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

Xu J (1†), Chen J (2, 3†), Song S (3,4,5,6†), Song (L7†), Wang (R8†), Hao J (9), Du X (10), Cao D (11), Gao Y (12), Lan X (13), Yang A (14), Miao W (15), Xu H (16), Chen Y (17, 18, 19), Li L (20), Shi H (21, 22, 23) Yuan X (24), Ye F (25), Wang J (26), Xu N (27), Han X (28), Li X (29), Huang R (30), Zhang T (31, 32, 33), Li E (34), Wang R (35), Zhou Y (36), Chen H (37), Zhu X (38), Zhao J (39), Su X (40), Cui Y (41), Ren P (42), Wang P (43)
(1) Senior Department of Oncology, Chinese PLA General Hospital, Beijing
(2) Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai
(3) Department of Oncology, Shanghai Medical College, Fudan University, Shanghai
(4) Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai
(5) Center for Biomedical Imaging, Fudan University, Shanghai
(6) Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai
(7) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou
(8) Department of Nuclear Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing
(9) Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan
(10) Department of Oncology, Mianyang Central Hospital, Mianyang
(11) Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital and Sichuan University, Chengdu
(12) Department of Nuclear Medicine, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou
(13) Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
(14) The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an
(15) Department of Nuclear Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou
(16) Department of Nuclear Medicine, The First Affiliated Hospital of Jinan University, Guangzhou
(17) Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Luzhou
(18) Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou
(19) Institute of Nuclear Medicine, Southwest Medical University, Luzhou
(20) Department of Nuclear Medicine, Zhejiang Cancer Hospital, Hangzhou
(21) Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai
(22) Shanghai Institute of Medical Imaging, Shanghai
(23) Institute of Nuclear Medicine, Fudan University, Shanghai
(24) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
(25) Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen
(26) Department of Nuclear Medicine, Xijing Hospital, Xi’an
(27) Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou
(28) The First Affiliated Hospital of Zhengzhou University, Zhengzhou
(29) Department of Nuclear Medicine, Qilu Hospital of Shandong University, Jinan
(30) Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu
(31) Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
(32) Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
(33) Hubei Key Laboratory of Precision Radiation Oncology, Wuhan
(34) Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an
(35) Department of Medical Oncology, The First Affiliated Hospital of Fujian Medical University, Fuzhou
(36) Zhongshan Hospital, Fudan University, Shanghai
(37) Department of Nuclear Medicine, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen
(38) Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
(39) Research Center of Cancer Diagnosis and Therapy, Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou
(40) Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou
(41) Department of Oncology, Henan Provincial People’s Hospital, Zhengzhou
(42) Affiliated Hospital of Southwest Medical University, Luzhou
(43) Beijing Sinotau Intl. Pharmaceutical Technology Co., Ltd., Beijing, China

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. Key words: XTR008, 177Lu-Dotatate, gastroenteropancreatic neuroendocrine tumour, GEP-NET, peptide receptor radionuclide therapy, PRRT