A Conversation on AXL Inhibition in Advanced RCC: Promising Results from a Phase I/IIb Trial - Kathryn Beckermann

July 31, 2023

Pedro Barata speaks with Kathryn Beckermann regarding a groundbreaking Phase I/IIb trial she presented at ASCO. This trial explored the use of a new AXL inhibitor, in conjunction with cabozantinib and nivolumab, for advanced Renal Cell Carcinoma (RCC). Dr. Beckermann elucidates the rationale behind targeting the Gas6 AXL pathway, known for its upregulation in kidney cancer and its role as a resistance mechanism against tyrosine kinase inhibitors. This trial is especially interesting for the use of batiraxcept, a novel agent that 'mops up' ligand to prevent resistance that a small molecule might otherwise encounter. Dr. Beckermann also shares encouraging results from the trial, indicating good safety data and promising results for patients who were refractory to previous treatments. Drs. Barata and Beckermann look forward to the continuation of this research, hinting at possible directions for future Phase III trials.


Kathryn Beckermann, MD, PhD, Assistant Professor of Medicine, Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN

Pedro C. Barata, MD, MSc, Leader of the Clinical GU Medical Oncology Research Program, University Hospitals Seidman Cancer Center, Associate Professor of Medicine, Case Western University, Cleveland, OH

Read the Full Video Transcript

Pedro Barata: Hi, and welcome. My name is Pedro Barata. I'm a GU oncologist at University Hospitals Seidman Cancer Center, and I'm very happy to be joined today by Kathryn Beckermann. Dr. Beckermann is an Assistant Professor of Medicine at Vanderbilt University Medical Center from the hematology oncology division. She's also a friend and colleague, so welcome.

Kathryn Beckermann: Thank you. It's wonderful to chat with you today, Pedro.

Pedro Barata: Absolutely. And first, congrats. You did a fantastic job presenting a very interesting trial, in my opinion, exploring these new AXL inhibitor, with cabozantinib and nivolumab, in this kind of Phase I/IIb trial at ASCO. What a great, great, great work, and I was hoping we could chat a little bit about that.

Kathryn Beckermann: Yeah, great.

Pedro Barata: All right. So maybe first things first, right? So some of us might be less familiar with it. Can you tell us a little bit about why inhibiting AXL in advanced RCC?

Kathryn Beckermann: Yeah. I think there's a couple great reasons, and lots of some nice preclinical rationale. So in general we know that, and I'll be speaking kind of regarding clear cell kidney cancer, the most common form of kidney cancer. But that we see that part of the biology that is driving downstream loss of VHL and upregulation of HIF alpha, are cell surface receptors that allow these cancer cells to grow. So one of those is this dual combination of Gas6 and AXL, and we've known that for some time, and some of the drugs, including a drug called cabozantinib, can sometimes target these cell surface receptors.

We also know, that in addition to just this being upregulated in kidney cancer, that it can also be a mechanism of resistance. So patients who've had prior tyrosine kinase inhibitors, these oral agents that we've used for a long time, that typically we think of as blocking VEGF, but can block other surface risk cell receptors, that, for example, in historical times, when we were using more commonly sunitinib in front-line, that one of the mechanisms of resistance was upregulation of this Gas6 AXL pathway.

And so, this is a novel way then of targeting Gas6 AXL because it, batiraxcept, is the drug that we're talking about in this trial, and it basically mops up the ligand. So really tightly binds in a different method, so you don't get the same resistance that like a small molecule would if it were binding the receptor. And so, that's kind of the preclinical rationale for considering, in the resistance setting, as well as, why we would even consider targeting it in kidney cancer.

Pedro Barata: Got it. That makes a lot of sense, and explains why you're exploring this in the refractory RCC setting, right? So great. So perfect segue. Can you walk us through, because you have different course in this refractory RCC study, can you walk us through the design, why the different cohorts with the AXL inhibitor monotherapy and combined? And feel free to share a little bit of the take home points from the efficacy piece of what you've seen here as promising results.

Kathryn Beckermann: Yeah. Thank you. We'd previously discussed and presented the kind of Phase Ib safety, and then, this Phase II is a little bit different than some other Phase IIs because it wasn't solely just in one patient population. We actually had a few different cohorts as you just mentioned. So the largest enrolling cohort was in the refractory setting, where we said we have good safety data for the combination of cabozantinib plus batiraxcept. And so, that was the main purpose of the Phase II. Again, looking at a refractory patient population, and combining it with a standard of care therapy.

We did also open a monotherapy batiraxcept, and there, we were going to get information for two reasons. One, is this drug efficacious on its own? The hypothesis was that it would not necessarily have as much efficacy as single agent, that we really needed the combination therapy. But it also would give us safety data. So as a monotherapy, are there special safety signals we need to be thoughtful about?

And then, we also had a cohort that was in the front-line, and there, the hypothesis was, well, if we already know that it can be a driver of resistance, what if we offer it in the front-line? Does this help increase duration of benefit on front-line therapy, and having good safety signal up front? Maybe this is a good triplet combination, where other triplets have been challenged by toxicity. So that was a long-winded answer, and maybe I'll focus in that, again, in that refractory. So second and later line therapy combination, cabo plus batiraxcept, kind of an overarching about 40% response rate. We see a little bit of a differential effect if a patient on front-line had prior IO/TKI. And the way I'm rationalizing that that might be the case, is because you're putting on the gas on the pedal to up-regulate that Gas6 AXL, and then targeting it.

So basically, if a patient, front-line, had IO/TKI, there was some signal, some suggestion of a signal that perhaps those were the patients that did better with the batiraxcept. The objective response rate for the front-line triplet looked pretty close to what we saw with cabo/nivo historical data. So about 55, 56% there. No increased toxicity. That was a great thing to see. So in the triplet, it was well tolerated, and I think what we'll need to look at there, again, small numbers, but does this increase the durability of cabo/nivo? So that will take longer follow up.

The last cohort, only 10 patients, these were patients who were very refractory to treatment. A median, I believe, was five, if I'm remembering correctly. And we had a patient with stable disease, but otherwise, not a lot of tumor shrinkage objective response there in the monotherapy. It did nicely show us that really, it was quite safe and well tolerated, some fatigue. And there is a known infusion related reaction that can occur across any of these cohorts, that we were able to really mitigate if we pre-med it. So if we provided steroids or H1, H2 blockade, that was-

Pedro Barata: Yeah. So no, that's very, very, very interesting, right? Because you were exploring this in different fashions, as you elegantly explain, and it sounds like, at least in the community, IO/TKIs are the leaders, or the preferred regimens of choice. So it's quite interesting to come up with these potential combination upon progression.

So what are you thinking, that you now learn the role of the AXL inhibitor by itself? Very favorable safety profile, allowing you to combine with IO, IO/TKI, what do you think next steps look like? Because you can go in different directions, I can imagine. What are your thoughts on that?

Kathryn Beckermann: I think, we'll gather some longer term follow up. But I think hopefully, if this proceeds to Phase III trial, that we'll focus in the refractory setting. That's kind of where the signal of response has been, in combination with a TKI, and compare that to TKI alone. And focus this trial, even though we were in the refractory setting, several of those patients actually were third and fourth-line, and still seeing that 40% or so objective response rate. So I think we'll move it a little bit earlier. So focusing, really, on kind of a second-line patient population.

Pedro Barata: Got it. Those are definitely exciting times, and as we're trying to optimize what to do for patients who unfortunately end up progressing on front-line regimen, right?

Kathryn Beckermann: Definitely.

Pedro Barata: So that seems to make a lot of sense. That's fantastic. Well, I want to congratulate you, again, great presentation during ASCO, and thank you for putting this work together. I know we took a village, and a lot of important sites and colleagues being part of these efforts. So, big congratulations to you for leading these efforts.

Kathryn Beckermann: Well, thank you so much for inviting me to chitchat about it. Always good to talk about kidney cancer, so.

Pedro Barata: Absolutely. We'll talk soon. Thank you so much.

Kathryn Beckermann: Yeah. Thank you.

Pedro Barata: Bye-bye.