Targeted Alpha Therapy With [225Ac]Ac-DOTATATE Versus Salvage Retreatment PRRT With [177Lu]Lu-DOTATATE in Progressive Metastatic Neuroendocrine Tumor Patients After Initial Course of [177Lu]Lu-DOTATATE Treatment

OBJECTIVES: To evaluate and compare the therapeutic response, progression-free survival (PFS), overall survival (OS), and clinical toxicity of targeted alpha therapy (TAT) [225Ac]Ac-DOTATATE and salvage [177Lu]Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in metastatic neuroendocrine tumor (NET) patients who showed an objective response or disease stabilization following an initial course of [177Lu]Lu-DOTATATE PRRT and eventually developed progressive disease after a time interval of more than 6 months. PATIENTS AND METHODS: This was a single-institution, retrospective observational analysis conducted at a tertiary care institute. The medical records of metastatic NET patients who had been previously treated with an initial course of PRRT (I-PRRT) with 4-6 cycles of [177Lu]Lu-DOTATATE and showed an objective response or stable disease (SD) on the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) criteria after I-PRRT, but eventually developed progressive disease (PD) after a time gap of more than 6 months, and subsequently received [225Ac]Ac-DOTATATE or salvage [177Lu]Lu-DOTATATE were analyzed. These patients with matched baseline characteristics (site of primary disease, WHO grading of tumors, Ki-67 index, disease burden, [18F]F-FDG avidity, and previously treatments) were divided into the 2 treatment arms based on the treatment received by them, which in turn depended upon availability of therapeutic radionuclide, patient choice, and financial constraints as follows: Arm A: [225Ac]Ac-DOTATATE and Arm B: salvage [177Lu]Lu-DOTATATE. The treatment response was evaluated under 3 categories for all patients: (a) symptomatic, (b) biochemical, and (c) functional and anatomic imaging response. RESULTS: A total of 40 patients with metastatic NET (20 in each arm) were included and analyzed in the study. On the symptomatic response, 3 (15%) patients demonstrated a complete response (CR), and 7 (35%) patients demonstrated partial response (PR) in arm A, compared with no CR and PR of 4 (20%) patients in arm B. Biochemical response assessed by using serum CgA showed partial improvement in 10 (50%) patients in arm A versus 5 (25%) patients in arm B. On anatomic imaging, the disease control rate (DCR) was found to be 80% in arm A and 60% in arm B. The objective response rate (ORR) calculated based upon RECIST 1.1 criteria was 35% in arm A and 10% in arm B. The median progression-free survival was 10 months (95% CI, 6.0-24.0) in arm A and 12 months (95% CI, 4.0-33.0) in arm B, while the median overall survival was 16 months (95% CI, 10-16) in arm A and was not reached in arm B; neither difference reached statistical significance. Toxicities in both arms were predominantly mild and manageable, with no grade 3 or higher adverse events in either arm. CONCLUSIONS: This observational study shows that [225Ac]Ac-DOTATATE and salvage PRRT with [177Lu]Lu-DOTATATE are both efficacious and well-tolerated treatments for progressive metastatic NETs without high-grade toxicity. The numerically superior clinical, biochemical, and imaging response rates observed with TAT indicate that alpha-emitting radionuclides may partly overcome resistance to prior beta-emitter therapy. Prospective, larger multicenter randomized trials are needed to validate these findings, refine patient selection, and determine the appropriate treatment of alpha- or salvage beta-emitting radionuclide therapies in progressive NETs.