NETTER-2: First-Line [177Lu]Lu-DOTA-TATE plus Octreotide in Advanced G2-G3 GEP-NETs

The phase 3 NETTER-2 trial previously showed that first-line [177Lu]Lu-DOTA-TATE significantly prolonged progression-free survival compared with high-dose octreotide in patients with newly diagnosed, advanced, well-differentiated, higher grade 2 or grade 3, somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors.

A new analysis now provides a closer look at whether this benefit is maintained across different tumor grades, primary tumor sites, and levels of somatostatin receptor uptake.

In August 2026, eClinicalMedicine published the study titled “[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.”

Authors: Diego Ferone, Marianne Pavel, Ken Herrmann, Pamela L. Kunz, Sten Myrehaug, Daniel Halperin, Beth Chasen, Jaume Capdevila, Amparo García-Burillo, Salvatore Tafuto, Secondo Lastoria, Do-Youn Oh, Changhoon Yoo, Stephen Falk, Thorvardur R. Halfdanarson, Maddalena Sansovini, Laura Gerard, Emmanuel Deshayes, Angelina Filice, Ilya Folitar, Yufen Zhang, Wouter W. de Herder, and Simron Singh.

A Closer Look at NETTER-2

NETTER-2 was a prospective, open-label, randomized phase 3 trial conducted across 45 centers in nine countries. It enrolled patients aged 15 years or older with newly diagnosed, advanced, well-differentiated, higher grade 2 or grade 3 GEP-NETs, with a Ki67 index of at least 10% and no more than 55%, and positive somatostatin receptor imaging.

Patients were randomly assigned in a 2:1 ratio to receive [177Lu]Lu-DOTA-TATE plus octreotide long-acting repeatable 30 mg or high-dose octreotide LAR 60 mg.

In the experimental arm, [177Lu]Lu-DOTA-TATE was administered at 7.4 GBq every 8 weeks for four cycles. Octreotide LAR 30 mg was given after each [177Lu]Lu-DOTA-TATE infusion and then every 4 weeks. Patients in the control group received octreotide LAR 60 mg every 4 weeks.

Between January 22, 2020, and October 13, 2022, 261 patients were screened and 226 were randomly assigned, including 151 to [177Lu]Lu-DOTA-TATE and 75 to control. Among the 226 patients, 147 had grade 2 NETs and 79 had grade 3 disease. The primary tumor originated in the pancreas in 123 patients, while 103 had gastrointestinal NETs.

The previously reported primary NETTER-2 analysis showed a substantial progression-free survival advantage with [177Lu]Lu-DOTA-TATE. Median PFS was 22.8 months compared with 8.5 months with high-dose octreotide, corresponding to a 72% reduction in the risk of disease progression or death.

Objective response rate was also higher with [177Lu]Lu-DOTA-TATE, at 43% compared with 9% in the control arm. The new publication focused on whether these benefits were maintained across NET grade, primary tumor origin, and baseline somatostatin receptor uptake.

Benefit Maintained in Both Grade 2 and Grade 3 NETs

In the preplanned subgroup analysis, [177Lu]Lu-DOTA-TATE reduced the risk of disease progression or death in both grade 2 and grade 3 NETs. For patients with grade 2 disease, the hazard ratio for progression or death was 0.31, with a 95% confidence interval of 0.18–0.53.

For those with grade 3 NETs, the hazard ratio was 0.27, with a 95% confidence interval of 0.14–0.49. Median PFS with [177Lu]Lu-DOTA-TATE was 29.0 months in patients with grade 2 NETs and 22.2 months in those with grade 3 disease. The improvement was also reflected in tumor response.

Among patients with grade 2 NETs, the objective response rate was 40.4% with [177Lu]Lu-DOTA-TATE compared with 10.4% with high-dose octreotide. Among those with grade 3 NETs, response rates were 48.1% and 7.4%, respectively. The findings are particularly relevant for grade 3 well-differentiated NETs, a population for which prospective randomized data supporting first-line treatment options have historically been limited.

Benefit by Tumor Origin

The benefit of [177Lu]Lu-DOTA-TATE was also observed regardless of the primary tumor site. Among patients with pancreatic NETs, the hazard ratio for progression or death was 0.34, with a 95% confidence interval of 0.20–0.56. For gastrointestinal NETs, the corresponding hazard ratio was 0.23, with a 95% confidence interval of 0.12–0.46.

Median PFS with[177Lu]Lu-DOTA-TATE was 19.4 months among patients with pancreatic NETs. In patients with gastrointestinal NETs, median PFS was not estimable, with a 95% confidence interval of 22.6 months to not estimable.

Differences were seen in objective response rates between the two groups. Among patients with pancreatic NETs, the objective response rate was 51.2% with [177Lu]Lu-DOTA-TATE compared with 12.2% with control. For gastrointestinal NETs, the response rate was 33.3% compared with 5.9%, respectively.

Post-hoc analyses combining tumor grade and site of origin also showed a consistent treatment benefit across grade 2 pancreatic, grade 2 gastrointestinal, grade 3 pancreatic, and grade 3 gastrointestinal NETs.

What About Somatostatin Receptor Uptake?

The investigators also examined whether the efficacy of [177Lu]Lu-DOTA-TATE varied according to the baseline somatostatin receptor uptake score. Among the 226 randomized patients, 34 (15%) had an uptake score of 3, defined as uptake greater than the liver but lower than the spleen, while 185 (82%) had a score of 4, indicating uptake greater than the spleen.

The PFS benefit with [177Lu]Lu-DOTA-TATE was maintained in both groups. For patients with an uptake score of 3, the hazard ratio for progression or death was 0.31. Median PFS was not estimable with [177Lu]Lu-DOTA-TATE compared with 8.0 months with control.

Among patients with an uptake score of 4, the hazard ratio was 0.30, with median PFS of 22.8 months compared with 8.7 months. Objective response rates with [177Lu]Lu-DOTA-TATE were 45.8% for patients with an uptake score of 3 and 42.3% for those with a score of 4.

No responses were observed among the 10 control patients with an uptake score of 3, while the objective response rate in the control group with a score of 4 was 11.3%.

Treatment Effect Remained After Adjustment for Baseline Factors

The investigators additionally performed post-hoc multivariate analyses to assess the treatment effect after adjustment for baseline clinical and disease characteristics.

These models incorporated age, sex, primary NET site, tumor grade, Ki67 index, metastatic spread, chromogranin A levels, and baseline somatostatin receptor uptake score. Because 24 patients had at least one missing covariate, 202 patients were included in the final multivariable analyses.

After adjustment, the hazard ratio for progression or death with [177Lu]Lu-DOTA-TATE versus control was 0.212, compared with 0.276 in the unadjusted primary analysis. The adjusted odds ratio for objective response was 10.43, compared with 7.81 in the unadjusted analysis.

According to the authors, treatment assignment had the greatest influence on both PFS and objective response among the variables evaluated, while adjustment for baseline characteristics had only a limited effect on the treatment benefit.

Where Could 177Lu-DOTATATE Fit in First-Line Treatment?

The findings reinforce the primary NETTER-2 results and provide additional evidence that the benefit of first-line [177Lu]Lu-DOTA-TATE is not restricted to one tumor grade or anatomical subgroup. The study population, however, is important when interpreting the results.

NETTER-2 enrolled patients with newly diagnosed, advanced, well-differentiated, higher grade 2 or grade 3 GEP-NETs with Ki67 between 10% and 55% and strong somatostatin receptor expression. Patients for whom chemotherapy was considered more appropriate than the study treatments were excluded.

The results therefore should not be extrapolated to patients with somatostatin receptor-heterogeneous or somatostatin receptor-negative grade 3 NETs, high-grade tumors with rapid clinical decline, or patients considered more appropriate candidates for first-line chemotherapy.

The investigators noted that the relatively high response rates observed in some of the more aggressive subgroups may be clinically relevant when reduction in tumor burden is an important treatment objective.

In particular, patients with pancreatic NETs had an objective response rate of 51% with [177Lu]Lu-DOTA-TATE, while patients with grade 3 disease had a response rate of 48%. At the same time, the authors emphasized that treatment selection should remain individualized and based on the overall clinical profile.

Important Limitations

Several limitations should be considered when interpreting these analyses. The subgroup sample sizes were relatively small, particularly when patients were divided simultaneously according to NET grade and primary tumor site. The subgroup analyses were descriptive, and no formal statistical tests were performed.

In addition, 18F-FDG PET/CT imaging was not mandated by the NETTER-2 protocol. Baseline 18F-FDG PET/CT data were therefore unavailable, preventing analysis of treatment outcomes according to FDG avidity.

The trial also selected patients with somatostatin receptor-positive disease and excluded those whom investigators considered more appropriate candidates for chemotherapy. Direct comparisons between NETTER-2 and chemotherapy studies should therefore be interpreted cautiously because the underlying patient populations differ.

Further research is also needed to evaluate the effectiveness of [177Lu]Lu-DOTA-TATE relative to other available therapies and to establish optimal treatment sequencing for subsequent therapies.

Expanding the Evidence for Earlier Radioligand Therapy

The new NETTER-2 analyses extend the primary findings by showing that the PFS and objective response benefits of first-line [177Lu]Lu-DOTA-TATE were maintained across higher grade 2 and grade 3 disease, pancreatic and gastrointestinal primary tumors, and baseline somatostatin receptor uptake scores of 3 and 4.

For patients with newly diagnosed, advanced, well-differentiated, higher grade 2–3, somatostatin receptor-positive GEP-NETs for whom chemotherapy is not considered the most appropriate first-line treatment, the authors concluded that the findings support earlier integration of [177Lu]Lu-DOTA-TATE into the treatment pathway.

The results also reinforce the importance of somatostatin receptor imaging in identifying patients who may be appropriate candidates for radioligand therapy and provide additional evidence for the use of [177Lu]Lu-DOTA-TATE across the heterogeneous GEP-NET population studied in NETTER-2.

The full article is available in eClinicalMedicine.

Discover more articles like this on OncoDaily.