Alpha-emitting radiopharmaceutical therapy with 212Pb-DOTAMTATE demonstrated meaningful clinical activity and a favorable safety profile in patients with unresectable or metastatic, somatostatin receptor (SSTR)–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who had previously received beta-emitting peptide receptor radionuclide therapy (PRRT), according to new phase 2 results from the ALPHAMEDIX 02 study. 

These findings were presented at the NANETs 2025 Multidisciplinary NET Medical Symposium.

While ¹⁷⁷Lu-labeled somatostatin analogs have become a mainstay for well-differentiated GEP-NETs, therapeutic options remain limited following disease progression on PRRT. 212Pb-DOTAMTATE, an investigational alpha-emitting radiopharmaceutical, delivers high–linear energy transfer radiation that induces double-stranded DNA breaks, potentially overcoming resistance to prior beta-based therapies.

In the PRRT-exposed cohort (n = 26), patients had histologically confirmed, SSTR-positive GEP-NETs with measurable disease and progression after up to four prior doses of ¹⁷⁷Lu-SSA, with at least 6 months since their last treatment. Participants received 212Pb-DOTAMTATE 67.6 μCi/kg every 8 weeks for up to 4 cycles.

The most common primary tumor sites were the pancreas and small intestine (42.3% each), and 77% of patients had grade 1 to 2 disease. Among evaluable patients, 8 achieved confirmed partial responses (30.8%), 17 (65.4%) had stable disease, and only 1 (3.8%) experienced progression, yielding a 96.2% disease control rate. Notably, 7 of 8 responders maintained their responses at the time of data cutoff, indicating durable benefit.

Treatment was generally well tolerated. All patients experienced at least one treatment-emergent adverse event (TEAE), and nine (34.6%) had grade ≥3 events. The most frequent severe toxicity was lymphopenia (15.4%), consistent with the hematologic profile observed in radionuclide therapy. No new safety signals emerged, and adverse events were manageable.

These findings build on previously reported data from the PRRT-naïve cohort, which demonstrated a 54% response rate, and suggest that 212Pb-DOTAMTATE retains activity in patients who have progressed after prior PRRT. Collectively, the results support continued investigation of alpha-targeted radiopharmaceuticals as a next-generation treatment strategy for advanced SSTR-positive neuroendocrine tumors.

Source:

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 NANETs 2025 Multidisciplinary NET Medical Symposium; October 23-25, 2025. Austin, Texas. Abstract ID 33429