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Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today for an ESMO 2024 discussion with Dr. Laurence Albiges from Gustave Roussy in France. Laurence, thanks very much for joining us today.

Laurence Albiges: My pleasure. Thank you.

Zachary Klaassen: So we're going to discuss the CaboPoint Phase II Trial, which you presented at ESMO. But for context, maybe just set up the second-line, post-immune checkpoint inhibitor, first-line disease space, because it's really gotten interesting over the last 6 to 12 months, hasn't it?

Laurence Albiges: Absolutely. So the good news for our patients is that the field is evolving rapidly. And so our first-line treatment strategy for patients with clear cell RCC is combination therapy, either a doublet of IO-IO, nivolumab plus ipilimumab, or an IO-TKI strategy. And there we have different combinations that have been approved such as axitinib-pembrolizumab, lenvatinib-pembrolizumab, or cabozantinib plus nivolumab.

And so the big picture is what should be our second-line strategy. And as of now, we are using a TKI in sequence that we haven't used in the past. There has been an attempt to demonstrate is there a role for sustained PD-1/PD-L1 inhibition; CONTACT-03 was the first study which did not demonstrate that adding atezolizumab on top of cabo was providing further benefit. And at this ESMO meeting, we had the results of TiNivo-2 Study, which similarly failed to demonstrate the added value of nivolumab on top of tivozanib. But one has to stress that these studies were not conducted in pure second-line studies. It was patients enrolled in second, third line. Some of them were even post-adjuvant. So it was a mixed bag.

And the CaboPoint Study is here to give the information on what is the activity of single-agent cabozantinib as a pure second-line strategy, meaning that the patients had failed a prior combination regimen. And so for that purpose, we launched a study that is developed in second-line setting in patients that had failed at least one line, nivolumab plus ipilimumab or an IO-TKI strategy, which of course wasn't based on cabozantinib.

So the CaboPoint Study is an open-label, single-arm phase II across Europe, which enrolls specifically the patients either in cohort A that failed nivolumab-ipilimumab or cohort B, patients who progressed after IO-TKI. And patients were to receive cabozantinib standard dose 60 milligrams daily. The primary endpoint is response rate assessed by an independent central review. And so what this study is showing us? Well, it's showing us that in patients who failed nivolumab-ipilimumab, the response rate in about 80 patients is 40.5%. So this is the benchmark of what you expect from a potent VEGF-TKI after nivolumab-ipilimumab, meaning those patients had never seen a TKI before.

And then cohort B is patients who received IO-TKI and mostly axitinib plus cabozantinib. And here the response rate is 27.5%, so below 30%, where cabozantinib is being used after prior exposure to a VEGF-TKI in combination with an immune checkpoint inhibitor.

So a clear activity, what is the duration of response, what is the PFS? Progression-free survival to the right part of this slide is for patients who had never seen a TKI post nivolumab-ipilimumab, almost 11 months. This is what you expect from cabozantinib in this setting. And with regard to cohort B, prior exposure to prior IO-TKI, 8.3 months.

These data are important because they provide the benchmark of our pure second-line setting. And here we see cabozantinib in patients who previously failed first line. So I think it's important, it's a first prospective trial using cabozantinib as a pure second-line regimen after combination. It is going to be used for benchmarking with the future study, hopefully randomized, to see now what is the right TKI we want to use if we're able to generate data. And I hope in the future, combination therapy, maybe not with an immune checkpoint backbone, but with new drugs.

Zachary Klaassen: Wonderful presentation. So I think as we sort of distill the second-line setting, we saw you mentioned the TiNivo-2 Trial and looking at CaboPoint. Right now it looks like cabozantinib is the clear delineation, if we're treating a patient tomorrow. What would you say is coming from a phase III standpoint as trials continue to accrue, maybe we get design, what are we looking towards over the next couple of years?

Laurence Albiges: So the current guidelines say we use a TKI that hasn't been used in first line. Cabozantinib has the data I've shown you with the CaboPoint Study. We are eager to clearly define where belzutifan should stand. It is routinely being used as a third or fourth line setting right now, based on the LITESPARK-005 data that were presented last year at ESMO 2023, published in the New England Journal of Medicine meanwhile and for which we had the overall survival data presented at this ESMO. So I think it's important to define where we should be using belzutifan for patients, and in the future we are waiting for combination trials. I'm thinking of the lenvatinib plus belzutifan versus cabozantinib study. I think they will be important to see, is there an added value of having, I would say, upstream-downstream pathway inhibition with a dual lenvatinib-belzutifan strategy.

Zachary Klaassen: Wonderful. I think as we move forward, certainly we've learned from negative trials, we've learned from these trials, and I think ultimately we're getting better clarity for options for our patients. Would you agree?

Laurence Albiges: I agree. And I'm glad that we're able to see new agents being developed.

Zachary Klaassen: Yeah, absolutely. Professor Albiges, always great speaking with you. Thank you for your time and expertise discussing the CaboPoint Trial today.

Laurence Albiges: Thank you.