Wenxin (Vincent) Xu: Thanks so much, Dr. Zhang, for including me, and I'm so glad to be here.
Tian Zhang: Wanted to get a rundown of your recent presentation at GU ASCO. Would you talk us through your presentation on KIM-1 in non-clear cell kidney cancers?
Wenxin (Vincent) Xu: Sure. Thanks, Dr. Zhang. And I want to point out that this is your presentation too, as you're an author on the poster as well. I'll bring up, now, the poster, so that we can see it.
So the CAN-I trial was a non-clear cell RCC trial, and the trial enrolled patients with divergent histologies with renal cell carcinoma. Patients could be enrolled who were either first-line or subsequent-line, and the subsequent line patients were generally after treatment with prior TKI.
The parent trial, which was CAN-I, was investigating whether the combination triplet therapy, of cabozantinib, ipilimumab, and nivolumab, would have clinical efficacy in non-clear cell kidney cancer. As a biomarker analysis of this trial, we looked at baseline and follow-up KIM-1 values in these patients who were treated as part of the trial, since we knew from other studies that KIM-1 was a potentially useful biomarker in the clear cell population. So we wanted to ask a similar question in these non-clear cell histologies.
Tian Zhang: So tell us a little bit more about KIM-1. What does it stand for? Do we expect it to be elevated or not for non-clear cell versus clear cell? Any differences in the biology? What do you think?
Wenxin (Vincent) Xu: Yeah, so KIM-1 is a protein which is highly overexpressed in renal cell carcinomas. And in particular, it's highly overexpressed in renal cell carcinomas that derive from proximal tubular epithelium. KIM-1 stands for kidney injury molecule one. So it's essentially a protein that demarcates dedifferentiated kidney cells.
And KIM-1 has been known for a long time to be a molecule that has a role in the hypoxic kidney repair pathways. And we've known recently that KIM-1 is at very high levels in clear cell kidney cancer, where it has an extracellular domain which sits outside of the cell and is cleaved off and circulates in the plasma or serum. In that sense, KIM-1 is useful, because you can detect circulating KIM-1 as a non-invasive biomarker of kidney cancer.
And we know in clear cell, that KIM-1 levels are high prior to nephrectomy, that high KIM-1 levels after nephrectomy portend recurrence of disease, and that in the metastatic setting, decrease in KIM-1 after treatment can be correlated with response to treatment. And since a lot of the non-clear cell histologies have the same cell of origin as clear cell kidney cancer, namely the proximal tubular cell, we wanted to see which histologies would express KIM-1 and which would not.
Tian Zhang: And I think it's the first bullet here, but talk us through which histologies express KIM-1, and is overexpressed, and which ones are not, and what we can tell from the circulating marker.
Wenxin (Vincent) Xu: Yeah, thanks, Dr. Zhang. So, I think it was really nice to see that the clinical data matches up nicely with our preclinical hypothesis, which is that KIM-1 is overexpressed in tumors that derived from the proximal tubular epithelium.
So, we know that papillary and translocation RCCs can come from the proximal tubule. And unclassified RCCs, many of them do as well, although of course it's a very heterogeneous group of patients.
On the other hand, chromophobe RCC does not express KIM-1 at all. And in fact, the levels of circulating KIM-1 among our chromophobe RCCs in this population, with a median of only 63, was very similar to healthy volunteers. And so, that corresponds with the biology of chromophobe RCC, which derives from the intercalated cell of the kidney, which is a different cell type without the ability to overexpress KIM-1.
Tian Zhang: It's a really nice feature that you've seen here. And tell us about the dynamic nature of KIM-1. You've learned a lot about KIM-1 and clear cell on the phase-three trials, but tell us a little bit about what you saw here in the CAN-I trial.
Wenxin (Vincent) Xu: Yeah. So our pretest hypothesis was to see whether a decrease in KIM-1 after treatment would be correlated with better response to treatment as it is in clear cell. And indeed, this was the case. When you look at patients with matched plasma, comparing baseline to cycle three day one, which was the time point that we had available, patients who had a decrease in KIM-1, between baseline and the follow-up time point, did better and had longer survival compared to patients who did not have a decrease or had an increase in KIM-1 in the same time period.
And if you look at the 12-month overall survival, it was 79% among the decreasers and 42% among the increasers. Now, I would add the caveat that this is a heterogeneous population, and it's a relatively modestly sized phase-two trial, but certainly the signal is going in the right direction.
Tian Zhang: Yeah, no, it's really helpful. Is KIM-1 available commercially? A lot of our treating oncologists, can they get this marker if they are curious about it in their clinical setting, or still on the research front?
Wenxin (Vincent) Xu: It's not available commercially as of today. So we currently don't have a patient lab that can clinically run KIM-1s in real time, but this is very near on the horizon. And we're currently working on developing this in our own CLIA lab for clinical use, and we want to validate this in trials.
And so, Dr. Zhang, as you're well aware, we're trying to develop integral KIM-1-guided trials through the Alliance Cooperative Group, a trial called CHIMERA in the first-line setting. And so the hope is we'll have clinical grade KIM-1 tests available within about a year, and hopefully also around the same timeframe, have trials that really prove that using these clinical KIM-1 assays can help make better decisions.
Tian Zhang: Sure. Sounds really exciting, and I wish you good luck in the ongoing efforts. You've certainly done a lot with KIM-1 over the last couple of years. So it's an emerging story. I'm glad to see it's panning out both in clear cell, and then also in certain types of non-clear cell kidney cancer. But it drives home, these histologies are certainly different. For those with chromophobe RCC, maybe we're not looking for KIM-1, but in papillary translocation unclassified, they're similar biomarker, and we might want to explore it further in future studies.
Wenxin (Vincent) Xu: Yeah, absolutely. This is an unmet need, and one that, Dr. Zhang, you've contributed to in a lot of ways through your work on pedigree and other trials. But the clinical decision-making is so difficult in kidney cancer, and part of that difficulty is the lack of circulating biomarkers. And so hopefully, as time goes on, we'll have better ways to detect and monitor this disease.
And some of this data may involve, in the future, combining KIM-1 with other biomarkers, such as ctDNA, or other proteomic biomarkers as well.
Tian Zhang: Awesome. Well, thank you so much for joining me. Any other takeaways for the UroToday audience?
Wenxin (Vincent) Xu: I just want to thank everyone for taking a look at this poster. And, certainly if you're interested in collaborating on any KIM-1 related projects, we have a lot of experience with the assay, and we're happy to share anything that you want to know. Thanks very much.
Tian Zhang: Wonderful. Thanks, Vincent.