177Lu-Dotatate Combo Shows Consistent Efficacy Across GEP-NET Subgroups

First-line lutetium Lu 177 dotatate (¹⁷⁷Lu-dotatate; Lutathera) plus octreotide (Sandostatin) long-acting repeatable (LAR) demonstrated consistent efficacy regardless of tumor grade or site of origin in patients with advanced, well-differentiated, somatostatin receptor (SSTR)–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), according to preplanned and post-hoc efficacy analyses from the phase 3 NETTER-2 trial (NCT03972488) published in eClinicalMedicine.

In preplanned progression-free survival (PFS) subgroup analyses, hazard ratios (HRs) for disease progression or death with ¹⁷⁷Lu-dotatate vs high-dose octreotide LAR 60 mg were 0.306 (95% CI, 0.176–0.530) for grade 2 NETs and 0.266 (95% CI, 0.145–0.489) for grade 3 NETs. The median PFS in the ¹⁷⁷Lu-dotatate arm was 29.0 months (95% CI, 21.8–not estimable [NE]) for grade 2 disease vs 13.8 months (95% CI, 8.4–19.3) with control, and 22.2 months (95% CI, 13.9–27.8) vs 5.6 months (95% CI, 3.7–8.9) for grade 3 disease.

By primary tumor site, the HR was 0.336 (95% CI, 0.200–0.562) for pancreatic NETs and 0.233 (95% CI, 0.117–0.462) for gastrointestinal NETs. The median PFS was 19.4 months (95% CI, 16.6–24.9) with ¹⁷⁷Lu-dotatate vs 8.5 months (95% CI, 3.8–16.6) in the control arm for pancreatic NETs, and NE (95% CI, 22.6–NE) vs 8.7 months (95% CI, 5.6–19.3) for gastrointestinal NETs.

The objective response rates (ORRs) with ¹⁷⁷Lu-dotatate favored the treatment arm across all subgroups. The ORR was 40.4% (95% CI, 30.7%–50.7%) vs 10.4% (95% CI, 3.5%–22.7%) in grade 2 NETs (odds ratio [OR], 5.83; 95% CI, 2.12–16.00) and 48.1% (95% CI, 34.0%–62.4%) vs 7.4% (95% CI, 0.9%–24.3%) in grade 3 NETs (OR, 11.57; 95% CI, 2.48–53.97). Additionally, the ORR was 51.2% (95% CI, 39.9%–62.4%) vs 12.2% (95% CI, 4.1%–26.2%) for pancreatic NETs (OR, 7.56; 95% CI, 2.70–21.19) and 33.3% (95% CI, 22.4%–45.7%) vs 5.9% (95% CI, 0.7%–19.7%) for gastrointestinal NETs (OR, 8.00; 95% CI, 1.76–36.35).

Moreover, the PFS benefit held across central baseline SSTR uptake scores of 3 (HR, 0.31; 95% CI, 0.10–0.89) and 4 (HR, 0.30; 95% CI, 0.19–0.47). Post-hoc multivariate analyses confirmed treatment as the strongest predictor of both outcomes after adjusting for key baseline covariates, with an adjusted PFS HR of 0.212 (95% CI, 0.134–0.337; P <.0001) and an adjusted ORR OR of 10.43 (95% CI, 3.98–27.29; P <.0001).

“Our results suggest that first-line ¹⁷⁷Lu-dotatate should be considered as a standard of care for patients with advanced, well-differentiated, higher grade 2 or 3, SSTR–positive GEP-NETs, and for whom chemotherapy is not considered the most appropriate treatment option,” corresponding author Simron Singh, MD, MSc, professor in the Department of Medicine at the University of Toronto and medical oncologist at Sunnybrook Odette Cancer Centre, wrote in the publication with study coinvestigator. “Overall, our findings suggest that molecular imaging should be a gatekeeper for daily therapeutic decision-making.”

NETTER-2 was an open-label, parallel-group, randomized phase 3 study conducted across 45 centers in 9 countries. Between January 22, 2020, and October 13, 2022, investigators enrolled 226 patients, randomly assigning 2:1 151 patients to ¹⁷⁷Lu-dotatate at 7.4 GBq every 8 weeks for 4 cycles plus octreotide LAR 30 mg every 4 weeks or to high-dose octreotide LAR 60 mg every 4 weeks. Eligible patients were aged 15 years or older with newly diagnosed, advanced, well-differentiated, higher grade 2 or 3, SSTR–positive GEP-NETs; those for whom chemotherapy was considered more appropriate were excluded.

The primary end point was PFS in the NETTER-2 protocol, and key secondary end points including ORR and safety, were previously reported. Preplanned analyses reported here assessed PFS and ORR by NET grade, site of origin, and SSTR uptake score; post-hoc analyses evaluated outcomes by combined grade and site of origin subgroups and by multivariate regression.

The authors noted that 18F-fluorodeoxyglucose PET/CT imaging was not mandated, precluding subgroup analyses by metabolic avidity. They further acknowledged that subgroup analyses were descriptive, without formal statistical testing, and that sample sizes were limited, particularly for grade-plus–site-of-origin subgroups.

Pancreatic NET findings were broadly consistent with those from the phase 2 OCLURANDOM trial (NCT02230176), in which ¹⁷⁷Lu-dotatate produced a median PFS of 20.7 months (90% CI, 17.2-23.7) and an ORR of 63% in patients with progressive pancreatic NETs.² The ongoing phase 3 COMPOSE trial (NCT04919226), evaluating 177Lu-edotreotide vs physicians' choice in patients with higher-proliferative, SSTR–positive GEP-NETs, is expected to further inform optimal treatment sequencing in this population.³

References

1. Ferone D, Pavel M, Herrmann K, et al. [177Lu]Lu-DOTA-TATE plus long-acting octreotide in patients with newly diagnosed, advanced, grade 2–3, gastroenteropancreatic neuroendocrine tumours: preplanned and post-hoc efficacy analyses from the randomised, phase 3 NETTER-2 trial. eClinicalMedicine. 2026;98:104109. doi:10.1016/j.eclinm.2026.104109
2. Baudin E, Durand A, Beron A, et al. [177Lu]Lu-dota-tate versus sunitinib in patients with metastatic progressive neuroendocrine tumours of the pancreas (OCLURANDOM): a randomised, controlled, phase 2 trial. Lancet Oncol. 2026;27(6):699-710. doi:10.1016/S1470-2045(26)00108-7
3. Lutetium 177Lu-edotreotide versus best standard of care in well-differentiated aggressive grade-2 and grade-3 gastroenteropancreatic neuroendocrine tumors (GEP-NETs) - COMPOSE (COMPOSE). ClinicalTrials.gov. Updated September 10, 2026. Accessed August 13, 2026. https://tinyurl.com/h8r9p899