Targeted α -Emitter Therapy with 212 Pb-DOTAMTATE for the Treatment of Metastatic SSTR-Expressing Neuroendocrine Tumors: First-in-Humans Dose-Escalation Clinical Trial

Peptide receptor radiotherapy (PRRT) with somatostatin analogs has been successfully utilized as a treatment for somatostatin overexpressing tumors for years. Treatment of neuroendocrine tumors (NETs) with the beta particle emitter 177Lu-DOTATATE is currently considered the standard of care for subjects with gastroenteropancreatic NETs. Despite the overwhelming success of 177Lu-DOTATATE, there remains significant room for improvement in terms of both safety and efficacy. Targeted alpha-emitter therapy with isotopes such as lead-212 (212Pb) has the potential to improve both. Herein, we present the preliminary results of the phase 1 first-in-human dose-escalation trial evaluating 212Pb-DOTAMTATE in patients with somatostatin receptor positive NETs. Methods: A total of 20 subjects with histologically confirmed NETs, prior positive somatostatin analogue scans, and no prior history of 177Lu/90Y/111In PRRT, with different primary sites of the disease, were enrolled. Treatment began with single ascending doses of 212Pb-DOTAMTATE, with subsequent cohorts receiving an incremental 30% dose increase, which was continued until a tumor response or a dose-limiting toxicity was observed. This was followed by a multiple ascending dose regimen. The recommended phase 2 dose (RP2D) regimen consisted of 4 cycles of 2.50 MBq/kg (67.6 µCi/kg) of 212Pb-DOTAMTATE administrated at 8-week intervals, intravenously. Results: Ten subjects received the highest dose of 2.50 MBq/kg/cycle (67.6 µCi/kg/cycle). Treatment was well tolerated, with the most common treatment-emergent adverse events (TEAEs) being nausea, fatigue, and alopecia. No serious TEAEs were related to the study drug, and no subjects required treatment delay or a dose reduction. An objective radiological response (ORR) of 80% was observed for the first 10 subjects treated at the RP2D. Conclusion: Targeted alpha therapy with 212Pb-DOTAMTATE has been shown to be a well-tolerated and highly effective treatment in patients with metastatic NETs. With an ORR of 80%, further development of 212Pb-DOTAMTATE is warranted as it represents a significant improvement over the current standard of care and has the potential to be a breakthrough alternative for the treatment of metastatic NETs.