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Pedro Barata: Hi, my name is Pedro Barata. I'm a GU medical oncologist. I have the privilege to be joined by professor of GU at MD Anderson in Houston, Texas, Dr. Nizar Tannir. And he's a friend, he's a mentor, he's a key opinion leader. Very well respected for all the many, many, many trials he led successfully. And as we were sharing previously, some were positive, some were negative, but we took important lessons for the future. And specifically, for the treatment of advanced renal cell carcinoma. So with that, we have the pleasure to have Dr. Tannir today, in the context of the very important paper that came out addressing the CANTATA Phase III trial. So. Dr. Tannir, it's a privilege and a pleasure to have you here.

Nizar Tannir: Thank you, Pedro, for the kind invitation. It is my pleasure, my privilege and honor, to join you in today's interview.

Pedro Barata: Again, congrats. JAMA Oncology became one of the most popular journals. Right? And a highly, highly impact factor journal, for us to actually submit important hard to do research in GU, and specifically in RCC. So, and that's the reflection of that impact factor going up. So congratulations for having CANTATA trial published there. We all know it's an active study, but what we're going to try to do here is, go beyond those results, and get a little bit of the context for that particular trial. Which I think, was a very important trial. And one of the reasons why I really think it was an important trial, is because it explored a new mechanism of action in RCC. Right? And we're talking about metabolism, we're talking about glutaminase, if you will, and this inhibition of the glutaminase. So maybe instead of me, I'll let you do that.

Nizar Tannir: Sure.

Pedro Barata: Let me just ask you, can you tell us a little bit, for those who are listening and watching this, less familiar with the role of metabolism RCC, can you kind of present that for us? Which was kind of what leverage the trial to be designed and conducted?

Nizar Tannir: Sure. It's a very important question, Pedro. Thank you. Of course, we know the therapies that have been approved in RCC back in the days of old cytokines, high dose IL-2 interferon. And then of course, we all then benefited from the insights into the biology of RCC. With all derived from VHL and then the HIF pathway. And then, over expression, up regulation of downstream targets of HIF, and that's the VEGF. And of course, all that class of agents of VEGF receptor TKIs. And we have several of those approved over the years. And then the mTOR inhibitor pathways. And of course, most recently, the immune checkpoint inhibitors. So really, if you will, the MOA, they got cytokines, you've got VEGF, and you got mTOR, and then you got the immune checkpoints, the inhibitors, CTLA-4, PD-1, PD-L1, et cetera.

So I think, we understand more and more now about the biology of RCC, particularly clear cell. But this applies to other variant histologists, what we call the non-clear cell. So I think, if you look at a normal cell, normal cell derives its energy from glucose, and it produces ATP through glycolysis. But then, in a tumor cell, that under the influence of an anchor gene, the glucose metabolism is shifted, is towards lactate, through the Warburg Effect. So a tumor cell faced with an abnormal glucose, inefficient glucose pathway, glucose metabolism pathway, has to rely on some other pathways to produce energy. And that's where the glutamine becomes important. And the glutamine has been shown to be an active, used pathway by tumor cells.

So glutamine is converted to glutamate by glutaminase, and then, glutamate is then part of the TCA cycle, ultimately producing energy for the cell. So this is now what tumor cells use. And I think, targeting that pathway was the MOA for this class of agents, that we call glutaminase-1 inhibitors. And the agent that we worked with, with a company, Calithera Biosciences, a small biotech company in California, they had this first in its class tumor metabolism drug that's a glutaminase inhibitor. So it blocks glutaminase, so it blocks the production of glutamine.

And then, if you look at tumor tissues, and then of course, we looked at RCC, clear cell, Chromophobe, and of course, breast, and many other tumor types, there was overexpression, when you look at these human tissues. Overexpression of glutaminase in these tumor samples. So really, validating that perhaps, targeting the glutaminase pathway will produce the desired results, because you know, you're depriving that cellular machinery of its energy, and therefore hopefully, you will kill, you'll target killing of tumor cells by blocking or inhibiting glutaminase.

And of course, you go through the preclinical data, you show the importance of that pathway preclinically, in PDXs models, et cetera. And then of course, the next step was to go to a Phase I. And when we did a Phase I, monotherapy, we did not see a lot of responses. There were a few responses, but importantly, there were many patients that had stable disease for an extended long, long period of time. And of course, when we obviously, after establishing the safety of this drug that we, I mean, initially had the name of CB, after Calithera Biosciences, CB-839, and then, had the name telaglenastat, we did the first combinations. One combination was with everolimus, one combination was with cabozantinib. And then, the results of the monotherapy was published in CCR. Subsequently, the results of the combination with everolimus and with cabozantinib was also, the results of that Phase I were published in CCR.

And interestingly, although the number of patients is small, when we combined CB-839, or telaglenastat, at the dose of 800 milligram twice daily, which was a safe dose, with minimal adverse events as monotherapy. When we combined it with cabozantinib, at 60 milligram daily, we saw 50% objective response rate. Those responses were partial responses, but 50% ORR in the second-line, third-line, so that's all salvage setting. So this was really encouraging to go to two trials. One was ENTRATA, which was placebo controlled, the CB-839, or telaglenastat, plus everolimus, versus placebo plus everolimus. And this was presented in 2019 at ESMO. The primary endpoint was PFS. And we saw, we observed doubling of the median PFS with telaglenastat plus everolimus, versus placebo plus everolimus. But the number of patient was small. This was a 69 patient randomized Phase II trial, which were published recently just a few months ago, in CCR again.

And obviously, cabozantinib is the approved salvage therapy, if you will, in second-line, third-line, based on METEOR Phase II trial. So it was natural to combine cabozantinib with telaglenastat. And as I said, it's one number of patients in a Phase I cohort, that combination produced 50% ORR in a salvage setting. And so, we designed the trial of telaglenastat plus cabozantinib, versus placebo plus cabozantinib, as second-line or third-line. And that was the CANTATA trial, which was, as you mentioned, published recently in JAMA Oncology. In fact, it just came out September 1st, online.

Pedro Barata: Fantastic summary as well, for the context, and also for the design. We know it's an active study, as you mentioned, but I'd like you to, can you comment a little bit on the safety and efficacy? And maybe on efficacy, I'm going to point out, to me, one thing that caught my eye was, I was actually surprised to see how well the Cabo group performed, to be honest. Because PFS was the primary endpoint. And so, it is actually for patients who were... I know not 100% of patients did receive prior TKI, but the median PFS was over nine months, if I remember correctly, for the Cabo, and I predict, and that and the response rate. But I'll let you comment a little bit on that.

Nizar Tannir: Yeah.

Pedro Barata: And also on safety, because I think to your point, it was shown to be safe to do it.

Nizar Tannir: Sure. I mean, first the easy part, safety. CB-839, or telaglenastat, was a drug that was very deliverable, at 800 milligram twice daily. And then again, when you look at platelets, you do pharmacodynamic studies, you show, we were able to show that you really inhibit glutaminase, to almost 100%. So really, it did do its job, when you look at a surrogate platelet, and you see that inhibition. So it was safe. It was combinable at the full dose of monotherapy, which is 800 milligram twice daily, with a full dose. Back with the ENTRATA, with everolimus, it was 10 milligram daily. As we know, that's the dosing for everolimus monotherapy. For cabozantinib, 60 milligram. And so for safety, it was no problem.

I thank for your observation, you're absolutely right. The results of CANTATA showed that the combination on cabozantinib plus placebo performed really well. But the reason is, about 20% or so of those patients on CANTATA, who are recruited, enrolled, and randomized to CANTATA, did not have prior TKI. Those who were patients who received nivo/ipi, as you know, the trial CANTATA was launched after already nivo/ipi was approved as first-line therapy for intermediate risk. So we had about 20% of those patients. CANTATA again, to remind the audience, is a 444 patient randomized trial. So we called it Phase III, but you can say, well is it Phase II, Phase III? But ultimately, it was powered enough to really look at the question of PFS as primary endpoint, which we thought was valid. But so, of those 444 patients recruited to CANTATA, 20% had only nivo/ipi. So the results I think, that showed PFS, you were right. Placebo plus cabozantinib had a median PFS of 9.3 months. And telaglenastat plus cabozantinib had a median PFS of 9.2 months.

So I think, those results compared favorably with the results of METEOR, where the median PFS... Of course, there was no placebo there; it was Cabo versus everolimus, open label in METEOR. The median PFS with cabozantinib was 7.4 months, as you recall, Pedro, from METEOR. So really, an improvement of about 1.8 months, median improvement in PFS. I think in a large part, due to the fact that by definition, METEOR recruited patients that had progressed through one, or two, or more TKIs, everybody had to have a prior TKI. Here, they did not have to have prior TKI.

Pedro Barata: That's a great summary, and I couldn't concur with you more on those points. To me, bringing novel mechanisms of action is actually super, super important in advanced RCC. You did a great summary of all the options we have available, but that's kind of a common theme, we want to see more and different mechanisms of action. This one, it was emerged as a very promising MOA. Of course, we have the HIF inhibitor. So my guess, my question to you is, is there any room for us to leverage the metabolism of RCC in future research?

Nizar Tannir: Yes, I think great question. I think, looking back at CANTATA, and ENTRATA, and then for other companies that may have compounds in the metabolism space, I think really, coming back to biomarkers, I think it was important, and I think this may be the reason we did not see an improvement in PFS with telaglenastat plus Cabo, versus placebo plus Cabo, because this was an unselected patient population. We did not really select patients based on tumors that really had high glutaminase expression. And so I really think, this comes back to again, what we talk about all the time; making sure we select the right tumor that has the right, again, vulnerability. It's important to underscore, underline that vulnerability, to try to really maximize the effect of your agent. So perhaps if we had selected first maybe, the cabozantinib part, partner with telaglenastat, was not the best agent to combine telaglenastat with.

Again, there was a signal with ENTRATA. The median PFS was 3.8 months with telaglenastat plus everolimus, versus placebo plus everolimus, in ENTRATA, doubling the median PFS. Maybe we should have, again, this is hindsight now, use a different drug than cabozantinib, a drug that works also through tumor metabolism. Now, I don't think cabozantinib works through tumor metabolism. We all know cabozantinib is a VEGFR TKI and a MET inhibitor, AXL inhibitor, et cetera, but not considered a tumor metabolism drug. So target agent targeting these pathways are important, relevant in RCC. In clear cell, as well as say, papillary, et cetera. But maybe choosing another agent to combine telaglenastat, which is a tumor metabolism drug, with another drug that is tumor metabolism drug. And perhaps, the mTOR inhibitors would have been. And maybe we should have done a Phase III, power the trial to really use the vulnerability of the tumor, by combining it with an agent.

Now, are there other tumors that one could go after with this agent, telaglenastat? I think here, one could think of many tumors. In RCC, for example, there are several that are considered to be highly metabolic, and then maybe you could use a PET scan there, an FDG PET scans, to really also see those, which tumors. I think one could think of HLRCC, hereditary leiomyomata, associated with RCC as a metabolic tumor. Maybe test that in HLRCC, rather than that unselected patient with clear cell RCC, where we know the heterogeneity there could be immense. Maybe a real met carcinoma. And I think again, trying to go back to bench and do those models, where you can see the vulnerability due to metabolism, and then select those tumors that, where you think a sort of clinical trial in the lab in PDXs, to really then have confidence, when you take it to the clinic, you will really achieve the results.

So is tumor metabolism still a valid pathway? Absolutely there may be. CANTATA, ENTRATA, et cetera, focused on glutaminase, but there are other metabolism pathway that are important in each one of these RCC subtypes. So I don't think it's over for the tumor metabolism.

Now we talk, there are several papers coming out about ferroptosis, the role of ferroptosis. And so for example, Chromophobe, maybe other tumor types in RCC, and other tumors as well. So I really think, there are some other agents leveraging tumor metabolism, and different pathways that tumor cells use. So we can really go after. So we definitely need to pursue this. I hope we will see more trials focusing on tumor metabolism.

Pedro Barata: You highlight such important points. Maybe I'll just speak on two, the precision oncology piece of the story, better selection of our patients. But in addition to that, highlighting patients with non-clear cell histologies. Right? So important. Of course, you've led a lot of the research that ultimately provide data for us to use. So difficult to enroll for trials in non-clear cell, and actually, your center has been pivotal in those efforts. So kudos to you for that.

And so, with that, Dr. Nizar, this was great. Thank you so much for taking the time. Again, congrats. I encourage everybody to read the paper, really well written. And yeah, I'm looking forward to the next piece of data that you're going to present.

Nizar Tannir: Thank you, Pedro. Appreciate the opportunity to be with you today, and your audience. It's a pleasure. And I again, as I said, look forward to following your path, and your trajectory in academia. So it's always at the end, it's our patients that are in the center of what we do, and I hope, I hope, we will rid the world of cancer, RCC, and others as well.

Pedro Barata: Well said. Thank you.

Nizar Tannir: Thank you.