NETTER-2: 177Lu-Dotatate With Octreotide LAR Extends PFS for Grade 2, 3 GEP-NETs

As there are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), Simron Singh, MD, and colleagues sought to determine the efficacy and safety of first-line [¹⁷⁷Lu]Lu-DOTA-TATE (¹⁷⁷Lu-Dotatate) in this patient population.

The phase 3, randomized NETTER-2 study began in 2019 to compare the efficacy of ¹⁷⁷Lu-Dotatate plus long-acting octreotide with high-dose long-acting octreotide alone. Patients enrolled in the study were 15 years of age or older with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced GEP-NETs.

Patients were recruited from 45 centers across 9 countries in North America, Europe, and Asia. They were randomly assigned 2:1 to receive either 4 cycles (cycle interval: 8 weeks ± 1 week) of intravenous ¹⁷⁷Lu-Dotatate plus long-acting repeatable (LAR) intramuscular octreotide 30 mg followed by octreotide 30 mg LAR every 4 weeks (¹⁷⁷Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group).

Tumor assessments were taken at baseline, week 16, and week 24, then every 12 weeks until disease progression or death. The primary end point was progression-free survival (PFS).

A total of 261 patients were screened between January 2020 and October 2022, and 35 patients were excluded from the trial. The ¹⁷⁷Lu-Dotatate group included 151 (67%) patients, while the control group included 75 (33%).

The median PFS was 8.5 months (95% CI, 7.7-13.8) in the control group and 22.8 months (95% CI, 19.4 to not estimated) in the ¹⁷⁷Lu-Dotatate group (stratified hazard ratio, 0.276 [0.182-0.418]; P<.0001). Adverse events of any grade occurred in 136 (93%) of 147 treated patients in the ¹⁷⁷Lu-Dotatate group and in 69 (95%) of 73 treated patients in the control group. No study drug-related deaths during the treatment period were observed.

First-line ¹⁷⁷Lu-Dotatate in combination with octreotide LAR can extend median PFS by 14 months in patients with grade 2 or 3 advanced GEP-NETs. It can be considered a new standard-of-care first-line treatment in this population.