The NETTER-2 trial has presented intriguing results regarding the use of lutetium 177 dotatate (177Lu-dotatate; Lutathera) in patients with high-grade 2 and grade 3 gastroenteropancreatic neuroendocrine tumors (NETs). While the study demonstrated a significant improvement in progression-free survival (PFS), questions remain about the optimal timing and patient selection for this therapy, particularly concerning quality of life (QOL) and potential toxicities.
NETTER-2 Trial Results
The NETTER-2 trial (NCT03972488) was a phase 3 international, randomized study involving patients with locally advanced or metastatic, well-differentiated, somatostatin receptor–positive, high grade 2 (Ki67 ≥ 10% and ≤ 20%) or grade 3 (Ki67 > 20% and ≤ 55%) gastroenteropancreatic NETs. Patients were randomized to either 4 cycles of 177Lu-dotatate plus intramuscular octreotide 30 mg LAR followed by octreotide 30 mg LAR every 4 weeks (n = 151) or high-dose octreotide 60 mg LAR every 4 weeks (n = 75). The primary endpoint was PFS, with secondary endpoints including objective response rate (ORR), disease control rate (DCR), QOL, overall survival (OS), and safety.
The median PFS was 22.8 months (95% CI, 19.4-not estimated) in the 177Lu-dotatate group and 8.5 months (95% CI, 7.7-13.8) in the control group. Response rates were significantly higher in the 177Lu-dotatate group (ORR, 43.0%; DCR, 90.7%) compared with the control group (ORR, 9.3%; DCR, 66.7%). However, there was no significant difference in QOL measurements between the groups. OS data are still immature, with the median not yet reached in either arm.
Safety and Tolerability
The most common adverse effects of any grade were nausea (27% vs 18%), diarrhea (26% vs 34%), and abdominal pain (18% vs 27%) in the 177Lu-dotatate and control groups, respectively. Grade 3 or higher hematologic toxicities were reported in 20 patients (14%) in the 177Lu-dotatate arm and 1 patient (1%) in the control arm. One patient in the 177Lu-dotatate arm developed myelodysplastic syndrome (MDS). No study drug-related deaths occurred during the treatment period.
Quality of Life Considerations
Despite the promising PFS data, the absence of a significant improvement in QOL raises concerns. A survey study indicated that most patients with advanced NETs prioritize maintaining QOL and reducing pain/symptoms over survival. The lack of QOL benefit in NETTER-2 makes it difficult to recommend 177Lu-dotatate as a first-line therapy for all patients with high-grade NETs.
Long-Term Efficacy and Sequencing of Therapies
Data from both NETTER-1 and NETTER-2 trials have not shown significant improvements in overall survival, suggesting that subsequent lines of therapy may be impactful. The median OS for patients with well-differentiated grade 3 NETs has been reported as 33.8 months, indicating the potential for multiple lines of therapy. Therefore, further investigation is needed to determine the optimal timing for 177Lu-dotatate treatment compared to other available therapies.
Conclusion
NETTER-2 provides valuable insights into the management of high grade 2 and grade 3 NETs. However, the absence of an OS advantage and QOL improvement, coupled with the risk of MDS and acute leukemias, necessitates further studies to identify the ideal sequencing of therapies and the optimal timing for 177Lu-dotatate treatment. Long-term data on OS, QOL, and safety from NETTER-2 will be crucial in determining the role of 177Lu-dotatate in the first-line setting for these patients.
