Efficacy, Safety of 212Pb-DOTAMTATE in PRRT-Naive Patients With GEP-NETs

At the 2025 North American Neuroendocrine Tumor Society (NANETS) Multidisciplinary NET Medical Symposium, Mary Maluccio, MD, MPH, FACS, presented the follow-up efficacy and safety data of the phase 2 ALPHAMEDIX-02 trial (NCT05153772) evaluating the novel targeted alpha therapy ²¹²Pb-DOTAMTATE (AlphaMedix) in a cohort of peptide receptor radionuclide therapy (PRRT)–naive patients with SSTR-expressing, unresectable or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs).¹

²¹²Pb-DOTAMTATE, a targeted alpha therapy, is the first of its kind to have received FDA breakthrough therapy designation. The open-label, multicenter, single-arm phase 2 ALPHAMEDIX-02 trial is evaluating the agent in about 69 patients across 2 cohorts: a PRRT-exposed cohort and a PRRT-naive cohort,² the latter of which was the focus of Maluccio’s presentation.

In an interview with Targeted Oncology®, Maluccio, study investigator and professor of surgery, chief of the Surgical Oncology Division, and medical director of the Louisiana Neuroendocrine Tumor Program at Louisiana State University School of Medicine, highlighted key efficacy and safety points from this treatment-naive population and outlined next steps for the agent in both an upcoming phase 3 trial as well as continuation of the phase 2 trial.

Targeted Oncology®: What were the efficacy and safety outcomes with ²¹²Pb-DOTAMTATE in this cohort of patients in the phase 2 ALPHAMEDIX 02 trial?

Mary Maluccio, MD, MPH, FACS: Start[ing] with the response rates, unlike other radioligand therapy options, the objective response rates [ORRs] have been relatively low, probably in the 15%, maybe up toward around 20%, in patients. Alpha particles were hopeful in their ability to raise that [ORR] in this trial in particular. In both patients that had never received a radioligand-type therapy before and in patients that had already received a beta particle radioligand and were then treated as in the second line, the [ORRs] were well above 50%.

In the radioligand therapy-naive patients—that was the presentation that I gave—it was a 60% [ORR]. And so, for community oncologists, they understand that that means 60% of [patients] had a greater than 30% reduction in an index lesion. There was an additional 34.1% of patients that had a stable disease rate. So, in the presentation, they look at the [ORR], 60%, then add the 34% for overall disease control rate—that hit around 94.3%, so probably unexpectedly good, I think, going into that clinical trial.

Now, the safety is also something that we brought up. There was a lot of discussion in the question-and-answer session on the safety profile. We highlighted 2 things that I think we're going to look a lot closer at as we go into the phase 3 trial, and that would be renal toxicity, an inherent safety issue with radioligand therapy, but really, we did not see any significant renal or long-term renal toxicity with beta particles. The investment in alpha particle is likely associated with a bit more renal toxicity, people with elevated creatinine levels, or in people that ultimately developed chronic kidney disease over not only the course of treatment, but we didn't start seeing [renal toxicity] until after the fourth dose of treatment. What are we going to do differently? I think we're probably going to have to change the protocol a bit on how we treat those people during the initial recovery after each of those doses, in hopes of trying to bring down that renal toxicity. In the patients we treated within the New Orleans program, we didn't really see any [patients] within that renal toxicity group that required significant medical intervention. But I think what came up in the discussion session was that there were definitely sites and/or practitioners within the group that had patients experience some more significant renal toxicity.

Then, the dysphagia question that came up was somewhat unexpected, and therefore it's a little bit difficult for us to understand what that means in the context of a treatment that, for all intents and purposes, wouldn't have necessarily led to a functional, esophageal or gastroesophageal dysfunction. And so, the dysphagia also led to a lot of discussion during the question-and-answer phase. I think that going into phase 3, we're going to be a lot more sensitive to what types of comorbid conditions patients come into the trial with, that come under the umbrella of dysphagia, that we may want to evaluate before we do it, so that [patients] with potentially with functional problems beforehand, maybe they would be at higher risk for developing worsening of those functional problems with this treatment. Then there are going to be [patients] with a pattern of distribution of disease where they will likely get a treatment go to a part of the chest or mediastinum that would put them at increased risk for developing dysphagia type of problems. The dysphagia question was probably discussed a lot more, but not with clear-cut answers to why it happened, but more in the context of what we would do differently with respect to patients with dysphagia, either in standardizing our evaluation of those patients, either during treatment or after treatment, or some of the strategies that we've used to diminish some of those functional things, like Botox injections.

What are the next steps with ²¹²Pb-DOTAMTATE in GEP-NETs?

The same molecule is now going into a phase 3 trial. It is only going to be in the PRRT-naive [patients], so [patients] who have not previously been exposed to radioligand therapy. It's going to be done in comparison to standard-of-care beta, which is a classic setup for a phase 3 trial. Now, in keeping with the last question that we answered, I think that that will be a very good comparison of some of the issues. What I say are issues are the additional investment that patients would be making if they were to randomize into that alpha particle arm vs a beta particle, which many of us have given hundreds, if not thousands, of those doses. And so, we're really comfortable, understand[ing] the protocols and the expectations of what [patients] would experience. So, the phase 3 is either open or soon to be open at our site, and I think there are going to be a number of sites that will open over the next several months.

Now [for] phase 2, they are continuing to follow those patients, and I think that in a good way, they needed that longer-term follow-up. What was presented was that when you're looking at the power of the observation, so you can clearly discuss with patients the risks and benefits—both short-term, meaning 1 to 2 years, but long term, 3- to 5-year outcome data—well, when you don't meet even the median event rate at the 2-year mark, you would love to see that follow-up go well beyond that 2-year mark and almost hit the point where at least 50% of [patients] would have then progressed or required additional treatment.

Or you could then look at the evolution of the dysphagia or renal dysfunction, or even late myelodysplastic syndromes [MDS]. The 1 thing I think surprised us is in neither the radioligand-naive [patients] [n]or the previously treated radioligand [patients], which are heavily treated patients, we didn't really see any events of MDS in that initial 24- or 36-month follow-up. I think the fact that we are continuing on trial, meaning those patients continue to be followed every 3 months for an additional 2 years, you're going to then have over this next year—we present it at places like the American Society of Clinical Oncology [ASCO], ASCO [Gastrointestinal Cancers Symposium], or NANETS—real 36- or 48-month follow-up, meaning a critical mass of people would have then been followed up with their renal function, dysphagia, and [ORR] for much longer than the follow-up was really initially done even in beta particle PRRT, before it got through the FDA. I think that for all the right reasons, the phase 2 is continuing, even though obviously all of the patients have been accrued, but we are continuing to follow them on trial for both safety and efficacy. That is paralleling the phase 3 that is either open at our site or imminently going to open, and then it's going to open over the next several months at several sites.

REFERENCES:

1. Maluccio, M. Long-term follow-up of PRRT-naïve patients with GEP-NETs treated with targeted alpha therapy 212Pb-DOTAMTATE in the phase 2 ALPHAMEDIX 02 trial. Presented at: 2025 NANETS Multidisciplinary NET Medical Symposium; October 23-25, 2025; Austin, TX.

2. Targeted alpha-emitter therapy of PRRT naïve and previous PRRT neuroendocrine tumor patients (ALPHAMEDIX02). ClinicalTrials.gov. Updated June 4, 2025. Accessed October 28, 2025. https://www.clinicaltrials.gov/study/NCT05153772