177Lu-DOTATATE significantly prolongs PFS in patients with GEP-NETs: The phase III NETTER-2 trial

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 177Lu-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

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