Pedro Barata: Hi there. Thanks for joining us today. Today we have super remarkable, important topic. We're going to be talking about KIM-1 as a prognostic marker in renal cell carcinoma. I'm Pedro Barata, a GU oncologist at University Hospital Seidman Cancer Center in Cleveland, Ohio. And I'm super thrilled to be joined by the super expert Wenxin Xu, assistant professor at the Dana-Farber, medical oncologist with expertise in GU tumors. He has been everywhere teaching all of us about KIM-1. Wenxin, thanks so much for joining us.

Wenxin Xu: Dr. Barata, thanks so much for the invitation. I'm so glad to be here on my favorite topic.

Pedro Barata: Yeah, this is fantastic. Thank you for taking the time. And I'm kind of looking forward to learn from you on this, and I'm sure many of the folks going to be watching this going to learn as well from you as always. So let me get right into it because you have been one of the first with other folks that have been showing us or teaching us all about KIM-1 as maybe the first biomarker, I would say, with easy way to do it in clinics. But maybe first things first, can you tell us what KIM-1 maybe stands for and what is it and how do we detect it in the blood.

Wenxin Xu: Yeah, thanks Pedro. So KIM-1 has several names, as many proteins do. KIM-1 stands for Kidney Injury Molecule 1. Another name for it is actually HAVCR-1. It's the Hepatitis A Viral Cellular Receptor 1, as well as TIM‐1, which is a homolog of TIM-3, the immune checkpoints, the T-cell immunoglobulin domain. So this protein really has multiple functions. But specifically kidney cancer, what's interesting about KIM-1 is that it's highly upregulated in kidney tumors that come from the proximal tubule. That includes all clear cell kidney cancers and it also includes papillary kidney cancers and many other proximal tubular tumors, translocation RCC, for example. When this protein is upregulated, you can see it on the surface of cancer cells. But what's really interesting to me is that you can also detect it circulating in plasma. There's an ectodomain of KIM-1, which is shed off the tumor surface and can be pretty easily detected with blood-based antibody tests, and it can act almost like a PSA, as a circulating biomarker for kidney cancer.

Pedro Barata: So Wenxin, let me stop you there because one of the common questions I hear all the time is, "Listen, but I talk to the companies out there, I talk to my lab and I don't have a way to test for it." What would be your comment to that? How can we make these available?

Wenxin Xu: Yeah, it's a great question. As of today, KIM-1 is not a standard blood test that's commonly available in commercial labs. But it is available and it's not difficult to do because at the end of the day it's an antibody-based chemiluminescence assay. There are CLIA labs that can run KIM-1. But I think my main takeaway when people ask me in the clinic is that we need to make sure the lab that's running it is using the same assay, the same antibody, the same protocol that we've been using in our analyses of large trials. Because at the end of the day, just like with PSA and maybe even worse than PSA, if you use a different antibody, different protocol, you're going to get a different measurement.

Pedro Barata: Got it. So I guess the take-home message is because it's not ready for primetime yet, but as we're putting protocols together, trying to run studies on it, and many of us are trying to do that, trying to do it in the right way, and as we get more data and perhaps that gets validated, probably you see the world evolving to a place where we can be able to order it in clinical practice. Is that kind of what I'm hearing?

Wenxin Xu: That's right. I think now we have now quite a bit of clinical data in multiple clinical scenarios, renal masses, pre-diagnosis, post-adjuvant therapy, post-nephrectomy to risk stratify patients, and metastatic patients to risk stratify patients and monitor for response to immunotherapy. So we have a lot of data across trials, but what we really need is a prospective trial. And I know folks are working on this. My opinion is that once the first big prospective trial with KIM-1 gets done, probably the assay will become more widely available once companies realize there's a market here for measuring this biomarker.

Pedro Barata: Right. Well said. And that's a perfect segue for my next question. Of course, you did wonderful discussions on the topic. Post-nephrectomy, high-risk patients we're trying to get our MRD assay, and maybe KIM-1 is it, right? And so we're a little bit behind when we think of urothelial cancer world, for example. But we can perhaps try to do that with KIM-1. And there's very, very interesting data that comes from the adjuvant atezolizumab and other data sets. But instead of me reporting on those, I would ask you, can you summarize for our listeners, can you summarize the data around adjuvant immunotherapy and the KIM-1 as a prognostic or predictive value?

Wenxin Xu: Yeah, absolutely. I think the take home is that the adjuvant data is really quite strong. The first large adjuvant trial that looked at KIM-1 levels after nephrectomy was actually the ASSURE adjuvant trial looking at adjuvant sunitinib and adjuvant sorafenib versus placebo. And that overall was a negative trial. There was no disease-free survival benefit in any of the arms. But when we looked at KIM-1 after nephrectomy in that trial, strongly the patients who had a high residual KIM-1 after surgery, those were the patients who were going to recur for kidney cancer.

And so based off of that data, we've looked at several other adjuvant trials. What was, I think, the most exciting was adjuvant atezolizumab as you alluded to, IMmotion010. And this was an analysis led by the folks at Genentech with Dr. Laurence Albiges and others showing that if you measure the KIM-1 protein in the blood after surgery, in this randomized trial, only the patients with high KIM-1 had benefit from adjuvant immunotherapy with atezolizumab. And in fact, the patients who had low KIM-1 had no benefit at all.

And it's overall a negative trial where essentially the high KIM-1 subset identifies a part of a negative trial, which was actually positive.
We looked at this in other trials, CheckMate 914 for example, which was the adjuvant NIVO-IPI or adjuvant NIVO trial. And we see a very similar signal where overall a negative trial, but the highest KIM-1 patients seem to have benefit from adjuvant immunotherapy. And now the sort of million-dollar question is, can this data be extrapolated to adjuvant pembrolizumab? Of course, we don't have yet data from KEYNOTE-564 with adjuvant pembrolizumab. Dr. Barata, you had a really phenomenal discussion of the pros and cons of adjuvant pembrolizumab, showing that essentially there's a 7% of patients that we're really pinpointing that really have that major benefit and are cured by adjuvant pembrolizumab. Perhaps KIM-1 can get us there, but we need to find out.

Pedro Barata: Well, yeah, wonderful. If I were to put that slide together again, I would have to update it and make the comment that KIM-1 might be added to that consideration of the pros and cons in the future. So the way you summarize is perfect, to actually start with the pre-checkpoint inhibition era with TKIs, ASSURE just for the listeners, adjuvant sorafenib or sunitinib, and then checkpoint inhibition, you alluded to atezolizumab adjuvant study as well as IPI-NIV or NIVO.

And so I guess because you had a wonderful review that was recently reported in very prestigious journal of European Urology Focus quite recent, and it's a beautiful comprehensive review on KIM-1 overall. So my question to you is because you just did that work of putting it all together and many people are testing it out in different settings, so that obvious question for you, Wenxin, would be, okay, so beyond adjuvant setting, where do you see KIM-1 pan out in the near future?

Wenxin Xu: Yeah, so I think for me, there's a few key questions clinically. Adjuvant, we talked about. Can we use KIM-1 to select for adjuvant immunotherapy and to avoid over-treating or under-treating patients? In the metastatic setting, I see two things. One is that KIM-1 is a really good prognostic tool. And when you look at just the KIM-1 blood test biomarker level, that alone is better than the IMDC with all the criteria together. And so it's really good at determining who's going to live longer with metastatic RCC at baseline.

But what to me is even more exciting than that is that KIM-1 seems like it's a very sensitive early biomarker for who's going to have those durable responses on immunotherapy. When we looked at CheckMate 214, after measuring KIM-1 before treatment and after just one cycle of IPI-NIVO, so a three week KIM-1 ratio, the one-third of patients who had a decrease in KIM-1 of 30% by the first cycle had outstanding overall survival, 85 months, over 70 month progression-free survival. So those are really exceptional responders.

And conversely, patients who had their KIM-1 going the wrong direction did not really seem to benefit from IPI-NIVO immunotherapy. We know from recent PDIGREE trial data presented by Dr. Tian Zhang, that when we look at that adaptive IPI-NIVO trial design, one third of patients don't make it past induction because of toxicity or because of progression early. A lot of IPI-NIVO patients don't make it to even step two of that trial. And so the key question really is, can we make IPI-NIVO safer if we had an effective biomarker so that we're getting the right patients on the right treatment? So that's the metastatic setting.

And in the localized setting, we have now lots of biomarkers that can have some sense of which patients with a renal mass are likely to be aggressive and malignant. We saw data from Dr. Brian Shuch from girentuximab PET for example, and I think KIM-1 is part of that story. When you have high KIM-1 with a renal mass, you're much likely to become metastatic later, and that might play some role in risk stratifying patients for surgeries.

Pedro Barata: As you said, you alluded to novel imaging, and girentuximab PET actually is being assessed by the regulatory agencies as we speak, and we'll see if we have news soon. It's quite a big change because we might get access to the PSMA PET for kidney cancer. Maybe PSMA might be a tracer for kidney cancer. Perhaps that's another video. And then beyond that, also, maybe we'll have our own PSA in the kidney cancer world, right? So it's quite interesting the way the field is evolving. Wenxin, this is amazing. Final thoughts before I let you go?

Wenxin Xu: Well, so I encourage everyone who's watching the video to participate in clinical trials. Hopefully we can get a clinical trial together across multiple institutions to look at this biomarker prospectively. And that, I think, will really convince the community to start using this. I think there's a lot of potential here. We have no blood tests that are currently commonly available for kidney cancer. Unfortunately, things like ctDNA don't work quite as well in kidney cancer as they do in bladder cancer or lung cancer. So we have this other thing, and hopefully it will pan out.

Pedro Barata: Wonderful. Well, perfect summary. I learned a lot as usual. Keep it up with an amazing job, and let's see if we can take this to the finish line because I think this allows selection of patients and help conversations also in practice and inform decisions about prognosis, but also prediction. And so truly important and remarkable work. So thank you, Wenxin. And again, I invite everybody to read the review that came out on European Urology Focus on this topic. Thank you so much. I'll see you soon.

Wenxin Xu: Thanks, Dr. Barata. See you around.