As reported in The Lancet Oncology by Jonathan R. Strosberg, MD, of Moffitt Cancer Center, and colleagues, the final overall survival analysis of the phase III NETTER-1 trial has shown an approximately 12-month benefit with the addition of lutetium Lu-177 dotatate to long-acting octreotide in patients with midgut neuroendocrine tumors, although the difference did not achieve statistical significance.1
The trial supported the January 2018 approval of Lu-177 dotatate in this setting based on the primary analysis of progression-free survival.2,3 At that time, median progression-free survival was not reached with Lu-177 dotatate vs 8.5 months with the high-dose long-acting octreotide control; median overall survival at an updated analysis was not reached vs 27.4 months.
Jonathan R. Strosberg, MD
In the open-label trial,1 231 patients from sites in eight countries in Europe and the United States with locally advanced or metastatic, well-differentiated, somatostatin receptor–positive midgut neuroendocrine tumors and disease progression on fixed-dose long-acting octreotide were randomly assigned between September 2012 and January 2016 to receive Lu-177 dotatate plus long-acting octreotide (n = 117) or high-dose long-acting octreotide alone (n = 114). Treatment consisted of intravenous Lu-177 dotatate at 7.4 GBq (200 mCi) every 8 weeks for four cycles plus intramuscular long-acting octreotide at 30 mg every 4 weeks vs high-dose long-acting intramuscular octreotide at 60 mg every 4 weeks.
Randomization was stratified by highest tumor uptake on OctreoScan (Krenning grade 2, 3, or 4) and by the length of time on the most recent fixed dose of long-acting octreotide (≤ 6 or > 6 months). The primary endpoint was progression-free survival. Final analysis of overall survival was prespecified to occur after the first of either occurrence of 158 deaths or at 5 years after random assignment of the last patient.
The final analysis occurred at 5 years after the last patient was randomly assigned (at the occurrence of 142 deaths). Median follow-up was 76.3 months (range = 0.4–95.0 months) with Lu-177 dotatate and 76.5 months (range = 0.1–92.3 months) with the control.
During long-term follow-up, 41 patients (36%) in the control group had documented crossover to radioligand therapy with peptide receptor radionuclide therapy, with 36 (32%) receiving Lu-177 dotatate. Overall, 23% crossed over within 24 months of randomization. A total of 14 patients (12%) in the Lu-177 dotatate group received further treatment with peptide receptor radionuclide therapy, with 8 receiving additional cycles of Lu-177 dotatate. A total of 55 of all 231 patients (24%) received other antineoplastic agents, including everolimus in 17 patients (15%) in the Lu-177 dotatate group and 20 (18%) in the control group.
Median overall survival was 48.0 months (95% confidence interval [CI] = 37.4–55.2 months) in the Lu-177 dotatate group vs 36.3 months (95% CI = 25.9–51.7 months) in the control group (hazard ratio [HR] = 0.84, 95% CI = 0.60–1.17, P = .30). Rates were 91.0% vs 79.7%, 76.0% vs 62.7%, 61.4% vs 50.1%, 49.5% vs 41.8%, and 37.1% vs 35.4%, at 1, 2, 3, 4, and 5 years, respectively. In an analysis adjusting for survival among the 36% of control group patients who crossed over to receive peptide receptor radionuclide therapy, the adjusted median overall survival was 30.9 months in the control group.
In the tumor uptake stratification subgroups, median overall survival was 36.8 vs 70.0 months (HR = 1.59, 95% CI = 0.59–4.26) among 24 patients with grade 2 uptake, 60.6 vs 30.5 months (HR = 0.66, 95% CI = 0.35–1.21) among 69 with grade 3 uptake, and 42.2 vs 30.9 months (HR = 0.83, 95% CI = 0.54–1.27) among 138 with grade 4 uptake. In the time on constant dose octreotide stratification subgroups, median overall survival was 55.9 vs 30.7 months (HR = 0.62, 95% CI = 0.32–1.23) among 60 patients on treatment for up to 6 months and 42.2 vs 40.9 months (HR = 0.93, 95% CI = 0.63–1.35) among 171 on treatment for more than 6 months.
Adverse Events During Follow-up
Adverse events of special interest were recorded only in the Lu-177 dotatate group during long-term follow-up. During follow-up, treatment-related grade ≥ 3 serious adverse events were reported in 3 of 111 patients (3%), consisting of death from myelodysplastic syndrome in 1, grade 3 respiratory tract infection and grade 3 refractory cytopenia with multilineage dysplasia in 1, and breast cancer in 1; no new treatment-related serious adverse events were reported after the safety analysis cutoff (June 2016).
Overall, myelodysplastic syndrome developed in 2 of 111 patients (2%); 1 died 33 months after random assignment, the sole Lu-177 dotatate treatment-related death. No new cases of myelodysplastic syndrome or acute myeloid leukemia were reported during long-term follow-up after the safety analysis cutoff.
The investigators concluded: “[Lu-177 dotatate] treatment did not significantly improve median overall survival versus high-dose long-acting octreotide. Despite final overall survival not reaching statistical significance, the 11.7-month difference in median overall survival with [Lu-177 dotatate] treatment versus high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up.”
DISCLOSURE: The study was funded by Advanced Accelerator Applications, a Novartis company. Dr. Strosberg has served as a consultant or advisor to Novartis; has been on speakers bureaus for Ipsen and Lexicon; and has received research funding from Novartis. For full disclosures of the other study authors, visit thelancet.com.
1. Strosberg JR, Caplin ME, Kunz PL, et al: 177 Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): Final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol 22:1752-1763, 2021.
2. Strosberg J, El-Haddad G, Wolin E, et al: Phase 3 trial of 177Lu-DOTATATE for midgut neuroendocrine tumors. N Engl J Med 376:125-135, 2017.
3. Lutathera (lutetium Lu 177 dotatate) injection prescribing information, Advanced Accelerator Applications USA, Inc, 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208700s000lbl.pdf. Accessed November 30, 2021.
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