The somatostatin receptor–targeted alpha therapy 212Pb-DOTAMTATE achieved durable, clinically meaningful responses and favorable survival outcomes in patients with unresectable or metastatic somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who were naïve to peptide receptor radionuclide therapy (PRRT).

This 2-year update from the ongoing ALPHAMEDIX 02 phase 2 trial was presented at the 2025 European Society of Medical Oncology (ESMO) by Jonathan Strosberg, MD, Moffitt Cancer Center, Tampa, Florida.

Alpha-emitting radioisotopes deliver potent cytotoxic effects via high linear energy transfer over short ranges, generating double-stranded DNA breaks in tumor cells while minimizing exposure to surrounding healthy tissue. 212Pb-DOTAMTATE, a next-generation somatostatin receptor-targeted alpha therapy, couples a somatostatin analogue with the alpha-emitting radionuclide lead-212, offering a potentially more powerful and localized therapeutic alternative to existing beta-emitters such as lutetium-177.

In the PRRT-naïve cohort (n = 35) of this open-label, multicenter phase 2 trial, patients with histologically confirmed, unresectable or metastatic somatostatin receptor–positive GEP-NETs and measurable disease received 212Pb-DOTAMTATE 67.6 μCi/kg every 8 weeks for up to 4 cycles. 

The primary trial end points were objective response rate (ORR) and safety, with progression-free survival (PFS) and overall survival (OS) as key secondary end points.

As of April 14, 2025, the median follow-up was approximately 2 years. Among PRRT-naïve patients, the most common primary sites were the pancreas (42.9%) and small intestine (42.9%); most had well-differentiated Grade 1 to 2 tumors (88.6%). The confirmed ORR was 57.1% (95% confidence interval [CI], 39.4 to 73.7), including 20 partial responses, 13 cases of stable disease (37.1%), and only 1 case of progression (2.9%). 

Durability of response was notable with 70% of responders maintaining benefit ≥12 months, and 2 patients achieved ongoing responses beyond 24 months.

At the 2-year landmark, PFS and OS rates were 71.3% and 88.2%, respectively, indicating sustained disease control and long-term survival benefit in this heavily pretreated population.

All patients experienced at least 1 treatment-emergent adverse event, most commonly transient hematologic toxicities. The most frequent Grade 3/4 event was decreased lymphocyte count (25.7%). Importantly, no new safety signals emerged with longer follow-up.

According to the study investigators, these findings underscore the durable efficacy and manageable safety of 212Pb-DOTAMTATE, reinforcing its potential as a next-generation targeted alpha therapy for advanced SSTR+ GEP-NETs. Phase 3 evaluation is anticipated to confirm its role in earlier-line treatment.

Source:

Strosberg J, Naqvi S, Cohn A, et al. Long-term follow-up of peptide receptor radionuclide therapy (PRRT)-naïve patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with targeted alpha therapy 212Pb-DOTAMTATE in the phase II ALPHAMEDIX 02 trial. Presented at the 2025 ESMO Congress; October 17-21, 2025. Berlin, Germany. 1034MO