researchers together. The trial is really accruing.

And it's important and it's so important to the field that in, compared to the rest of the studies that are ongoing, that study really built on preclinical rationale that checkpoint inhibitors was the primary in a lot of metastatic burden, a lot of antigens, they should result perhaps in a higher intratumor efficacy and anti-tumor effect through an immune effect. And I can tell you, looking at the lung cancer data, the breast cancer, I believe, triple negative breast cancer and lung cancer, non-small cell lung cancer data, checkpoint inhibitor used as neoadjuvant therapy resulted in a really very interesting pathologic CR rate. Same with bladder cancer.

Alicia Morgans: Yes.

Toni Choueiri: Two non-published studies presented at ASCO by Dr. Palos and Dr. Neki. Again, very encouraging, pathologic CR rate, almost equal, again, this is not, we are comparing across trial, but it seems that the pathologic CR rate could be similar to what neoadjuvant platinum-based chemotherapy would give you. So again, very important study, the PROSPER study of Dr. Harshman.

There are other studies ongoing, but these are all post nephrectomy, there's a study with atezolizumab the PD1 inhibitor that is studied with the combination of nivolumab and ipilimumab with Dr. Motzer that limits that combination to six months probably because of toxicity. And there's another trial that actually we are leading too, a year of pembrolizumab in also high-risk renal cell cancer. So again, extremely exciting times here.

Alicia Morgans: Yes, and just really a bit of a powerhouse group at the Dana Farber moving forward with kidney cancer and your colleagues, like you said, Rana McKay at UCSD really pushing the envelope to identify patients, who might be more attuned to having these responses. I know Rana, as you said, has done a lot of work with the bone metastasis arena. So we really look forward to seeing how your group changes the field.

The other thing I want to mention that you've alluded to, but I just want to make it clear to all the listeners, is that as you're thinking of moving these agents forward, in kidney cancer, it's very clear that groups designing these trials are thinking about not using indefinite checkpoint inhibitor therapy, but using a discreet amount, or using therapy over a discreet period of time, because we certainly in an adjuvant setting do not want to have patients for the rest of their lives on Q 3 week infusions of checkpoint inhibitors, so I appreciate the way, the groups that you're working with, and the groups in kidney cancer are making sure that they're designing these algorithms with a limit to the extent of treatment over time.

Toni Choueiri: I think that's very important. Actually, Lauren Harshman is leading another study with Rana McKay in the metastatic setting, where we give nivolumab and if the patient has a response, for six months we stop and we can again give nivolumab, in case of recurrence.

However, if they have progression of stable disease, we add ipilimumab at that time, too, to see if we can convert a progressor stable disease patient to a responder. And I think that's quite important. The right dose for the right patient. We built immunotherapy and checkpoint blockers to be given for a long period of time, sometimes upon progression. And it's unknown if you have a response that is durable, doesn't need to be CR if you need checkpoint blockers. I can tell you, in my practice, unpublished experience, I can see immune related adverse events such as colitis and pneumonitis and hepatitis happening after six months, nine months, ten months, and sometimes suddenly, without any major warning sign, where you think, deep down, that if your past, because that's what the clinical trial reported, that if your past the three, four months’ time that chances of the immuno-related adverse event happening is less and less.

So I think it's very important, and this is what precision oncology is, actually, it's not just sequencing the genome, but also, it is being precise in the amount of the drug that you give for each particular patient at a particular time, depending on their disease clinical characteristics.

Alicia Morgans: I absolutely agree. And also, being cognizant, as you were saying of the side effects that can happen over time, and limiting toxicities to our patients.
So, thank you for your time today, Dr. Choueiri.