Sumanta Pal: Hi. My name’s Monty Pal. I’m a GU Medical Oncologist at the City of Hope Comprehensive Cancer Center in Southern California. We have two big hubs for renal cell, my shop and Dr. Rana Mckay’s shop down in UC San Diego. Rana, thanks for joining us.

Rana Mckay: Thank you so much, Monty, for having me.

Sumanta Pal: Oh, gosh. Well, I am so excited for you. You’re doing this big oral discussion on Monday, can’t wait for it. Tell me a little bit about the abstracts that you’re going to be presenting. In particular, I want to get your take on Len Appleman’s abstract. I was actually the SWOG sub-PI on that trial. Of course, this was an ECOG study. Tell us more.

Rana Mckay: This is really a monumentous time for RCC. It has just been fantastic to see the field evolving so rapidly. Literally, within the last two months, in April, have a new approval for pembro/axi. May, new approval of avelumab/axitinib. I mean, this is just a remarkable time for our patients.

Thinking a little bit about the SWOG study, that basically looked at the utility of pazopanib, in patients who had high risk of M1 disease that was resected to NED, looking at the role of adjuvant, if you would have it, pazopanib in those people who had no visible evidence of metastases. It was a trial that was compared to placebo, patients received one year of adjuvant pazopanib.

I think it’s important to think about when this trial was developed and when this trial accrued patients because it was really developed, I mean accrual began in 2012 before any of the adjuvant studies reported out, before the reporting out of S-TRAC and ASSURE in 2016, the reporting out of ProtecT in 2017, and then the ATLAS study in 2018 of axitinib. So this was really, the data that we now have, we did not have when this study was developed.

Really the trial was ultimately a negative study. pazopanib did not demonstrate an improvement in disease-free survival for patients who received it compared to placebo. The disease-free survival was I think around 17 months for the pazopanib patients, 14 months for the placebo patients. When we look at the overall survival data, they actually favored placebo with a hazard ratio that was greater than two. I think when we think about the patients who were enrolled in the study, there was about a third of patients who discontinued treatment for an event other than progression or death. So that tells me really patients could not stay on the study. They either came off for toxicity or withdrew. I think about greater than 50% of patients received less than 50% of the intended pazopanib dose. So very similar to sort of what happened with the ProtecT trial.

Now they did not require an upfront dose reduction as we saw in ProtecT with the decrease dose going from pazopanib 800 to 600. But I really think what this data highlight is that even in your highest risk patient population, your highest risk population, I mean these are people who had metastatic disease resected to NED, your highest risk patients for microscopic metastatic disease, TKI therapy or targeted therapy really has just not met the bar for our patients. I really think that that’s kind of driven home and remained sort of an unmet need.

Now there are combinatorial therapies of … various trials now ongoing testing IO therapy in this space. Whether IO therapy can move the needle is yet to be determined, but I think unfortunately there is still this unmet need of treating microscopic disease.

Sumanta Pal: Yeah, great summary. I totally agree with that take. We had 20 plus patients on that trial. When I read the abstract a couple of months ahead of this meeting, I was just so disheartened. Really a big bummer. But let me ask you, moving on from this topic of adjuvant therapy, why don’t we move on to perioperative therapy, because we’ve got this great abstract from JJ Goa and the MD Anderson folks related to immunotherapy regimens upfront. Tell us a little bit about what that showed.

Rana Mckay: So on this trial this was, it’s an interesting trial because I think it went through various iterations. It was initially designed as a small pilot, really testing the safety and biomarker impact of perioperative therapy. It was a three-arm trial of nivolumab, nivolumab/bevacizumab or nivolumab and ipilimumab. Initially, the trial was designed for 15 patients per cohort and intended for those patients undergoing cytoreductive nephrectomies or metastasectomy.

I think a signal sort of was seen in those initial preliminary data. The trial was expanded and sample sizes increased. Then they struggled a little bit with accrual and then opened up the trial to allow patients who were non-operative candidates. So we have patients on the … It’s kind of a mixed bag of patients with people who actually underwent surgical resection versus people who just basically underwent a post-treatment biopsy that were not surgical candidates.

The trial really was not intended to look at differences between the arms. The trial was not intended to look at differences between surgical versus nonsurgical patients. I think ultimately the message is that the combination therapy and even nivolumab alone, is safe given perioperatively. But I think something to take home is the role of the surgical effect in achieving a response in patients. So when we factor in those patients who receive their therapy and actually underwent cytoreductive nephrectomy or metastasectomy, response rates were between 69% to 86% for those patients.

So obviously this is a small study. Obviously, it’s a pilot, but I think that kind of speaks to the role of cytoreductive nephrectomy and metastasectomy in this setting. There’s been kind of looking at cytoreductive nephrectomy in a different limelight with the CARMENA data, with the SURTIME data, really kind of questioning the role of cytoreductive nephrectomy and I think it’s all about patient population and patient selection.

So this trial really highlights that 1) it’s safe and 2) in a subset of patients, there can be deep responses with the combination of surgery and multimodality therapy.

Sumanta Pal: Got it. Real great summary and I kind of saved the best for last here. So we’ve all been talking about, and you alluded to this earlier, these combinations that we have now. So you’re going to be highlighting some of the axi/pembro data updates from KEYNOTE 426. Give us the scoop. What’s actually coming out of this study now?

Rana Mckay: So this is just, again, super exciting. We’ve now have three different IO combinations in the front line space. We have nivo/ipi, we have pembro/axi, we have avelumab/axi. Now I want to just stress that cross-trial comparisons really can’t be done. These are different trials, different patients and different endpoints, but I feel like we just can’t resist wanting to look at well who are the patients in this study and who are the patients in that study.

So just speaking a little bit to the KEYNOTE 426 data, one, it enrolled a higher proportion of patients with favorable-risk disease, and that’s important to kind of understand that when we look at the PFS and OS data that’s reported out for the study. I will highlight that the assay and definition of positivity for PD-L1 status differed across all these three studies with upwards of greater than 60% of patients having PD-L1 positive disease in KEYNOTE 426. Of course, the endpoints all differed. KEYNOTE 426 specifically looked at OS and PFS in the overall population, not necessarily an intermediate poor risk, not necessarily PD-L1 positive or negative.

Data are presented regarding the depth of responses that we’re seeing. So the team and investigators kind of assessed change in target lesion size on the study and really demonstrated that about 17% of patients had a greater than 80% decrease in the size of target lesions and 9% of patients had resolution of all target lesions. I think really what this data highlight is 1) the shortcomings of RESIST with regards to defining people who have a deep response. A definition of CR per RESIST is resolution of all measurable disease, resolution of all non-measurable disease, and we all know clinically the issues with non-measurable disease. Patients with bone metastases, they may persistently have something that’s seen on a scan that may not necessarily be reflective of truly active disease with lymph nodes less than one centimeter. So that’s the resist definition. But are there people who can achieve a deep remission and that deep remission be associated with durability and associated with overall survival?

Additionally, what they did is presented updated data from the favorable risk cohort, striking hazard ratio, striking response rates. Again, we should not compare but we can’t help but just kind of looking at the control arms of CheckMate 214 and the control arm of pembro/axi. Really in CheckMate 214, the Sutent cohort really overperformed. The PFS for Sutent in CheckMate 214 was 25 months. That is remarkable. I’ll compare it to the 12 month PFS of Sutent in the favorable risk arm for pembro/axi. So I think, again, these are different trials with different patient populations.

Then when we look at the intermediate and poor-risk data, again, hard to compare head-to-head, but comparable like to nivo/ipi and pembro/axi with dramatic response rates, good hazard ratio. So I think this is an active regimen in this disease.

Lastly, what was presented as an exploratory analysis of patients with sarcomatoid histology. Now there was data that was presented at KCA of the sarcomatoid population from CheckMate 214. I think we need to just keep in mind these are post-hoc, these are not based on central review. It’s I think literally based on a review of local pathology reports, whether or not it was mentioned in a local pathology report. But I think the key message here, and I think IMmotion151 data are going to be presented on Monday as well of the sarcomatoid population from IMmotion151. Really the take-home message is, this IO combination therapy, pembro/axi is specifically active in people who have sarcomatoid RCC. And this has historically been a population that has done very poorly. So I think this is a very positive thing for those patients.

Sumanta Pal: Absolutely. Great summary. So I think what our UroToday viewership wants to know at the end of this discussion is when you see a patient in clinic, and you can’t respond to clinical trial all right?

Rana Mckay: Okay.

Sumanta Pal: When you see a patient with intermediate poor-risk disease in your practice, what do you give them? No creative scenarios here, just your standard run of the mill, intermediate, poorest patient. What are you giving?

Rana Mckay: So my go-to right now has actually been nivolumab/ipilimumab. The regimen is actually now with education around management of toxicities, actually safe to administer. We are keen on watching out for immune-related adverse events. There’s just something to be said about the 1 in 10 are going to have this very complete response. There was data that was actually presented by Tom Powles, I believe, and Dave McDermott about this concept of treatment-free survival. Really what that kind of exploratory new endpoint that’s being defined in the context of IO is, is how many people when they discontinue the therapy that they’re on, have remained free of subsequent therapy and alive at x time point. When we look at that all comers from CheckMate 214, about 20% of patients at 24 months are still alive and still disease-free.

When we look at those patients with a CR and a PR, it approaches nearly 50%. Looking at the 1 in 10 are going to have a complete response, I think, like I’m going for gold, like I’m going for like as close to a cure that I can give these patients. So that’s sort of where I’m leaning to now. The data for pembro/axi is that two out of three are going to respond. So there’s going to be more responders. I think that’s because of that TKI effect, but now are we thinking about how many people can I actually cure potentially? Like we never even … The fact that I’m even using the word cure in this interview I think speaks to sort of the progress that we’ve made and that’s why I still kind of favor using nivo/ipi.

Sumanta Pal: Great. I’m going to end with a real zinger. If you thought that one was hard, okay. All right. Tell me, in your clinical practice, and again, clinical trial answer off-limits.

Rana Mckay: Okay.

Sumanta Pal: Where would you put axitinib/avelumab?

Rana Mckay: So that’s a little bit of a tricky question. So I have to say it’s hard to … The axitinib/avelumab data are very comparable. The OS data is not yet mature for of avelumab/axitinib, but kind of comparable to the pembro/axi data. I think the twice a week or Q2 week infusions, the increase for infusion reactions, I just feel like it’s just not going to have the uptake as pembro/axi. I think it’s just more of an administration of the drug. Like are patients going to want to come in every two weeks when they’re actually doing okay, to get their IV treatments? So I think that could be kind of a hindrance for the administration and delivery of care.

Now we’re even talking about the concept of stopping therapy when patients are out, they’re living longer, they’re on therapies longer. Do we really want our patients coming in every single two weeks for IV treatment? I know that it may sound silly, but I think these are the things that patients care about and physicians care about. I want you out living your life, not coming to the cancer center and not having to think about coming into the cancer center because you’re doing well.

Sumanta Pal: Well, I think you answered those zingers perfectly, just as I would but you get both of those right. Dr. McKay, thank you so much for joining.

Rana Mckay: Thank you so much.