First Study to Investigate 1L RLT Finds 177Lu-DOTATATE Improves ORR, PFS in GEP-NETs

For patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), there is currently no widely utilized first-line (1L) therapy for higher-grade, well-differentiated forms of the disease, resulting in an unmet need in this patient population. As radioligand therapy (RLT) has shown promise as an innovative cancer treatment, the phase 3 NETTER-2 study evaluated the use of [177Lu]Lu-DOTA-TATE (¹⁷⁷Lu-DOTATATE) as a 1L treatment in patients with grade (G) 2 and G3 GEP-NETs.

Dr. Simron Singh, of the University of Toronto, presented the study—the first of its kind to analyze 1L RLT in any solid tumor—at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

Patients eligible for the study were diagnosed with somatostatin receptor-positive high G2 or G3 advanced GEP-NETs. The study cohort comprised 226 patients who were randomized 2:1. The ¹⁷⁷Lu-DOTATATE arm included 151 patients who received 4 cycles of ¹⁷⁷Lu-DOTATATE in addition to long-acting release (LAR) octreotide 30 mg at 8 weekly intervals, then every 4 weeks. The control arm consisted of 75 patients, stratified by grade and tumor origin, who were administered LAR octreotide 60 mg every 4 weeks.

The primary end point was progression-free survival (PFS), and the key secondary end point was objective response rate (ORR). Most tumors were found to originate in the pancreas (54.4%) or small intestine (29.2%), and G3 tumors were reported in 35.0% of patients.

The median cumulative dose of ¹⁷⁷Lu-DOTATATE was 29.2 GBq, and 87.8% of patients received all 4 doses. The use of ¹⁷⁷Lu-DOTATATE resulted in a median PFS that was prolonged from 8.5 months to about 14.3 months in the control arm and 22.8 months in the ¹⁷⁷Lu-DOTATATE arm. The ORR was also significantly higher in the ¹⁷⁷Lu-DOTATATE arm (43.0%) than in the control arm (9.3%).

Adverse events, including G3 and G4 leukopenia, anemia, and thrombocytopenia, occurred in ≤3 of patients each in the ¹⁷⁷Lu-DOTATATE arm. One case of myelodysplastic syndromes was also reported in this treatment arm.

Patients with newly diagnosed advanced G2 or G3 GEP-NETs may benefit from ¹⁷⁷Lu-DOTATATE. While further studies investigating the use of RLT as a therapeutic option in other settings are needed, NETTER-2 is the first randomized study to demonstrate the efficacy of RLT as a 1L treatment for any form of cancer.

“These data have clinical practice-changing implications and support the use of ¹⁷⁷Lu-DOTATATE earlier within the disease course of high G2 and G3 GEP-NETs,” said Dr. Singh during his presentation of the results at the meeting.