Broadening Horizons with 225Ac-DOTATATE Targeted Alpha Therapy for Gastroenteropancreatic-Neuroendocrine Tumor Patients Stable or Refractory to 177Lu-DOTATATE PRRT: First Clinical Experience on the Efficacy and Safety

Abstract

Background: The curative option for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is surgery, but as the majority of the patients are diagnosed at the late stage with metastasis and require systemic treatment. Currently available systemic therapies are inadequate and produce only symptomatic relief or at the best stable disease. Therefore, there is an increasing need for novel therapeutic options in the treatment of metastatic GEP-NETs. Although beta-emitting peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE is one of the FDA approved standard treatment options, alpha therapy on the radiobiological basis is considered superior to beta-emitting 177Lutetium (177Lu) based PRRT. This is due to the double-stranded DNA breaks by alpha particles causing high cytotoxic activity on the cellular level with minimal bystander effects. However, clinical evidence in this context is sparse, hence, the objective of this study was to investigate and present the early 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: In this prospective study, we recruited patients with metastatic GEP-NETs who were stable or progressive disease on 177Lu-DOTATATE therapy. We offered 225Ac-DOTATATE therapy as an experimental treatment option after obtaining institutional review board approval. All patients underwent 68Ga-DOTANOC PET/CT scan to ensure high SSTR expression even after repeated 177Lu-DOTATATE therapy cycles. Systemic TAT was performed in all the patients with 225Ac-DOTATATE (100 KBq/Kg body weight) at an interval of 8 weeks. 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). The renal, hepatic, and haematological evaluation were performed before and after every cycle of 225Ac-DOTATATE TAT at 2, 4 and 8-week intervals. Findings: Between April 2018 and February 2019, 21 patients (9 females, 12 males, median age 54 years, IQR: 50 - 60 years) with either stable disease after completing 177Lu-DOTATATE therapy (12, 57%) or progressive disease on 177Lu-DOTATATE therapy (9, 43%) were included in the study. The mean administered cumulative 225Ac-DOTATATE therapy was 20794 ± 6660 KBq over a median of 3 cycles. The morphological response was assessed in 20/21 patients that revealed partial remission in 10 and stable disease in 10. There were no documented disease progression or deaths in the median follow-up of 9 months (range: 2 - 12 months). There was a significant decrease in the plasma chromogranin level post-225Ac-DOTATATE therapy (P=0·0019). While a significant decrease in the endocrine (P=0·0011) and gastrointestinal symptoms (P=0·0002) were noted, there was a significant improvement in the functional scale: disease-related worries (P<0·0001). The most common adverse effects (AEs) were loss of appetite, nausea, and vomiting, however, were limited to grade 1 or 2 toxicities. Majority of the patients experienced these AEs at the time of amino acid infusion which was co-administered with 225Ac-DOTATATE therapy and was resolved after a few hours of amino acid infusion. Interpretation: Our short-term clinical results indicate 225Ac-DOTATATE TAT as a promising treatment option which adds a new dimension in patients who are refractory to 177Lu-DOTATATE therapy, or have reached the maximum prescribed cycles of 177Lu-DOTATATE therapy. However, Longterm clinical data are in the process of collection for the assessment of sustained tumor response with 225Ac-DOTATATE TAT. Funding Statement: The authors state: None. Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: Ethical clearance received Ref. No IEC-517