Survival Outcomes in Metastatic Gastroenteropancreatic Neuroendocrine Tumor Patients receiving Concomitant ²²⁵Ac-DOTATATE Targeted Alpha Therapy and Capecitabine: A Real-world Scenario Management Based Long-term Outcome Study

Rationale: Although the short-term results of targeted alpha therapy (TAT) with ²²⁵Ac-DOTATATE in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have proven effective, none have assessed the long-term outcome results. In this study, we aimed to evaluate the long-term outcome of ²²⁵Ac-DOTATATE targeted alpha therapy (TAT) in patients with somatostatin receptor (SSTR)-expressing advanced-stage metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods: Patients with ⁶⁸Ga-DOTANOC PET/CT scans showing moderate-to-high SSTR expression were recruited. Systemic TAT was performed in 91 adults with GEP-NET [54 males, and 37 females] mean age 54 years (y) (range: 25-75y)] using ²²⁵Ac-DOTATATE (100-120 kBq/kg body weight). All patients were given capecitabine therapy as a radiosensitizer (dose 2 g/day) from day 0 to 14 of every ²²⁵Ac-DOTATATE treatment cycle. Patients were categorized into three groups based on the status of prior ¹⁷⁷Lu-PRRT: prior ¹⁷⁷Lu-PRRT-refractory-group; prior ¹⁷⁷Lu-PRRT-disease-control group; and ¹⁷⁷Lu-PRRT naïve group. Primary endpoints were overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective tumour response, clinical response, and the assessment of treatment-related toxicities. Results: Among the 91 patients, 57 underwent prior ¹⁷⁷Lu-DOTATATE therapy [24 disease controlled (PR/SD), 33 progressive diseases (PD)]. A total of 453 ²²⁵Ac-DOTATATE TAT cycles were administered [median four cycles per patient; range 1-10] in a median follow-up duration of 24 months (range 5-41mo). Median OS was not attained with a 24-month overall survival probability of 70.8%. In multivariate analysis, prognostic factors associated with a poor OS included, the presence bone metastases [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-month progression-free survival probability of 67.5%. The multivariate analysis revealed only ¹⁷⁷Lu-PRRT refractory disease 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 complete response; 38 (48%) had a partial response, 23 (29%) had SD, and 16 (20.2%) had PD. PD was observed in more patients from the prior ¹⁷⁷Lu-PRRT-refractory group (11/33; 34%) as compared to 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:13.91; 95% CI: 4.45 - 42.271; P = 0.0009]. A significant clinical benefit was achieved post ²²⁵Ac-DOTATATE therapy with minimal treatment-related toxicities. Conclusion: The long-term results reveal ²²⁵Ac-DOTATATE TAT has shown promising results and improves overall survival, even in patients refractory to prior ¹⁷⁷Lu-DOTATATE treatment, with transient and acceptable adverse effects.