Safety and Therapeutic Efficacy of 225Ac-DOTATATE Targeted Alpha Therapy in Metastatic Gastroenteropancreatic Neuroendocrine Tumors Stable or Refractory to 177Lu-DOTATATE PRRT (2020)

416 Objectives: The objective of this study was to investigate and present the results on the efficacy, safety, and quality of life of 225Ac-DOTATATE targeted alpha therapy (TAT) in patients with advanced, progressive, 177Lu-DOTATATE refractory, and somatostatin receptor (SSTR) expressing metastatic GEP-NETs.
 Methods: This study was approved by the Institute Ethics Committee (IEC No:517/2018). In this prospective study, we recruited patients with metastatic GEP-NETs who demonstrated stable or progressive disease on 177Lu-DOTATATE therapy. Patients underwent a screening 68Ga-DOTANOC PET/CT scan to assure high SSTR expression and progressive disease to prior therapies. Systemic TAT was performed in all the patients with 225Ac-DOTATATE (100 KBq/Kg body weight) at an interval of 8 weeks up to 7 cycles. The patients were treated between April 2018 to December 2019 with a median follow-up duration of 13 months (range: 6 - 20 months). Hematologic, kidney, and liver function tests were repeated before and after every cycle of 225Ac-DOTATATE TAT at 2, 4 and 8-week intervals. The primary end-point was to assess the objective response (measured by RECIST 1.1 and functional M. D. Anderson criteria). The secondary end-points included biochemical response assessment as per the Italian Trials in Medical Oncology (ITMO), adverse-event profile as per CTCAE v5.0, and clinical response assessment by the quality of life (assessed with EORTC QLQ-GI.NET21 patient-based questionnaire. Post-completion of 225Ac-DOTATATE cycles, patients were followed up for 48 months.
 Results: 65 patients (34 females, 31 males, mean age 57±7 years, 35 - 72 years) with either stable disease after completing 177Lu-DOTATATE therapy (44%) or progressive disease on 177Lu-DOTATATE therapy (56%) were included in the study. The morphological response was assessed in 53 patients and revealed complete remission in 1, partial remission in 41, stable disease in 9 and disease progression in 2 patients. Death was recorded in 1 patient. There was a significant decrease in the plasma chromogranin level post-225Ac-DOTATATE therapy (P<0.0001). None of the patients experienced grade 3 or 4 hematotoxicity, renal insufficiencies or hepatotoxicity. The most common adverse effects (AEs) were nausea, vomiting, gastritis, and appetite loss, but were limited to grade 1 or 2. Majority of the patients experienced these AEs at the time of amino acid infusion which was administered during 225Ac-DOTATATE therapy and was resolved after few hours of amino acid infusion. All the other AEs such as fatigue or asthenia, diarrhoea, appetite loss, abdominal pain, abdominal distension, weight loss, peripheral edema, headache, dizziness, and flushing were also identified which were limited to grade 1 or 2, except for 1 patient with grade 3 abdominal distension and fatigue.
 Conclusions: Our results indicate 225Ac-DOTATATE TAT safe with low and transient side-effects. It add to a new dimension in the treatment of end-stage GEP-NET who have exhausted all the standard treatment options.