[177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study

Diego Ferone; Daniel Halperin; Sten Myrehaug; Ken Herrmann; Marianne Pavel; Pamela Kunz; Beth Chasen; Jaume Capdevila; Salvatore Tafuto; Do-Youn Oh; Changhoon Yoo; Stephen Falk; Thorvardur R Halfdanarson; Ilya Folitar; Yufen Zhang; Paola Santoro; Paola Aimone; Herr Wouter W de; Simron Singh

doi:10.1530/endoabs.99.OC7.2

OC7.2

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Endocrine Abstracts (2024) 99 OC7.2 | DOI: 10.1530/endoabs.99.OC7.2

ECE2024 Oral Communications Oral Communications 7: Endocrine-related Cancer (6 abstracts)

[177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study

Diego Ferone ¹ , Daniel Halperin ² , Sten Myrehaug ³ , Ken Herrmann ^4,5 , Marianne Pavel ⁶ , Pamela Kunz ⁷ , Beth Chasen ² , Jaume Capdevila ⁸ , Salvatore Tafuto ⁹ , Do-Youn Oh ¹⁰ , Changhoon Yoo ¹¹ , Stephen Falk ¹² , Thorvardur R Halfdanarson ¹³ , Ilya Folitar ¹⁴ , Yufen Zhang ¹⁵ , Paola Santoro ¹⁵ , Paola Aimone ¹⁴ , Wouter W de Herder ¹⁶ & Simron Singh ³

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¹IRCCS Policlinico San Martino and DiMI, University of Genova, Endocrinology, Genova, Italy; ²MD Anderson Cancer Center, Houston, United States; ³University of Toronto, Toronto, Canada; ⁴National Center for Tumor Diseases (NCT), Heidelberg, Germany; ⁵University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Department of Nuclear Medicine, Essen, Germany; ⁶Uniklinikum Erlangen, Friedrich Alexander University Erlangen-Nuernberg, Erlangen, Germany; ⁷Yale School of Medicine, Yale University, New Haven, United States; ⁸Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; ⁹Oncologia Clinica e Sperimentale Sarcomi e Tumori Rari, Istituto Nazionale Tumori IRCCS, Naples, Italy; ¹⁰Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea, Rep. of South; ¹¹Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Rep. of South; ¹²Bristol Haematology and Oncology Centre, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom; ¹³Mayo Clinic, Rochester, United States; ¹⁴Novartis Pharma AG, Basel, Switzerland; ¹⁵Novartis Pharmaceuticals Corp, East Hanover, United States; ¹⁶Erasmus MC, Rotterdam, Netherlands

Background: There is no universally accepted first-line (1L) therapy for higher grade, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The Phase 3 NETTER-2 study (NCT03972488) evaluated [¹⁷⁷ Lu]Lu-DOTA-TATE (hereafter¹⁷⁷ Lu-DOTATATE) as 1L treatment in patients with grade (G)2 and G3 advanced GEP-NETs. This is the first trial to assess 1L radioligand therapy (RLT) in any solid tumor.

Methods: Eligible patients were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki-67 ≥10% and ≤55%) advanced GEP-NETs within the last 6 months prior to enrollment. Patients were randomized (2:1) to receive 4 cycles of ¹⁷⁷ Lu-DOTATATE (4 × 7.4 GBq) plus 30 mg octreotide long-acting release (LAR) at 8-weekly intervals during ¹⁷⁷ Lu-DOTATATE treatment then every 4 weeks (¹⁷⁷ Lu-DOTATATE arm), or 60 mg octreotide LAR every 4 weeks (control arm), stratified by grade (G2 vs G3) and tumor origin (pancreas vs other). The primary endpoint was progression-free survival (PFS), centrally assessed using RECIST 1.1. Objective response rate (ORR) was a key secondary endpoint.

Results: Overall, 226 patients were randomized to ¹⁷⁷ Lu-DOTATATE (n=151) or control (n=75). Most tumors originated in the pancreas (54.4%) or small intestine (29.2%); G3 tumors were reported in 35.0% of patients. Median cumulative dose of ¹⁷⁷ Lu-DOTATATE was 29.2 GBq, with 87.8% of patients receiving all 4 doses. Median PFS (95% confidence interval [CI]) was significantly prolonged by ~14.3 months from 8.5 months (7.7, 13.8) in the control arm to 22.8 months (19.4, not estimable) in the ¹⁷⁷ Lu-DOTATATE arm; stratified hazard ratio 0.276 (95% CI: 0.182, 0.418; P<0.0001). The ORR was significantly higher in the ¹⁷⁷ Lu-DOTATATE arm (43.0%) vs the control arm (9.3%); stratified odds ratio 7.81 (95% CI: 3.32, 18.4; P<0.0001). PFS and ORR results were consistent across all pre-specified demographic and prognostic subgroups. Among adverse events of special interest to RLT, G3/4 leukopenia, anemia and thrombocytopenia occurred in ≤3 patients each in the ¹⁷⁷ Lu-DOTATATE arm. One case of myelodysplastic syndrome was reported (¹⁷⁷ Lu-DOTATATE arm).

Conclusion: ¹⁷⁷ Lu-DOTATATE significantly prolonged PFS and demonstrated a clinically meaningful ORR, vs high-dose octreotide LAR, in patients with newly diagnosed advanced G2 and G3 GEP-NETs. Safety was in line with the established profile of ¹⁷⁷ Lu-DOTATATE. This is the first randomized study to demonstrate efficacy of RLT as first-line treatment in any solid tumor and will change clinical practice. © 2024 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2024 Gastrointestinal Cancers Symposium. All rights reserved.