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Oliver Sartor: Hi, I'm Dr. Oliver Sartor with UroToday. We have a really nice guest on this morning, Jeff Humphrey, who's the CMO from Lantheus. I have known Jeff for many, many years since his NCI days, but welcome, Jeff.

Jeff Humphrey: Thank you, Oliver. It's a pleasure to be here.

Oliver Sartor: We're really focusing in on the radioisotopes, and we're interviewing a number of people who are influential in the field. You're one. I wonder why, just for a brief moment, you could explain to our audience the radioisotopes? I mean, you could be going after ADCs. You could be going after CAR-Ts. You could be going after bispecifics, all these new modalities of care. Why radiopharmaceuticals for you and Lantheus?

Jeff Humphrey: Yeah, well, Oliver, as you know, when I was a chief fellow and you were my attending and we saw patients with prostate cancer at the NCI in the late '90s, end-stage prostate cancer, there was very little and has been very little for these patients for decades. The VISION trial and Pluvicto have shown this tremendous overall survival advantage and really given the ability to target tumor-specific antigens with radioisotopes that don't require, for example, internalization of the radioisotope in order to kill tumor.

This is a new modality with untapped potential. I think there's a lot to discover as we do clinical research in this space, and my hope will be that eventually radioligand therapy will evolve into a new major modality for the treatment of cancer.

Oliver Sartor: I agree with you, Jeff, and share that enthusiasm. It's remarkable what's been happening in the field, actually all of a sudden—new targets, new isotopes. I'm going to ask you about both of those here in a moment.

You mentioned very particularly the PSMA-617 lutetium, and you guys have been looking at lutetium. Are you looking beyond lutetium in terms of isotopes at this particular point? Anything about alphas, more betas, different betas? What's your thinking around the isotopes in general?

Jeff Humphrey: Yeah, Oliver, we certainly are. It is public knowledge that Lantheus has made equity investments in Perspective Therapeutics, which is focused on lead-212, and we're excited about lead-212 with the half-life of 10.6 hours and the ability to generate a single alpha emission without some of the complications that you might see from, for example, the daughters of actinium.

In addition, we have an effort at Lantheus to study astatine-211, and in fact, we recently published the AERO study, which was presented at ASTRO, and that used I-131, but as a halogen, we feel that astatine-211 would be preferable to iodine-131. We have an interest in lutetium. We have an interest in lead-212. We have an interest in astatine. We haven't ruled out the possibility in the future of working with actinium, but at this point we've restricted our focus to those three: lutetium, lead, and astatine.

Oliver Sartor: Now, interesting. What some of our readers may not necessarily know is that New England Nuclear is really the father of Lantheus in so many ways, or maybe some other. I'm not quite sure. But going back in time, New England Nuclear was a critical component in the development of isotopes, and now Lantheus has sprung from those early beginnings.

Jeff Humphrey: That's exactly right. In fact, New England Nuclear was started by a Manhattan Project scientist who wanted to use radioisotopes for medical purposes and not destructive purposes. We have a long history. It winds with big pharma at one point when New England Nuclear became DuPont, then DuPont Merck, was purchased by Bristol, and then was spun out by Bristol and ultimately took an IPO as Lantheus. From 1957, we've been through small pharma, big pharma, back to private, and then through IPO. Lantheus now is thriving with radionuclides as its focus.

Oliver Sartor: Yeah, no, you guys are doing quite well.

You've disclosed, of course, work on PSMA, and the question—and I'm not trying to get any proprietary information—do you have other targets that you're able to discuss at this particular time, or is it too early and maybe proprietary for you to do so?

Jeff Humphrey: Well, we're very excited about the gastrin-releasing peptide receptor, so GRPR. In fact, we have in-licensed Rn-2, both a gallium-68 version for imaging, and we anticipate a lutetium version for therapy as well.

What I find most interesting is that the expression of PSMA and the expression of GRPR seem to be inverse—that clones that express GRPR seem to not express PSMA and vice versa. You see GRPR expression in patients who have progressed on lutetium PSMA. Even in individual patients, when you image for both PSMA and GRPR, you can find tumors where bones have developed and different regions of the tumor will light up either for PSMA or for GRPR, but not both. I find that just fascinating.

I know there's an interest in combinations. How do we use radioligand therapy in combination? I think that provides one exciting opportunity that I'm particularly excited about, which is potentially the sequential use of lutetium PSMA followed by a GRPR-targeting agent to try to treat both sets of clones.

Oliver Sartor: I'm glad you're raising the heterogeneity issue. I think we're increasingly aware of the heterogeneity, and we see the PSMA PET scans, but we don't necessarily understand the microheterogeneity that's occurring at the cellular level. I'm really delighted to be able to hear that Lantheus is helping to think and address that particular issue, which I think is a really large issue in the field.

You mentioned briefly combinations, and of course, goodness gracious, we have hormonal therapies, we have isotopes, we have chemotherapies, radiation sensitizers, immunotherapies—a lot of discussion about the combinations. But I wonder if you might have any combinations in mind. You made an allusion to the PSMA GRPR, but what about other types of combinations that might be on your mind or in the sort of strategic thinking long term?

Jeff Humphrey: Yeah, yeah, I think combinations have always been important to progress in oncology therapy. The dogma is to find two agents with non-overlapping toxicity and different mechanisms of action. Certainly radioligand therapy is a brand-new mechanism of action. There's been a lot of speculation about the combination of radioligand therapy with DNA repair inhibitors such as the PARPs, and I think that makes a lot of common sense and is something I think that's very exciting.

But I don't rule out the possibility of combinations that are of real benefit that simply use a different mechanism of action, whether it be hormonal, potentially even ADC but against different targets, and potentially even chemotherapy. I think that's not something that we're going to understand for the next three to five years. It's going to take a while to really develop that data set, but I think there's tremendous untapped potential. It's part of the reason why I'm so excited about being involved in what could be a new modality of therapy that really would be a novel way of bringing forward a new mechanism that would combine with potentially every cancer therapy that's currently available.

Oliver Sartor: I like the way you started out, Jeff, with an allusion toward a really classic premise in oncology. Different mechanisms of action, non-overlapping toxicity harkens all the way back to Vince DeVita and MOPP days. I don't have any—

Jeff Humphrey: That's right.

Oliver Sartor: Vince DeVita did MOPP, but that was his mantra about combining these different drugs. Different toxicity profiles, different mechanisms of action, and putting four together and coming up with a cure. He did cure Hodgkin disease, which was a miracle at the time.

Jeff Humphrey: Agreed, agreed, and perhaps one day we'll cure prostate cancer.

Oliver Sartor: Oh, boy. That would be truly a dream come true.

Jeff Humphrey: Interestingly, actually, one area that we are very interested—you asked about different isotopes. One of the reasons why we're very interested in lead-212 is with the short half-life, there is a theory that there could be preservation of the anti-tumor immunity that might otherwise be harmed by persistent radiation at the tumor site. And so, in fact, we are currently studying a lutetium and PSMA in combination with an anti-PD-1 and have a real interest in this combination.

Again, the immuno-oncology approach has proven to show cures even in stage four with widely metastatic disease. I think it's an exciting combination.

Oliver Sartor: Jeff, I've heard about this concept of the short half-life of lead—and by the way, astatine would also apply here—to be able to damage the cell, trigger a response, but not interfere with the influx of immune cells that typically follow that initial insult. I think there's a lot of interesting work to be done in the short half-life isotopes, whether or not it be lead-212 or astatine, and this interaction with the immune system. I really look forward to learning more about that over time. I'm pleased to hear that Lantheus is interested.

Let me back off, and this will actually be my final question for you, Jeff. I have a crystal ball. It's right here. It's a little bit hard to see. I have trouble seeing it very well, but maybe you can see better than I. I wonder if you can look into that crystal ball and think about the next five years. Tell us what you think you might see developing over the next five years that we don't fully appreciate today, so just a forward-looking perspective on this big field moving fast.

Jeff Humphrey: Yeah, I look forward to understanding PSMA expression in other tumors and the activity of radioligand therapy in other tumors. I think that's a very interesting space to watch—breast cancer and others where there could be real value brought by this modality.

I think, in addition, there are a number of targets that have not been explored. We expressed neoantigens that are now expressed by the tumor and are not expressed by the rest of the body or are expressed only in limited tissues. I think the ideal target would be expressed only by the tumor, and I think the more that we look for that kind of a target, the more we will find it.

I think the other are targets that have the highest incidence among tumors of a particular type. PSMA expression—it's thought the incidence rate of PSMA expression is somewhere in the 70% range for prostate cancer—but looking for targets that are acceptable for radioligand therapy targeting that are expressed in 100% of tumors such that you can use the therapy without necessarily needing to preselect the patients.

I think we will find those targets, and I think they will become a focus for research in the next three to five years.

Oliver Sartor: Absolutely. I share your enthusiasm not only about the new targetry, the new isotopes, and the new combinations.

Well, Jeff, it's really been a pleasure to have you here today. I've enjoyed our brief conversation. I really look forward to your work at Lantheus. I think you've got a terrific platform on which to launch these new ideas and projects. Anything final you'd like to leave our listeners with before we say adieu?

Jeff Humphrey: No, I think you've said it already. I am very excited. Oliver, it's always a pleasure to see you. I always appreciate our conversations, and I look forward to seeing you in person on the West Coast shortly.

Oliver Sartor: Thank you, Jeff, and here at UroToday we're thankful to be able to have Jeff Humphrey from Lantheus, their CMO, provide us his perspective on radiopharmaceuticals in the future.

Thank you again, Jeff.

Jeff Humphrey: Thank you.