177Lu-DOTATATE Plus Capecitabine Versus 177Lu-DOTATATE Alone in Patients with Advanced Grade 1/2 Gastroenteropancreatic Neuroendocrine Tumors (LuCAP): A Randomized, Phase 2 Trial

177Lu-DOTATATE has emerged as a viable treatment strategy for advanced well-differentiated grade 1/2 gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Few retrospective studies have shown concomitant 177Lu-DOTATATE with radiosensitizing low-dose capecitabine to be effective in advanced NETs. However, this has not been validated in prospective randomized-controlled trials. Methods: In this investigator-initiated, parallel-group, open-label, phase 2 trial, patients with grade 1/2 GEP-NETs, having progressive somatostatin receptor- positive, locally advanced, or metastatic disease on 68Ga-DOTANOC PET/CT, were randomly assigned in a 1:1 ratio to 177Lu-DOTATATE plus capecitabine (experimental arm) or 177Lu-DOTATATE only (control arm). 177Lu-DOTATATE was administered at approximately 7.4 GBq/cycle intravenously, for up to 4 cycles, at 8 wk intervals, whereas capecitabine was given at 1,250 mg/m2/d orally from day 0 to day 14 of each cycle of 177Lu-DOTATATE. The primary endpoint was the objective response rate. Secondary endpoints included the disease control rate, progression-free survival, overall survival, and adverse events. Results: Seventy-two patients (median age, 53 y; range, 18-79 y) were enrolled. The objective response rate was 33.3% (95% CI, 18.6- 50.9%) in the experimental arm versus 30.6% (95% CI, 16.4-48.1%) in the control arm (P = 0:800). The disease control rate was 88.9% (95% CI, 73.9-96.9%) and 91.7% (95% CI, 77.5-98.2%) in the experimental and control arms, respectively (P = 1.000). The estimated median progression-free survival in the experimental arm was 29 mo (95% CI, 22-29 mo) versus 31 mo (95% CI, 29-32 mo) in the control arm (P = 0.401). The median overall survival was not reached in either arm (P = 0.876). Overall, adverse events of at least grade 3 were noted in 7 patients in the experimental arm versus 6 patients in the control arm (P = 0.759). Conclusion: Based on the results of this trial, the addition of low-dose capecitabine to 177Lu-DOTATATE in advanced grade 1/2 GEP-NETs did not lead to superior radiographic responses. Further studies are needed to evaluate its potential role in high-grade NETs.