Novel SSTR-Targeted Alpha Therapy Shows “Encouraging” Activity in GEP-NETs

At the 2025 NANETS Multidisciplinary NET Medical Symposium, CancerNetwork® spoke with Jonathan Strosberg, MD, and Mary Maluccio, MD, MPH, FACS, about their presentations on different cohorts from the phase 2 ALPHAMEDIX 02 trial (NCT05153772) assessing the investigational somatostatin receptor (SSTR)–targeted alpha therapy 212Pb-DOTAMTATE (AlphaMedixTM) for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Strosberg’s session focused on a cohort of patients who received prior treatment with peptide receptor radionuclide therapy (PRRT), while Maluccio presented long-term data on those who had no prior exposure to PRRTs.

Strosberg, a professor at Moffitt Cancer Center specializing in the management of neuroendocrine malignancies, highlighted data across both GEP-NET cohorts, detailing efficacy outcomes that were “quite good” in the PRRT-naive group and emphasizing a “strong level of activity” in patients who were previously treated with PRRT. He noted that additional randomized data were necessary to affirm the outcomes reported with 212Pb-DOTAMTATE and compare its efficacy with other standards of care.

Maluccio, a professor of Surgery at Louisiana State University School of Medicine, recapped the “unexpectedly good” findings in the PRRT-naive cohort of the trial before describing the most common adverse effects associated with the study treatment. She highlighted instances of renal toxicity—which may be more prevalent in those with elevated creatinine levels—and dysphagia, which raised questions on how to evaluate patients during and after treatment.

Transcript:

Strosberg: I presented data on 212Pb-DOTAMTATE. It’s a radioligand that targets somatostatin receptor-expressing neuroendocrine tumors. This was a phase 2 study that had 2 cohorts. One [included] patients who were PRRT naive, and the other [included] patients who had received prior lutetium-based PRRT. The primary endpoint for the study was overall response rate by investigator analysis, as well as adverse events. Secondary endpoints included progression-free survival and overall survival.

There were approximately 35 patients with gastroenteropancreatic NETs in the PRRT-naive cohort. They had all received prior treatment, primarily somatostatin analogs, but in about a quarter of [patients], also chemotherapy and targeted agents. The overall response rate was quite impressive. It was approximately 60%; most of the other patients had stable disease as best outcome. The PFS rate at 36 months was approximately 70% to 75%, and overall survival was also quite favorable. The overall survival rate at 36 months was approximately 88, so the efficacy outcomes were quite good.

As far as the PRRT-refractory cohort, it was a smaller group. [There were] 26 patients followed for a shorter amount of time because they were enrolled later in the study. The median follow-up there was about 14.5 months, and this was a heavily pretreated population. Not surprisingly, the response rate was lower. It was more or less 35%, and at 18 months, the PFS rate was approximately 75% to 80%.Again, [there was a] strong level of activity for a population of patients who had received prior lutetium-based PRRT, especially lutetium Lu 177 dotatate [Lutathera] plus, in many cases, other drugs; about half the patients had received prior chemotherapy.

To summarize, 212Pb-DOTAMTATE is a novel alpha-emitting PRRT with high efficacy, at least on single-arm data. Randomized data are… needed to ultimately compare its efficacy to current drugs. It certainly seems quite encouraging as far as efficacy, but there are some long-term toxicities that we also need to pay attention to.

Maluccio: In both the patients who had never received a radioligand therapy before, and in patients that had already received a beta particle radioligand and were then being treated in the second line, the objective response rates were well above 50%. In the [patients who were] radioligand therapy naive—that was the presentation that I gave—it was a 60% objective response rate. There was an additional [34.3%] of patients who had stable disease. In the presentation, they looked at the objective response rate of 60%, they then added the 34.3% for the overall disease control rate that hit around 94.3%. [This was] unexpectedly good 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 we are going to look a lot closer at as we go into the phase 3 trial. That would be renal toxicity, which is an inherent safety issue with radioligand therapy, but 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 in people with elevated creatinine levels, or in people who ultimately developed chronic kidney disease over not only the course of treatment...we did not start seeing [this] until after the fourth dose of treatment.

Renal toxicity is one. Then, the dysphagia question that came up was somewhat unexpected. Therefore, it’s a bit difficult for us to understand what that means in the context of a treatment that, for all intents and purposes, would not have necessarily led to a functional esophageal or gastroesophageal dysfunction. The dysphagia question was probably discussed a lot more, not with clear cut answers to why it happened, but more in the context of what we would maybe do differently with respect to patients with dysphagia, either in standardizing our evaluation of those patients during treatment or after treatment, or some of the strategies that we have used to diminish some of those functional things, like botulinum neurotoxin [Botox] injections.

References

1. Strosberg JR, Naqvi S, Cohn AL, et al. Phase 2 study of targeted alpha therapy 212Pb-DOTAMTATE in patients with advanced gastroenteropancreatic (GEP)-NETs previously treated with PRRT. Presented at the 2025 NANETS Multidisciplinary NET Medical Symposium; October 23-25, 2025; Austin, TX. Abstract 33429.
2. Strosberg JR, Naqvi S, Cohn AL, et al. Long-term follow-up of PRRT-naïve patients with GEPNETs treated with targeted alpha therapy 212PbDOTAMTATE in the phase 2 ALPHAMEDIX 02 trial. Presented at the 2025 NANETS Multidisciplinary NET Medical Symposium; October 23-25, 2025; Austin, TX. Abstract 33414.