Lutetium Lu 177 dotatate (¹⁷⁷Lu-DOTATATE) is a peptide receptor radionuclide therapy (PRRT) approved for the treatment of somatostatin receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).^1,2 The phase III NETTER-1 trial previously showed that ¹⁷⁷Lu-DOTATATE significantly improved progression-free survival (PFS) in patients with grades 1 and 2 well-differentiated midgut NETs.^1,2 However, the standard of care for GEP-NETs with a higher Kiel 67 (Ki-67) antigen presentation has yet to be established.¹ The phase III NETTER-2 trial sought to evaluate ¹⁷⁷Lu-DOTATATE as a first-line treatment in patients with advanced, grade 2/3 GEP-NETs, representing the first randomized trial to evaluate a radioligand as a first-line therapy for any metastatic solid tumor.^{1 177}Lu-DOTATATE was shown to significantly reduce the risk of progression or death, which supports its use as the standard of care for these patients.¹

Neuroendocrine cells are distributed throughout the body, but approximately two-thirds of NETs develop in the organs along the digestive tract, such as the stomach, intestines, and pancreas.³ In metastatic NET patients where surgery may not be applicable, PRRTs offer a targeted approach.³ PRRTs consist of a radioisotope that delivers the radiation chelated to a peptide that targets receptors present in cancer cells.^2,3 One such target is the SSTR which is expressed in >80% of well-differentiated NETs.² When the radioisotope Lutetium-177 (¹⁷⁷Lu) is chelated with an SSTR-binding somatostatin analog, it accumulates within tumor cells and delivers cytotoxic radiation to kill these cells.^2,3

The phase III NETTER-2 trial compared the efficacy and safety of ¹⁷⁷Lu-DOTATATE with high-dose long-acting release (LAR) octreotide (a somatostatin agonist) alone in newly diagnosed, advanced, grade 2/3 GEP-NET patients.¹ In this study, 226 patients ≥15 years of age, newly diagnosed with advanced, SSTR-positive, well-differentiated, grade 2 or 3 (Ki67 ≥10% and ≤55%) GEP-NET were randomized 2:1 to receive ¹⁷⁷Lu-DOTATATE plus 30mg octreotide LAR at 8-weekly intervals (n=151), or 60mg octreotide LAR every 4 weeks (n=75).¹ Patients from both arms were allowed to receive further ¹⁷⁷Lu-DOTATATE treatment upon disease progression in the extension phase.¹ Treatment arms were well-balanced in terms of patient age, sex, and race, and patients were followed up every 6 months for 3 years.¹

The primary endpoint of the study was PFS.¹ The median PFS was significantly extended in patients treated with ¹⁷⁷Lu-DOTATATE compared to those treated with high-dose octreotide alone (22.8 months vs. 8.5 months; stratified HR=0.276; 95% CI: 0.182-0.418; p<0.0001) which translated to a 72% reduction in risk of disease progression or death.¹ The PFS benefit was also consistent across prespecified subgroups when patients were stratified by age, gender, race, tumor grade, tumor origin, and SSTR uptake per central review.¹

Key secondary endpoints included objective response rate (ORR) and quality of life (QoL).¹ The ORR was significantly higher in patients in the treatment arm compared to the control arm (43.0% vs 9.3%; stratified odds ratio=7.81; 95% CI: 3.32-18.40; p<0.0001), including higher complete response (5.3% vs. 0%) and partial response (37.7% vs. 9.3%) rates.¹ Time to deterioration in QoL was numerically longer in the ¹⁷⁷Lu-DOTATATE arm but not significantly different from the high-dose octreotide arm with regards to the global health status (13.2 months vs. 8.6 months; HR=0.856; 95% CI: 0.570-1.283; p=0.2222).¹ The median time to deterioration in the measures of diarrhea, fatigue, and pain were also similar.¹

The safety profiles of ¹⁷⁷Lu-DOTATATE and octreotide LAR were in line with established profiles and no new safety concerns emerged in this patient population.¹ The most common all-grade adverse events (AEs) in both arms were nausea, diarrhea and abdominal pain.¹ Notably, higher rates of grade ≥3 AEs were observed in the ¹⁷⁷Lu-DOTATATE arm, including lymphocyte count decrease (n=8), small intestinal obstruction (n=5), and secondary hematologic malignancy (n=1).¹

In summary, the NETTER-2 trial demonstrated that ¹⁷⁷Lu-DOTATATE plus octreotide LAR when taken as a first-line treatment can significantly prolong PFS and improve ORR in patients with high-grade GEP-NETs compared to high-dose octreotide LAR alone.¹ These findings may impact clinical practice and support the use of ¹⁷⁷Lu-DOTATATE earlier within the disease course.¹