Dr. Alicia Morgans: Hi, this is Alicia Morgans. I'm a medical oncologist at Northwestern University and I am delighted to have with me here today, Dr. Tian Zhang, who is an Assistant Professor of Medicine in the Division of Medical Oncology and the Department of Medicine and a member of the Duke Cancer Institute. 

We are thrilled to have you here today to talk with us about Keynote 564 which is really a study aimed at providing some information to the question of whether adjuvant therapy after surgery for kidney cancer may be beneficial. So, thank you so much for being here with us today.

Dr. Tian Zhang: Absolutely. Thank you so much for having me.

Dr. Alicia Morgans: Of course. There have been a lot of advances, generally, in the treatment of kidney cancer and so I'm just wondering, can you give us a little bit of background on some of these advances, particularly as they pertain to immunotherapies and immuno-oncology approaches?

Dr. Tian Zhang: Yes, of course. As you know, the treatment landscape for kidney cancer has really progressed quite rapidly over the last decade or so, but really first-line treatment of renal cell carcinoma somewhat stagnated quite a bit with VEGF inhibitors and it was only in the last year or so that we've had immunotherapy approaches rise in the first-line setting with the advent of the combination of Ipilimumab and Nivolumab which is Checkmate 214 study that was presented at ESMO 2017 and the combination was approved in first-line treatment of metastatic renal cell carcinoma in April of this year in the U.S. 

We also had really interesting data in this metastatic setting of pembrolizumab and this was presented at ASCO this year. So, just to go into a little bit about Keynote 427 which was the trial for pembrolizumab that was presented this year. This was a phase two trial of first-line pembrolizumab in metastatic renal cell carcinoma and at ASCO this year, we heard the results of the clear cell renal cell carcinoma cohort treated with pembrolizumab 200 milligrams every three weeks and so this study, I think, really highlights the activity of pembrolizumab in the metastatic setting. 

Dr. Alicia Morgans: Great. Well, you know, I think in the metastatic setting as you've mentioned, there have been a lot of advances, a lot of data coming out, but where there is a little less clarity, I think, is in the adjuvant setting. And I'm wondering if you can talk to us a little bit about that particular setting and kind of the impetus for designing the study that you're here to talk about today?

Dr. Tian Zhang: Yes, of course. In the adjuvant setting, we've had three very large phase three trials comparing VEGF inhibitors that are active in clear cell renal cell carcinoma to placebo. The S-TRAC trial was the only one that was positive for improving median disease-free survival and it compares to Sunitinib versus placebo, and treated everyone for a year. 

So, it improved median disease pre-survival up by about 1.2 years, but it did not prolong overall survival for these patients. And in the meantime, we also had results from both the ASSURE trial comparing sunitinib and sorafenib as well as placebo, as well as the PROTECT trial which compared pazopanib and placebo. And both of those trials resulted in negative signals for disease-free survival improvements. 

And so, over the past year we have had an approval from the U.S. FDA of using sunitinib for a year in the adjuvant setting based on the S-TRAC trial. But as you know, most patients who receive sunitinib treatment have some toxicities and we have a conversation in the adjuvant setting with these patients and we really talk about this risk for toxicities and the improvement in disease-free survival but not overall survival. 

And so standard of care treatment for now in the adjuvant setting can include sunitinib but most patients are actually just in surveillance as usual without additional treatment. And the question is really as we're having more and more of these lower toxicity treatments, immunotherapies, that are active in metastatic renal cell carcinoma, can we bring that into this adjuvant setting where they might have micrometastasis and high-risk disease and higher risk for recurrence for these patients?

Dr. Alicia Morgans: Absolutely. I'm wondering, can you tell us a little bit, Tian, about the design for the study that you've put together? This Keynote 564 and why you chose pembrolizumab? Maybe you want to start with that, why you chose pembrolizumab as the best treatment for the adjuvant setting.

Dr. Tian Zhang: Yeah, I think that's a great point. We can go back to the results of Keynote 427 that were highlighted at ASCO this year. The primary endpoint for this phase two trial was objective response rates and they accrued 110 patients. The objective response rates comprised of the complete responses and partial responses was about 38%. This is very similar in context with the ipilimumab (ipi), nivolumab (nivo) data. 

And then in addition to that 38%, about 31.8% had stable disease. And if we look at some of the waterfall plots from that trial, we can see that 74 of the 110 patients actually had some reduction and stability in their tumor burden. 

And so, this really highlights the activity of pembrolizumab in the metastatic setting. We compare and we don't want to do a lot of cross-trial comparisons but we certainly ... this is interesting to think about all the immunotherapy agents that we have now, and comparing cross-trials, looking at pembrolizumab activity versus nivolumab and ipilimumab combination activity. The objective response rates were quite similar for all comers. The complete response rate was a little bit lower, it was about three percent for pembrolizumab versus nine percent for nivo and ipi.

But when we think about treatment discontinuation due to adverse events, pembrolizumab was much better tolerated, only about 11% of patients discontinued treatment due to adverse events compared to 22% for patients treated with the combination of nivo and ipi. 

And so, while pembrolizumab has some lower complete response rates, it seems to be much better tolerated compared to the combination. And so, this really forms the basis and the rationale for using pembrolizumab in the adjuvant trial, the Keynote 564, that we're discussing today.

Dr. Alicia Morgans: I think it's particularly important to really hit home and recognize the importance of having a low toxicity treatment in the adjuvant setting where the standard right now is sunitinib which does have a pretty significant amount of toxicity for some patients, and really again as you mentioned, is not affecting survival. 

And then our alternative there is potentially surveillance. Having an adjuvant therapy that for most patients is as well tolerated almost, as not being on treatment, is really, really important. I would also emphasize the importance of adjuvant studies and really enrolling on a clinical trial in the adjuvant setting for high risk RCC, really should be our standard of care until we figure this out. I commend you for putting this study together and I appreciate that you've chosen such a generally, I would not say no toxicity, but a generally low toxicity and well-tolerated treatment for use in this patient population. 

Dr. Tian Zhang: Yeah. That's a great point and I think we certainly want to improve treatments in the adjuvant space and certainly using treatments that are lower in toxicity is an important part of treatment plan for patients in this low disease burden setting where we can hopefully improve both disease-free survival and as well as the goal would be to extend patients' lives and have them live longer by improving overall survival.

I do want to highlight that there are a couple of other trials in this adjuvant space along with Keynote 564, we can talk more in depth about Keynote 564 in just a little bit. 

There are about three other studies that also are active in the space, and so I don't want to leave those out and they include IMmotion010, which is atezolizumab versus placebo, as well as a perioperative trial and the cooperative group called PROSPER and that's lead by Lauren Harshman, up at the Farber. And this is a trial that randomizes patients to nephrectomy and observation versus neoadjuvant, nivolumab, followed by their nephrectomy and then adjuvant nivolumab afterward.

And then finally, there is another trial of adjuvant nivolumab plus ipilimumab which is the combination that is approved now in first-line treatment of metastatic renal cell carcinoma, and we're really trying to see if the combination is necessary in this adjuvant setting. 

Love to talk more now about the Keynote trial if we can.

Dr. Alicia Morgans: That sounds great. And thank you for reviewing the other trials,  as I mentioned, really standard of care should be consideration of a clinical trial for patients who are fit enough and who have access because we really need to answer some of these questions. And so, I appreciate you reviewing all of our options as we try to figure out which or maybe what approach might be beneficial, and hopefully which drug is going to work for us here in the adjuvant setting. But please do tell us more about Keynote 564. It'd be great to learn about this study.

Dr. Tian Zhang: Keynote 564, is as we've been discussing quite a bit is the adjuvant trial enrolling patients with renal cell carcinoma, all with clear cell components. And we're taking patients in the post nephrectomy setting with intermediate to high risk risk of occurrence and including patients who have some metastatic disease so they can be M1 patients who develop metastasis about within a year after the nephrectomy, and who have metastasectomy, so you'll remember in renal cell carcinoma this is the only setting where metastasectomy can improve overall outcomes. 

And so, the patients who have either undergone nephrectomy or metastasectomy and are now disease-free, those patients we are randomizing to either treatment with pembrolizumab 200 milligrams every three weeks IV for 17 cycles basically about a year or placebo and also that is IV infusions every three weeks for 17 cycles. 

Our primary objectives in this trial is disease-free survival with secondary objectives including overall survival, the safety and tolerability of pembrolizumab in the setting, disease-specific survival so patients who die because of disease recurrence and the renal cell carcinoma, as well as stratifying patients by PD-L1 status and looking at disease-free survival and overall survival for PD-L1 positive and negative patients.

And then the final secondary objective is quality of life. 

Dr. Alicia Morgans: Will you give us an update as listeners, as  It looks like the study is open pretty broadly across North America, Australia, Latin South America there, and then getting into Europe, and even into Asia. How is accrual, because if someone is interested and wants to get involved, I'm sure they want to know that there are still slots available on the study.

Dr. Tian Zhang: That's right, absolutely. Our sample size for this study is quite high a number so we're looking for 950 patients overall. We are, as you highlighted, open on five continents including Canada and the U.S. here in North America. We're open in Brazil, Argentina, and Chile, and South America, Australia, and then in Asia, in Russia, and Europe as well. Sorry, Russia and Japan, as well as South Korea. And then in a host of countries in Europe as well.

So certainly, many places to access this trial. There are 54 sites that are open in recruiting here in the U.S. and really depends on the geographic location of patients and their access to the study. But I would hope that it would be accessible for many patients who are at higher risk of recurrence in the adjuvant setting. 

Dr. Alicia Morgans: Great. I'm sure the study is in clinicaltrials.gov as well, so certainly patients or clinicians who are interested in enrolling their patients can go on to the website and type in Keynote 564 or adjuvant pembrolizumab for renal cell carcinoma, and can find sites they always list the locations at the bottom of that page. I know that this is something that if you are a community site and you want to send a patient to participate in the study would be potentially very beneficial to patients, and then those academic centers I'm sure will be happy to collaborate with community sites to try to make things manageable because I know that can always be a concern.

I would highly encourage patients and providers who might be interested who have these patients to go on the website and find a local place that might provide access to your patients, and get involved so we can answer some of these questions.

You must have this study open at Duke, Tian, how are patients doing? They seem to be enrolling relatively well and doing okay, I would hope. 

Dr. Tian Zhang: Oh, to tell you the truth across sites I think because there are other open adjuvant studies, we are still looking for patients. And so, there are certainly ... you asked earlier about accessibility and whether the trial's still open. We are absolutely still open for accrual and looking for patients. I think it is an important trial in the setting to find good candidates for study. 

Oftentimes in the academic centers, we see a lot of patients who come from far away.  I get asked a lot about the randomization to placebo for example, in the setting. And I think that even every three weeks touching base with patients even who are randomized to placebo, those patients are still having more access to care and more access to their medical oncologist on the study. 

Generally, pretty well tolerated. We see some of the immunotherapy- related side effects of pembrolizumab but those are pretty low in recurrence and of course placebo, we generally don't have much side effects. It's finding the right patients and enrolling them which is truly an important piece of carrying out the study. 

Dr. Alicia Morgans: It's never a bad idea to enroll in a clinical trial even if you're on placebo, you have access to some of the greatest nurses and physicians and you have their ear a little bit more because of your access through the clinical trial. And that can be helpful no matter where you live and how far away you live if you have the ability to get to those centers. So even being on a placebo arm which is a completely reasonable standard of care option for these patients can benefit patients, so I commend you for doing this work.

Dr. Tian Zhang: Yes, I absolutely agree. And certainly, I hope will help us answer the question of whether immunotherapy specifically pembrolizumab has activity and can improve outcomes in this minimal disease, but high risk for recurrence setting. 

Dr. Alicia Morgans:  I really appreciated your time today.

Dr. Tian Zhang: Thanks so much for having me, Alicia.