Long-term outcome of ²²⁵Ac-DOTATATE Targeted Alpha Therapy in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumors

Objectives: The objective of this study was to study the long-term outcome of ²²⁵Ac-DOTATATE targeted alpha therapy (TAT) in patients with advanced stage somatostatin receptor (SSTR) expressing metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

Methods: This study was approved by the Institute Ethics Committee (IEC No:517/2018). In this prospective study, prior to the initiation of treatment, patients underwent a screening ⁶⁸Ga-DOTANOC PET/CT scan to assure high SSTR expression. Systemic TAT was performed in all the patients with ²²⁵Ac-DOTATATE (100-150 KBq/Kg body weight) at an interval of 8 weeks up to 9 cycles. The patients were treated between April 2018 to December 2020 with a median follow-up duration of 17 months (IQR: 11 - 24 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 overall and progression free survival. Secondary objectives included molecular response according to PERCIST1 criteria, quality of life assessment. Treatment-related side effects were assessed every 2 weeks on the basis of physical examination, vital signs, laboratory results (hematologic, kidney and liver function levels) and adverse events graded according to the CTCAE v5.0. Post-completion of ²²⁵Ac-DOTATATE therapy regimen, patients were followed up on a two-monthly basis with laboratory parameters, chromogranin A and ⁶⁸Ga-DOTANOC PET/CT scan.

Results: 82 patients (35 females, 47 males, mean age 50.7±11 years, 25 - 74 years) were treated with a median of five ²²⁵Ac-DOTATATE TAT cycles. Among them, 26 (32%) patients did not receive prior PRRT, 25 (30%) demonstrated stable disease after completing ¹⁷⁷Lu-DOTATATE therapy, and 31 patients progressed on ¹⁷⁷Lu-DOTATATE therapy (38%) were included in the study. During the median follow-up duration of 17 months, 10 patients experienced disease progression and 20 patients died. A significantly prolonged survival was attained where both median PFS and OS were not reached with a 24-month PFS and OS probability of 80.7% and 67.3%, respectively. PERCIST criteria was assessed in 77 patients, among whom, a sustained complete response (CR) was attained in 1 (1.2%) patient, partial response in 33 (43%), stable disease in 35 (45.4%), and progressive disease in 6 (8%) patients. Two patients initially experienced CR, but demonstrated disease recurrence at a median follow-up of 12 months post completion of ²²⁵Ac-DOTATATE therapy regimen. Among the entire series of patients only 2 patients experienced grade III anemia and two patients experienced grade II thrombocytopenia. No grade 3 renal or hepatotoxicities were observed. No other unexpected longer-term adverse events were observed with ²²⁵Ac-DOTATATE therapy.

Conclusions: Our long-term results demonstrate ²²⁵Ac-DOTATATE safe with transient, low-grade side-effects. ²²⁵Ac-DOTATATE demonstrated high response rates, improved quality of life and prolonged the progression and overall survival in end-stage GEP-NET patients.