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Oliver Sartor: Hi, I am Oliver Sartor, and it's a pleasure for me to be here today with Phil Kantoff, very well known among prostate cancer circles. And I'll simply say that I've known Phil for years and years. He was the Chief of Genitourinary Oncology at Dana-Farber. He was Head of Medicine at Memorial Sloan Kettering. He is now the CEO and Co-founder of Convergent, and he's also on the Prostate Cancer Foundation Board. So Phil, you've kind of done a lot of things and now you're off on this new journey with Convergent. First of all, is there anything else you'd like to say in terms of introduction or things that you'd like people to know about you, you're a medical oncologist, long prominent in the field?

Philip Kantoff: Yeah, I want people to remember the fact that Oliver Sartor was one of the first people to get excited about radiopharmaceuticals. I remember in the 1990s Oliver, you were involved in the first generation of radiopharmaceuticals, strontium, samarium, rhenium, and you were one of the first to recognize the potential value of Radium 223 when you were in the office next to me and you showed me the early data. So you've been in this field a long time. I just want people out there to know that you're one of the first, one of the pioneers of the field.

Oliver Sartor: Well, thank you Phil, and it's been a little bit of a stroke of luck, but it's been a good ride. Let's delve into this a little bit further because obviously you're a radiopharmaceutical company, but we are living in a world where they're CAR T cells and ADCs and bispecifics and a lot of ways to be able to target cancer cells today. Why radiopharmaceuticals, why are you enthusiastic about this field?

Philip Kantoff: Well, let me just back up a second and say that there's a whole world out there of targeting surface molecules on cancer cells. And I don't think as an oncologist or as somebody involved in this field that there's one strategy that fits all targets. I think there'll be targets that are more amenable to ADCs, some for T-cell engagers, and radiopharmaceuticals. The reason I got excited about radiopharmaceuticals or the reason I went into this field right now was Neil Bander approached me back in 2020 after I decided to move back to Boston from Memorial Sloan Kettering, and he said, "I'd love for you to run this company called Convergent." And I said, "I don't know anything about Convergent." And he said, "Well, you got to see this data that we've generated at Cornell." And I eventually saw the data Oliver, that was generated by Scott Tagawa and Neil when Neil was at Cornell.

And it was a phase one study, single-dose experiment. And I've rarely seen activity to that level in a dose escalation phase one study where about 45% of patients had a 50% decline in their PSA, some durable responses, minimal toxicity, no pre-selection. So that got me excited about the field. And as you know, I was not a radiopharma guy to begin with. I spent most of my career doing other things, but the data was very compelling and it's continued to be very compelling since that time. And of course, as you know when you led Pluvicto and Lutathera and it's really an emerging field. I think it's going to be a fantastic field for the next decade or two in terms of emerging technologies. So I'm excited about it. Everybody's still sorting things out. Are large molecules better than small molecules? Are alphas better than betas? What type of alpha, et cetera.

And I don't think there's one size fits all. I think it's going to be very much context dependent, target dependent in terms of what is the best approach for any target. I will jump and cut to the chase in saying that I do feel that when it comes to PSMA targeting, prostate specific membrane antigen targeting, delivering actinium-225 specifically alpha, the antibody approach appears to be the best approach, both in terms of efficacy, in terms of toxicity. That may or may not be the case in other contexts. And certainly there's a place for small molecules, peptides, et cetera, certainly a place for beta radiation as well. But in the context of PSMA targeting with alphas, I do think the large molecule approach is the ideal approach.

Oliver Sartor: Interesting. And I was going to ask a little bit about the rationale for the antibody because most of the molecules, and this would be the SSTR2 targeted therapies and the PSMA targeted therapies that are FDA approved both with lutetium. Both betas are small molecules. And help us understand why the antibodies are preferable in your opinion for this particular isotope in target.

Philip Kantoff: Yeah, the question is why have the small molecules emerged? And I think you know probably as well as I do, they emerged more as initially imaging agents that were then developed into therapeutic agents. Antibodies have been therapeutic for many, many years, as you know, in terms of naked antibodies, antibody drug conjugates, and other approaches as well. So the rationale behind radio antibodies is the fact that antibodies are retained by the cancer cell for a longer period of time than the small molecules are. And as you well know, the small molecules are taken up into the endosome and are then recycled back out to the cell membrane and maybe recycled over and over again. Whereas the antibody approach, it does get taken up into the endosome, but it is then trafficked into the lysosome where it remains in the cell for a longer period of time. So that's one reason why I think the antibody approach is superior, particularly in the context of PSMA targeting, maybe in the context of other approaches.

But in addition, with regard to PSMA targeting, it appears that while the antibody does bind to the PSMA molecules on the salivary glands and lacrimal glands, they don't penetrate into those normal tissues as profoundly as the small molecules do. That may be the mechanism by which the antibodies have less xerostomia and dry eyes than the small molecules do. I am not sure what the mechanism is, but what we think about is the fact that they're larger molecules and they're harder to get through the basement membrane in normal tissues. So the two advantages of the antibody approach in the context of actinium delivery to PSMA targets are better retention by the cancer cell and less effect on the salivary glands and lacrimal glands.

Oliver Sartor: Yeah, very important part. And then Phil, you also made a brief allusion to the renal excretion, and that's one of the issues that's been problematic with the small molecules is sort of the specter of renal toxicity because you do have some retention in the proximal tubule, it's not just flushed through. And the antibody itself is not going to be part of the glomerular filtration, not going to hit the proximal tubules and not have that retention. And to be able to spare the salivary, spare the kidneys, I think does give an advantage. And that's one of the bugaboos, if you will, about the small molecules that people have been very concerned about.

Philip Kantoff: That said, Oliver, there hasn't been a lot of clinically significant renal toxicity associated with say Pluvicto, although there are studies that demonstrate a decrease in GFR, which is probably not clinically significant. How important that is when you deliver alpha radiation remains to be seen. At least there doesn't appear to be a lot of acute toxicity to the kidneys. But one could get a little bit more concerned when you treat patients with earlier stages of disease who have a longer life expectancy and will there be subacute or chronic renal toxicity as a result of small molecule alpha approaches.

Oliver Sartor: Point very well taken Phil. But I think what you've delineated is a solid rationale for the antibody approach with actinium and I think that's going to await in the end the data. But your compelling phase one and initial preliminary data is certainly I think provocative and enough to get you onto the next stages. Now let's briefly talk about something that may be a little bit premature, but I'd like to get your input, combination therapies. And I know that Scott Tagawa has looked at a little bit of immunotherapy, but I just wonder more generally if you might speak about combinations in radiopharmaceuticals. Anything you're enthusiastic about, anything you'd like to highlight in terms of your own thinking?

Philip Kantoff: Scott has done an experiment combining Pembro with our lead agent, which is we call CONV01-alpha, which is basically the antibody that Neil developed called J591 attached to actinium-225. And in the phase one study of a single dose of CONV01-alpha, which is the antibody actinium combined with continuous Pembro, there were three patients out of six in the phase one study who received 80 kilobecquerels per kilogram of the CONV01-alpha in addition to Pembro who have remained in remission now well over two years. And what I mean by remission is free from PSA recurrence. They had a profound decline in their PSA and have remained PSA recurrence free now two years out or greater from receiving the radiopharmaceutical and now off of Pembro as well. So there may be something to it. And our colleagues at UCSF have done an experiment with Pluvicto combined with, I believe it was Pembro, and they saw some interesting results as well.

So the question is there something about that combination? Is it unleashing of neoantigens by alphas or even betas perhaps that sensitizes the prostate cancer, which is, as we both know, not very sensitive to Pembro in the first place to Pembro. Or is in our case, is it just treating patients a little bit earlier in their disease where you see these profound durable remissions? So that's one combo that we're very interested in pursuing.

Obviously, another combination is in combination with what I call ARSIs or androgen receptor signaling inhibitors. Everybody has a different abbreviation for it. We favor ARSIs and as you know, ARSIs will increase the expression of PSMA and may increase the efficacy of our agent. As you had demonstrated in the vision trial, patients who remained on an ARSI seem to do better. So there may be something about that combination. And finally, Scott has generated some very interesting data with Neil combining CONV01-alpha along with small molecule lutetium. In this case it was INT.

And the rationale behind that combination is based on preclinical data that Neil had generated, Neil Bander had generated. Demonstrating that the antibody approach, whether it be radiolabeled or not, will increase the retention of the small molecule beta in the cancer cell. Demonstrated that in xenograft models, demonstrated that in animal models. And there is a phase one study that was conducted at Cornell that demonstrated remarkable efficacy of low doses of CONV01-alpha, really half the dose that we're pursuing along with I'll say half the dose of PSMA-Lutetium-INT giving only two of the four doses. And the majority of patients had a PSA-50. 28% of patients had a PSA-90. And there were some durable responses there too out to two years as well. That was almost no toxicity. So that study was halted when Lantheus and Lilly acquired Point and ceased conducting IITs. But Scott is about to resurrect that trial with higher doses and we're very interested in that as well. Is the combination of small molecule beta or for that matter, small molecule alpha and CONV01-alpha.

Oliver Sartor: Very interesting, Phil. I don't think people are aware of that data. I've heard a little bit of allusion, but just explain it a little more in detail. I can see your enthusiasm for combination is high and you've got a good rationale, that's quite provocative. In the two years without progression for those treated with Pembro and one dose, so the CONV01-alpha. Again, very impressive. I'm now going to ask you to put your crystal ball into play, hopefully it's not too cloudy. And Phil, think about maybe looking into that crystal ball about five years into the future and share with our audience a little bit about where you think the field will be in five years and just your concept and vision about what you think will take place. I think it'll be very provocative for the audience to be able to hear you think in that way.

Philip Kantoff: I alluded to this before. I think we're in the early stages, not only in radiopharmaceuticals, but antibody drug conjugates, T-cell engagers and I don't think we have a good biological understanding of what is the optimal approach against a particular surface target with regard to those different strategies, whether alphas may be better than betas. So I think we need to have a better biological understanding of what are the parameters that determine why one approach might be better than another. For example, why do ADCs work so well in breast cancer against the HER2 target and other approaches may not be as efficacious. I think those are the sort of questions that need to be answered. So is it uptake of the antibody or small molecule? Is it the target density? There are so many different parameters to think about with regard to developing a rational approach toward targeted therapies.

I don't think we really fully understand what approach is best. Having said that, there are many targets in many cancers. And I hate to think that everything is going to be empiric going forward. Trial and error of let's try an antibody, let's try a small molecule, let's try a beta, let's try an alpha. Which approach is going to be best in the case of radiopharmaceuticals? But I think this is just the beginning of a fantastic area of targeting surface molecules. And I think one of the approaches is going to be radiopharmaceuticals. As we already know, it's clinically validated, it's commercially validated in the case of Pluvicto and Lutathera, maybe even in the case of Radium-223, Xofigo.

So I think it's going to be a very interesting period of time in the next 5 to 10 years in pursuing each of these approaches. And I think that radiopharmaceuticals will have an important role in the treatment of cancer. And conceivably, we think about this a lot, and I think you probably do too. It is conceivable that if you move into early stages of cancer, say prostate cancer, and you use an alpha and you're targeting microscopic metastatic disease, it's possible that you could generate even a curative approach. So very exciting times ahead of us Oliver. And thank you for starting us all off in the field 25 years ago.

Oliver Sartor: Well, thank you, Phil. That was really fun. Thank you for sharing your thoughts. I think our audience will really appreciate that. I want to mention one more thing about Phil, and that is at the recent ASCO 2024, Phil got an ASCO Mentoring Award for the incredible number of trainees who've been under his tutelage who've gone on to have real success. So it would take a long time to name them all, but Phil has really been immensely influential in our field for training and bringing so many young people along that have now become successful. So Phil, with that, I'm going to say thank you. Appreciate your time this afternoon and all the best with Convergent. I think things are going to go very well for you.

Philip Kantoff: Thank you, Oliver. Have a nice evening. Thank you everybody.

Oliver Sartor: Bye-bye.

Philip Kantoff: Bye-bye.