Dr Strosberg Highlights Positive 212Pb-DOTAMTATE Data in GEP-NETs

At the 2025 NANETS Symposium, Jonathan Strosberg, MD, discussed outcomes with the targeted alpha therapy ²¹²Pb-DOTAMTATE (AlphaMedix) from the phase 2 ALPHAMEDIX-02 trial.¹

The open-label study explored ²¹²Pb-DOTAMTATE in patients with peptide receptor radionuclide therapy (PRRT)-naïve and -exposed, somatostatin receptor (SSTR)-positive, unresectable or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). At the NANETS Symposium, Strosberg, lead study author and a professor at Moffitt Cancer Center, highlighted the trial design and the safety and efficacy outcomes with ²¹²Pb-DOTAMTATE  in this setting.

Targeted Oncology: Please describe the design of the ALPHAMEDIX-02 trial.

Jonathan Strosberg, MD: The phase 2 ALPHAMEDIX-02 trial is exploring ²¹²Pb-DOTAMTATE,a radioligand that targets somatostatin receptor–expressing neuroendocrine tumors, in patients with metastatic GEP-NETs. The study had two cohorts. One was comprised of patients who were PRRT-naive and the other was comprised of patients had received prior lutetium-based PRRT. The primary end points for the study were overall response rate by investigator analysis and adverse events. Secondary end points included progression-free survival (PFS) and overall survival (OS).

What are the efficacy outcomes so far for the ALPHAMEDIX-02 trial?

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

As far as the PRRT-refractory cohort,² it was a smaller group. I think it was 26 patients who were followed for a shorter amount of time than the PRRT-naïve cohort because they were enrolled later in the study. The median follow-up there was about 14 and a half months, and this was a heavily pretreated population. So not surprisingly, the response rate was lower. It was about 35% and at 18 months the PFS rate was approximately 75% to 80%. So again, a strong level of activity for a population of patients who had received prior lutetium-based PRRT, especially lutetium dotatate, plus, in many cases, other drugs. About half the patients had received prior chemotherapy. More than half had received prior targeted agents. All had received parser somatostatin analogs. So, I would say these are fairly impressive efficacy outcomes, both in the naive and the refractory cohorts.

What was the safety profile of 12Pb-DOTAMTATE in the ALPHAMEDIX-02 trial?

When it came to short-term side effects, they were as expected for this drug. Alopecia is quite common, nausea, very common, fatigue, very common, but mostly grade 1 or 2. Cytopenias tend to be not that bad. There was a high rate of lymphopenia, including grade 3/4 lymphopenia, but not very clinically significant.

But we do also see some long-term toxicities. One of them is renal insufficiency, and we see that, perhaps counterintuitively, more in the treatment-naive cohort than the treatment-refractory cohort, although the reason for that almost certainly is the longer follow-up. This is a pretty late toxicity, and it takes a long time. It starts to evolve after completion of all treatments, so a large percentage of patients had some degree of renal insufficiency in the treatment-naive cohort, and I think about 17% had grade 3/4 renal toxicity. So that is one side effect that I think people are going to need more follow-up to really determine the ultimate extent of renal insufficiency.

Another perhaps unique side effect with this drug that we've been seeing is achalasia.Patients are developing esophageal dysmotility. It manifests as tightness of the lower esophageal sphincter—failure to relax with swallowing. It's not something that you can observe with an EGD. You don't see inflammation or edema. You really need to do manometry or other motility techniques to detect this. And it is chronic. It's something that generally does not go away without intervention. And for many patients, treatment has involved Botox injections to the lower esophageal sphincter. That seems to provide some temporary relief for many patients, but we've had some patients who require surgical procedures, such as per oral endoscopic myotomy or laparoscopic myotomy. So this is something that we're really just starting to learn about. The mechanism isn't quite clear. It probably has to do with some metastatic receptor expression in the myenteric plexus. But we definitely need to learn more about this.

What is the take-home message from the results of the ALPHAMEDIX-02 trial?

To summarize, ²¹²Pb-DOTAMTATE is a is a novel alpha-emitting PRT with a very high efficacy, at least based on single-arm data. I do think that randomized data is going to be 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.

REFERENCES:

1. Strosberg JR. Long-term Follow-up of PRRT-Naïve Patients with GEP-NETs Treated with Targeted Alpha Therapy 212Pb-DOTAMTATE in the Phase 2 ALPHAMEDIX 02 TrialPresented at: 2025 NANETS Symposium; October 23-25, 2025; Austin, TX.

2. Strosberg JR, Naqvi S, Cohn A, et al. Efficacy and safety of targeted alpha therapy 212Pb-DOTAMTATE in patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) previously treated with peptide receptor radionuclide therapy (PRRT): Results of a phase II study. Presented at: 2025 ESMO Congress; October 17–20, 2025; Berlin, Germany. Abstract 1032O.