Survival Outcomes in Metastatic Gastroenteropancreatic Neuroendocrine Tumor Patients Receiving Concomitant 225 Ac-DOTATATE–Targeted α-Therapy and Capecitabine: A Real-World-Scenario Management-Based Long-Term Outcome Study

Although the short-term results of targeted α-therapy (TAT) with 225Ac-DOTATATE in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have proven the therapy to be effective, to our knowledge no one has assessed the long-term outcome results. In this study, we aimed to evaluate the long-term outcome of 225Ac-DOTATATE TAT in patients with somatostatin receptor–expressing advanced-stage metastatic GEP-NETs. Methods: Patients with 68Ga-DOTANOC PET/CT scans showing moderate-to-high somatostatin receptor expression were recruited. Systemic TAT was performed on 91 adults with GEP-NETs (54 men and 37 women; mean age, 54.3 y; range, 25–75 y) using 225Ac-DOTATATE (100–120 kBq/kg of body weight). All patients were given capecitabine therapy as a radiosensitizer (2 g/d) from days 0 to 14 of every 225Ac-DOTATATE treatment cycle. Patients were categorized into 3 groups based on the status of prior 177Lu-peptide receptor radionuclide therapy (PRRT): a prior-177Lu-PRRT–refractory group; a prior-177Lu-PRRT disease-control group; and a 177Lu-PRRT–naïve group. Primary endpoints were overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective tumor response, clinical response, and assessment of treatment-related toxicities. Results: Among the 91 patients, 57 underwent prior 177Lu-DOTATATE therapy (24 with controlled disease [partial response/stable disease] and 33 with progressive disease [PD]). In total, 453 225Ac-DOTATATE TAT cycles were administered (median, 4 cycles per patient; range, 1–10) in a median follow-up of 24 mo (range, 5–41 mo). Median OS was not attained, with a 24-mo OS probability of 70.8%. In multivariate analysis, prognostic factors associated with a poor OS included the presence bone metastases (hazard ratio [HR], 2.501; 95% CI, 1.826–5.791; P < 0.032) and 225Ac-DOTATATE therapy–refractory disease (HR, 8.781; 95% CI, 3.843–20.062; P < 0.0001). Median PFS was also not reached, with a 24-mo PFS probability of 67.5%. The multivariate analysis revealed only 177Lu-PRRT–refractory disease to be significantly associated with a reduced PFS (HR, 14.338; 95% CI, 1.853–97.698; P = 0.011). Two of 79 patients (2.5%) with assessable disease experienced a complete response, 38 (48%) had a partial response, 23 (29%) had stable disease, and 16 (20.2%) had PD. PD was observed in more patients from the prior-177Lu-PRRT–refractory group (11/33, 34%) than in 177Lu-PRRT–naïve patients (4/24, 11%; P = 0.056). Patients from the prior-177Lu-PRRT–refractory group had the highest risk of poor PFS (HR, 13.553; 95% CI, 4.343–42.271; P = 0.0009). A significant clinical benefit was achieved after 225Ac-DOTATATE therapy with minimal treatment-related toxicities. Conclusion: In long-term results, 225Ac-DOTATATE TAT showed promise and improved the OS, even in patients refractory to prior 177Lu-DOTATATE treatment, with transient and acceptable adverse effects.