Safety, tolerability and efficacy of 212Pb-DOTAMTATE as a targeted alpha therapy for subjects with unresectable or metastatic somatostatin receptor-expressing gastroenteropancreatic neuroendocrine tumors (SSTR+ GEP-NETs): A phase 2 study.

person Jonathan R. Strosberg H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL info_outline Jonathan R. Strosberg, Shagufta Naqvi, Allen Lee Cohn, Ebrahim Delpassand, Volker Jean Wagner, Julien Torgue, Rachel Woloski, Allison Manuel, Mary Alice Maluccio

Authors person Jonathan R. Strosberg H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL info_outline Jonathan R. Strosberg, Shagufta Naqvi, Allen Lee Cohn, Ebrahim Delpassand, Volker Jean Wagner, Julien Torgue, Rachel Woloski, Allison Manuel, Mary Alice Maluccio Organizations H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, Excel Diagnostics Nuclear Oncology Center, Houston, TX, Rocky Mountain Cancer Centers, Denver, CO, RadioMedix Inc., Houston, TX, Orano Med SAS, Chatillon, France, Orano Med LLC, Plano, TX, Louisiana State University, New Orleans, LA Abstract Disclosures Research Funding No funding sources reported Background: 212 Pb-DOTAMTATE is a Targeted Alpha Therapy (TAT) in clinical development for subjects with SSTR+ neuroendocrine tumors. A phase I dose-escalation study has already been completed (Delpassand et al. J Nucl Med 2022). TAT holds the promise to improve outcomes versus Peptide Receptor Radionuclide Therapy (PRRT) with beta-emitters like 177 Lu-DOTATATE, currently considered the standard of care for subjects with GEP-NETs. Methods: ALPHAMEDIX 02 is a Phase II, open-label, multicenter study evaluating the safety, tolerability and efficacy of 212 Pb-DOTAMTATE in PRRT-naïve (Cohort 1, N = 36) and PRRT-refractory (Cohort 2, Target N = 30) subjects with histologically confirmed unresectable or metastatic GEP-NETs, positive somatostatin analogue imaging and at least 1 site of measurable disease per RECIST 1.1. 212 Pb-DOTAMTATE was administered at 67.6 μCi/kg per cycle, with a maximum activity administered per cycle of 5.5 mCi every 8 weeks, for up to 4 cycles. Primary endpoints include overall response rate (ORR) per RECIST1.1, and incidence and severity of adverse events (AEs). Secondary endpoints include progression free survival, overall survival , and health-related quality of life. Initial results of the already completed cohort 1 are presented. Results: In cohort 1, 17 out of 36 subjects with metastatic SSTR+ GEP-NETs achieved a confirmed response (ORR 47.2% (32.0-63.0%)). In the Phase I trial, five out of eight PRRT- naïve subjects with SSTR+ GEP-NETs treated with the same regimen of 212 Pb-DOTAMTATE achieved a response (ORR 62.5% (30.6-86.3%)): the combined ORR from both studies is 50% (22 out of 44, 95%-CI:36% - 64%). Median Duration of Response (DOR) has not been reached in both studies. Four out of five subjects (80%) with confirmed response in Phase I had a DOR of ≥ 12 months. In the ongoing Phase II study the response follow-up for 10 subjects with confirmed response is currently shorter than 6 months: so far 7 out of 17 subjects (41%) with confirmed response had a DOR of ≥ 6 months, and one of these subjects had a DOR of ≥ 12 months. Lymphocytopenia is a lead cause of the 59% grade 3 and 4 AEs reported in subjects in cohort 1. Overall, 4 fatal AEs were reported: death / progressive disease (N = 2), carcinoid syndrome (N = 1) and sepsis (N = 1). Conclusions: In PRRT-naïve subjects with SSTR+ unresectable or metastatic GEP-NETs treatment with up to 4 cycles of ²¹²Pb-DOTAMTATE (67.6 μCi/kg/cycle) was well-tolerated, with a safety profile consistent with the underlying disease and expected toxicities of radioligand therapy, similar to 177 Lu-DOTATATE. The ORR of 47.2% in cohort 1 (50% in the pooled dataset) appears to be substantially higher than the ORR previously reported for 177 Lu-DOTATATE in the pivotal NETTER-1 study (ORR 18% (10–25%)). Clinical trial information: NCT05153772.

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