177Lu-Dotatate versus high-dose long-acting octreotide for the treatment of patients with advanced, grade 1-2, well-differentiated gastroenteropancreatic neuroendocrine tumours (XT-XTR008-3-01): an open-label, randomised, phase III trial.

Abstract

Background: The phase III trial, XT-XTR008-3-01, was a randomised controlled trial (RCT) that evaluated the efficacy and safety of XTR008, a novel no-carrier-added lutetium-177 (¹⁷⁷Lu)-Dotatate, for the first time in a later-line therapy setting for gastroenteropancreatic neuroendocrine tumours (GEP-NETs) of all origins.

Patients and methods: Patients with grade 1-2, unresectable, locally advanced or metastatic GEP-NETs who had progressed within the last 12 months before randomisation were randomly allocated 1 : 1 to XTR008 (four cycles every 8 weeks) or octreotide 60 mg (every 4 weeks), stratified by primary tumour site (pancreatic versus non-pancreatic), pathological tumour grade (1 versus 2), and duration of prior somatostatin analogues treatment (≤6 versus >6 months). The primary endpoint was progression-free survival (PFS) by a blinded independent review committee. The key secondary endpoints included overall response rate (ORR); overall survival (OS); quality of life, evaluated using the European Organisation for Research and Treatment of Cancer quality of life questionnaires QLQ-C30 and QLQ-GI.NET21; safety; pharmacokinetics; and dosimetry.

Results: Patients (N = 196) were randomized to XTR008 (n = 99) or control (n = 97). Primary tumour sites: pancreas (59%), rectum (28%), midgut (7%). Median follow-up: 11.1 months [interquartile range (IQR) 8.5-11.5, XTR008] versus 10.2 months (IQR 8.5-11.9 months, control). With 78 PFS events, median PFS was not reached [95% confidence interval (CI) 16.13 months to not estimated] versus 5.8 months (95% CI 5.65-8.41 months); stratified hazard ratio (HR) 0.06 (P < 0.0001). ORR: 43.4% (95% CI 33.50% to 53.77%) versus 1.0% (95% CI 0.03% to 5.61%). OS data were immature for both groups, with XTR008 showing a longer survival trend (HR 0.24, P = 0.0550). Treatment-related adverse events: 98% versus 89%; serious adverse events: 16.3% versus 12.5% (6.1% versus 3.1% drug-related). Myelodysplastic syndrome and grade ≥3 renal toxicity occurred in 1% of patients in the XTR008 group; no acute myeloid leukaemia or drug-related deaths occurred.

Conclusions: XTR008 monotherapy showed superior efficacy versus high-dose long-acting repeatable (LAR) octreotide monotherapy in advanced GEP-NET tumours of all origins in a later-line treatment setting, with manageable safety, supporting its use as a new treatment option.