The Future of Radiopharmaceuticals in the Treatment of Prostate Cancer - Philip Kantoff
October 16, 2022
Philip Kantoff, MD, Co-Founder & Chief Executive Officer, Convergent, Therapeutics, Inc.
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Targeted Molecular Therapies for Treatment of Advanced Prostate Cancer - Scott Tagawa
Safety and Activity of Alpha-Emitting Ac-225-PSMA-617 Radioligand Therapy in mCRPC That Has Progressed After Lu-177-PSMA, Journal Club – Christopher Wallis & Zachary Klaassen
Alicia Morgans: Hi. I'm so excited to be at ASCO 2022 where I have the opportunity to speak with Dr. Phil Kantoff, who is the CEO of Convergent Therapeutics and is here to talk to us about radiopharmaceuticals. Thank you so much for being here.
Phil Kantoff: Thanks, Alicia. Good to be here.
Alicia Morgans: Wonderful. So we have known each other for a long time. You've had so many roles in GU oncology and oncology in general. And so I just so appreciate you taking the time. Now with your new role at Convergent, I think it's exciting to think about where the field is now, and where we're going in terms of radiopharmaceuticals. Can you tell us a little bit about what you're doing?
Phil Kantoff: Sure. So beginning last year, I joined Convergent Therapeutics as the CEO and I was very excited about the data that had been generated by Scott Tagawa at Cornell and Neil Bander, who was the founder of the company. So, Neil discovered an antibody about 15, 20 years ago called J591, which is an antibody directed at the extracellular domain of the PSMA molecule, and has been trying to develop a therapy to use in prostate cancer. And he's developed ADCs. He's developed a number of radiopharmaceuticals. But what's really exciting and what really drew me into the company was the early data associated with the antibody coupled to actinium-225, which is an alpha-emitting radiopharmaceutical.
So now known as convo one alpha, Scott Tagawa presented at ASCO last year a phase one study of a single-dose dose escalation to study in unselected patients. Everybody had undergone a PSMA scan, but they were included even if their PSMA scan was negative. And in that dose escalation study of one dose of convo one alpha 45% of the patients responded with a PSA decline of greater than 50%. And that corresponded to changes, improvements in their other scans. So it was clinically meaningful and some of the responses were durable. And now we've entered into a multi-dose experiment with a variety of different schedules of convo one alpha and the data so far looks fantastic.
I think the interesting part of this is it's an antibody as opposed to a ligand, which is what Novartis's Pluvicto is using. The ligand that they use is associated with a beta particle — lutetium-177. This is an antibody associated with actinium-225, which is an alpha emitter. So they have very different biodistributions.
The radioligands are excreted through the kidneys and the antibodies are excreted in the hepatobiliary system. And alpha particles are very different than beta particles, and they're 1,000 times more powerful. They don't penetrate as far. And given that it's an antibody, interestingly, antibodies that are directed at PSMA don't bind to the salivary glands or lacrimal glands, so they don't cause the same xerostomia, dry mouth, dry eyes, that ligands do.
So, we're very excited. We think that the vision trial, which was the radio ligand trial, was a first step in this field. It prolonged progression-free survival, overall survival, but we think that this is a stepping stone for the future where radio antibodies, other radioligands, combination therapies, combinations of the two, combinations with other therapies in prostate cancer will be evaluated over the next few years.
Alicia Morgans: I think that's so exciting, the possibility of combinations we see in so many different types of cancer, solid tumors and of course, things look leukemia or lymphoma where we combine multiple different agents at once and really use them as a strategy to attack cancer cells from different angles and really kind of get at those mechanisms of resistance. Now let's check in a little bit more about how actinium might be useful in this strategy of using lots of different options. This is, as you said, it's an alpha particle. Many of our alpha particles undergo multiple decays. So can you tell me a little bit about actinium and how that process works for this?
Phil Kantoff: So, Actinium first of all is a alpha emitter. It has a half-life of 10 days. It emits four different alpha particles per molecule. And so it's a very powerful molecule. It is a very powerful alpha emitter. And as I said before, it doesn't penetrate very far. So it doesn't cause a lot of the off target effects that beta particles, which are much more penetrating, do. So there's a real difference between alpha emitters and beta emitters.
Alicia Morgans: Well, that's incredibly powerful to have these huge alpha particles times four here with that one molecule.
Phil Kantoff: Right.
Alicia Morgans: So how does that translate in the studies that you've done to the tolerability and the safety of these agents?
Phil Kantoff: Right. Very well tolerated. There's next to no dry mouth, dry eyes. The main side effect that we see with antibody alpha particle is hematopoietic toxicity. And the reason for that is not an off-target effect, but rather in my opinion, a bystander effect. Because prostate cancer, as you know, is mostly a bony disease, infiltration of the bone marrow.
And the patients that have been put on the study so far have very far advanced disease with very infiltrated bone marrow. So when you give an alpha particle to these patients, it goes to where the cancer is because it's targeted with the antibody. And as a bystander are the hematopoietic stem cells or the precursors that are affected. So you see transient thrombocytopenia. So that's the dose-limiting toxicity. So we're finding the appropriate dose to use, the appropriate schedule to use, but the efficacy so far has been really remarkable.
Alicia Morgans: Well, I think that's so exciting and really speaks to a potential need to move it earlier in the disease before the marrow is replaced with prostate cancer.
Phil Kantoff: Exactly. And furthermore, alpha particles are better at treating smaller volume disease than treating larger volume disease. Beta particles are probably better at larger volume disease than alpha particles. So that speaks to the synergy between the two also and speaks to what your point is, Alicia, and that is moving it earlier in disease when people have small volume microscopic or small volume metastatic disease.
Alicia Morgans: Well, and I think that's one of the exciting things about these approaches too. Maybe we can move them into even a biochemical recurrent population. Who knows? Although, we wouldn't necessarily have a lot of disease on even a PSMA PET scan at that time. But lots of opportunity potentially.
Phil Kantoff: Right. We'd like to go there, Alicia. We'd like to get to early disease where we could potentially cure patients with say PSMA positive disease, traditional scanning negative disease, and we have a chance at eradicating disease at that stage. It's a little early. That's a few studies away, but we're moving earlier and earlier in disease right now.
Alicia Morgans: Well, that's great. One of the things that I have hoped for with radiopharmaceuticals, and so feel free to comment on the whole spectrum of options here, is that maybe we can use these targeted therapies without castration. And I think that that may be a little pie in the sky, but I think is something that we all hope for because men have so many consequences of that approach, and that's the best that we have right now. It is highly effective, but it may not be the be-all and end-all if we have other ways of targeting these cancer cells. What do you think?
Phil Kantoff: I absolutely agree. I think that there is the possibility of taking patients with biochemical recurrence who have microscopic metastatic disease and avoiding hormonal therapy for a period of time, and using alpha particle therapy, antibody therapy, or radioligand therapy early in disease systemically, and maybe using focal radiation as well for sites of disease and avoiding hormonal therapy and potentially curing patients. So studies like that are on our agenda.
Alicia Morgans: Wonderful.
Phil Kantoff: Yeah.
Alicia Morgans: Well, I look forward to hopefully taking part in some of those studies, and I think that patients sincerely look forward to having those studies come out. So, as you look to the future in radiopharmaceuticals, radioligands, and others, antibodies as well, what are you thinking about? Where do you want to go? What is your message to patients and clinicians who are really watching this space with anticipation?
Phil Kantoff: Well, I think this is a breakthrough. I think it's a new area, not only for prostate cancer, but for cancer in general. I think it's going to be very much part of the armamentarium for patients with prostate cancer. Initially in patients with advanced disease, but it's going to move earlier. It's going to be moved in combination with other therapies.
There's reason to think that there are synergies with other types of therapy like hormonal therapy, because when you use hormonal therapy, you depress androgen, and when you depress androgen, PSMA expression goes up. So there's reason to think that at least in vitro so far, there is synergy. So I see it very much a part of the treatment paradigm in prostate cancer and eventually in other diseases.
Alicia Morgans: Well, that is extremely exciting, certainly for me, but I think all for all of the viewers and for the patients as well. As the CEO of Convergent Therapeutics, I sincerely hope that you continue down this path. I wish you luck with your team. And certainly the patients are eager to get involved. So thank you for taking the time to share everything that you're looking forward to with us today.
Phil Kantoff: Thanks, Alicia. Thanks for inviting me.