CONTACT-03: New Insights on Immunotherapy and Kidney Cancer Treatment

Katy Beckermann, MD, PhD, of Vanderbilt University Medical Center, and Pedro Barata, MD, of University Hospitals Seidman Cancer Center, discuss key insights from the CONTACT-03 trial in kidney cancer. They explore the trial’s goals and design and its significance in evaluating the use of immune checkpoint inhibitors, specifically PD-L1 inhibitors, for patients who have progressed on previous immunotherapy. They highlight how the study reinforces the role of cabozantinib alone in an IO-refractory setting, questioning the benefit of additional PD-L1 therapy post-progression. Their conversation also touches on the future of kidney cancer treatment, focusing on mechanisms of immune resistance and the potential for new drug targets in overcoming IO-refractory cases.

(0:00) CONTACT-03 Overview
(3:41) Control Arms and Dosages
(7:34) Study Results
(12:50) Drug Targets in IO Refractory Settings

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Dr. Beckermann:
So excited to be here today with GU Oncology Now welcoming Pedro Barata, associate professor at University Hospital Seidman Cancer Center. I’m Katy Beckerman, I’m an assistant professor at Vanderbilt. And we’re going to be just chatting a little bit about CONTACT-03 data in kidney cancer and trying to highlight why this trial was done, why it was needed. I think it answered a clinically impactful question. And then talk about big picture, what we got from this trial and maybe where it left us for the next steps. So Pedro, maybe just to start, why did you feel like this trial needed to be done?

Dr. Barata:
Yeah, so first of all, thanks for having me. So pretty important topic and I really agree in selecting this study to highlight and talk about a little bit, it’s a really clinical informative or practice informative study. And as you know, if you go back a few years ago right after the emergence of immune checkpoint inhibition, first we thought that bringing a CTLA-4 inhibitor would make sense at any point of the disease setting. And then we got a little bit disappointed about the limited activity when you start talking about refractory settings, but we never knew exactly if that was also true for PD-1 and PD-L1 inhibitors. So this trial was actually the first prospective randomized phase III study asking that question. There’s a lot of merits with it. I would argue one of them is actually the fact that you have the same backbone when you’re asking the question around salvage immune checkpoint inhibition for patients who progress on prior checkpoint inhibition, the fact that you have the same backbone of cabozantinib without dose reduction actually to me is important.

And to my knowledge, this was actually the first time it was done across solid tumors. So you can really in a clean way, understand the additional benefit or activity in this case of the PD-1 inhibitor atezolizumab. And it was done in the context of patients who were coming off an immune check inhibition. So we require progression within six months. So it’s clean from the perspective of you got a recent progression on, and the question is does it make sense to do more? And we know that was a consequence of what a lot of us were doing in clinical practice. We were actually using immune checkpoint inhibition in patients with refractory RCC, particularly clear cell that have progressed previously on other immune checkpoint inhibition, dual IO/IO like ipi/nivo or some PD-1 based approaches in frontline as they became standard of care. So I really think conducting this study is really, really important because it would allow us to understand for the first time in a prospective manner what was really the role of doing such an approach.

Dr. Beckermann:
Yeah, I think that’s a great highlight. I think in the community and in academics we had such high hopes because checkpoint inhibitors and kidney cancer has really been the only thing that’s provided that durable response. And while we know it’s not the majority of patients, and unfortunately the majority do go on requiring the subsequent therapy, many of us having that hope, we’re trying to use either continuation or we would consider it a switch going from PD-1, which has really had the primary overall survival data in that frontline setting and then maybe trying to switch to a PD-L1. And so maybe if you could talk a little bit about the drugs that were tested here and the dosages that were used in that sense, I believe the trial endpoints were co-primary endpoints of PFS and OS, and it was a randomized phase three. But maybe talk a little bit like you were mentioning how this was the first prospective study to have that control arm.

Dr. Barata:
So we established cabozantinib as standard of care at the dose of 60 milligrams is monotherapy. That data, it’s probably based on the METEOR phase III against everolimus that showed progression-free survival superiority as well as overall survival. And really in kidney cancer we’ve accepted, we understand clearly that PFS is a good reflection of clinical benefit for patients. So we’ve looked at PFS in a number of phase III trials and that has been considered by many of us as a good reflection of that benefit. So I think this phase III randomized trial taking PFS as one of the important endpoints of key endpoints for this trial, I think it’s absolutely appropriate in my opinion, the standard dose, which is also interesting because as we know, we can’t always combine a TKI with a standard dose of IO. In this case, atezolizumab was used as a standard dose 1200 and it was combined with a full dose of cabo.

You’re not really coming down on a TKI dosage. We combined with atezolizumab on the investigational arm. And I really think it’s important because you have the same backbone in terms of MOA, but also in terms of dosage. And we know TKI is dose dependent, both efficacy and perhaps safety as well. So I think that detail to me is very, very important to kind of put data into context. And so I like it. And then we can talk a little bit about the patients who got there, the prior exposure to checkpoints, because I think we had a good number of patients who were exposed to dual IO/IO; ipilimumab nivolumab, we actually have that broken down nicely in the last paper, about 30 or so percent of patients.

We also got PD-1 exposed patients with pembro for example, as well as nivo as monotherapy, which kind of reflects the changes in management in regards to CheckMate-025 when nivolumab was first approved in refractory setting. And then more like the frontline where patients in CheckMate 214 had ipi/nivo used in frontline as well as KEYNOTE-426 where axi/pembro emerged as the first IO/TKI. So this is a very contemporaneous dataset that is a consequence of how the practice has shifted from using a PD-1 monotherapy in second line nivolumab towards an IO based approach in frontline. So I think when we look at the patient population getting to CONTACT-03, it does really reflect what we’re doing, what we’ve been doing for the last recent years.

Dr. Beckermann:
Yeah, I think those are great. And they even made the point of when they did their randomization randomizing both based on IMDC criteria as well as what a patient had gotten as far as most recent treatment. And so I think it was a really well conducted study and does give us the most contemporary dataset for how does cabo either answering this question of should we continue immunotherapy, but just really how does cabo even now behave in a refractory setting post io o treatment because we’ve seen a lot of single arm kind of phase one two data of IO/TKIs in that setting. Just always a little bit hard to interpret. And so that was I think a really nice point of this trial. So maybe hearing that and us recognizing it was a contemporary dataset, what did you think of the results of this trial?

Dr. Barata:
So when we look at the efficacy endpoints first and then a comment or two on the safety because they go side by side, first of all, no arm underperformed or should I say the control arm did not underperform. So you look at cabozantinib, I think by many considered the standard option as by itself, second line in refractory setting. I mean we look at PFS over 10 months, responses of 40% is incorporating the TKI naive population. We know probably the first TKI is where you’re going to get the most benefit out and we know they work after progressive prior TKI, but it’s probably going to see the most benefit of TKI I is the first time we use it. So the fact that we had TKI naive patients I guess allows you to see those results. But that’s reassuring, right? I think it does establish cabozantinib is a very appropriate line of therapy in the refractory setting.

So that’s the number one. The number two is you actually don’t see any difference with the addition of atezolizumab. So no matter how we spin the data, we absolutely in any trial we can go after subgroup and kind of see IPOs generated for the future asking new questions. I don’t think that’s the case here. We look at the data and we really struggle to find something different. If anything, we actually would say, oh, cabo performed better, if anything compared to the combination arm. And that probably has to do with the safety, which is my final comment or two is you clearly see that patients who received a combination did experience adverse events numerically at higher grade that actually cabozantinib alone, which kind brings us back to the point not always more is good idea. And so I’m not sure we would anticipate those results as this, but absolutely no difference in terms of efficacy.

It’s very clear to me that there’s absolutely no benefit of adding atezolizumab in the context of safety. And so this is one of those cases where the trial as it was conducted set the conversation in regards to, at least with the PD-L1, knowing what we know today adds absolute no benefit to the standard of care. cabozantinib. And I really argue to being a negative study, so important to see these being published in a very reputable journal like Lancet because it is really informative to practitioners out there to use this dataset to say, you know what? We don’t do this because we have very good data to show us why we don’t do it.

Dr. Beckermann:
And I think to your earlier point, there’s really across solid tumors. This hadn’t been prospectively tested. And so it was a really nice, I mean, of course I wish maybe the outcome had been different, but there really was no difference. Those curves were so on top of each other. The OR was essentially exactly the same. Really PFS was so close. And then I think that emphasis on this did generate nice data to say, Hey, Cabo in an IO refractory patient population as monotherapy does have good ORR does perform perhaps even better than we saw. Well definitely better than historical meteor trial and things like that. And so I think it was practice informing we should not try to do the switch PD-1 to PD-L1. And I think that some of that is because we just really don’t understand in kidney cancer why patients are refractory.

If patients have this tumor intrinsic capacity to respond to immune therapy, then the idea of just continuing and switching PD-1 to PD-L1 doesn’t make a lot of sense. There’s a lot more data I think in melanoma and some other solid tumors where they’ve tried to get a better understanding of mechanisms of resistance. So I hope that this trial and some of the subsequent trials will lead us to say, okay, maybe just continuing checkpoint inhibition is not going to be the way to enhance an immune response after somebody’s progressed on frontline therapy and more translational and basic science. But really novel drug targets is I think where I hope things come into play next in that IO refractory setting because it is such a significant need. You mentioned how we accept PFS benefit because we know in sequencing therapy we want to focus on quality of life and trying to have an ORR/PFS benefit because we don’t typically see, unfortunately, that OS survival benefit. So hoping we’ll be seeing new drug targets that’ll be coming out to help combat these mechanisms of resistance to IO therapy. Is there anything along those lines, Pedro, that you’re kind of excited about in an IO refractory setting that you’ve seen?

Dr. Barata:
Yeah, so I completely agree with your comments regarding where probably the field needs to go. I think for this particular question about role of salvage immunotherapy, we are fortunate enough to have two studies. I mean some would argue for contact three, it doesn’t really answer all the questions we had. Two important questions would be, what about PD-1 inhibitors instead of PD-L1 inhibitors? And the second would be, how about we give a break from a checkpoint and see if that how helps us later on? And fortunately enough, you have a very fresh data set from TiNivo-2, which I know that conversation will come up where it’s actually a perfect segue. I think the story looks way better when you think of CONTACT-03 followed by TiNivo-2, I think it provides us a lot of more rational to how it’s informing providers how to address and how to answer the question regarding IO salvage.

And so from that perspective, I think we are going to see a shift towards, as you said, while we explore potential ways to reverse the mechanism of resistance to immunotherapy, probably explore different MOAs in the context of post immunotherapy and see if there’s enhanced activity from that perspective. And there are different scenarios and different MOAs. We could be talking special ADCs or even radioligand therapy or novel generation, HIF inhibition, et cetera, are probably some of the studies and efforts we’re going to be seeing in the near future. But I think this is really a good example how two negative trials, and we haven’t talked as much about TiNivo-2, but how negative trials are extremely important for the field and helping the way we treat patients on a daily basis.

Dr. Beckermann:
Yeah. No, that’s great. And yeah, looking forward to future conversations about TiNivo-2 and how that, I think finished hammering in the nail that we should not be continuing checkpoint inhibitor in an IO refractory situation. But yeah, I’m hopeful in next couple years, probably not the sheer necessarily, but in future years that we’ll have some new mechanisms of action that can help patients. So thank you so much for joining and I’ll always enjoy chatting with you about research and kidney cancer.