As reported in The Lancet Oncology by Jonathan R. Strosberg, MD, and colleagues, the final overall survival analysis of the pivotal phase III NETTER-1 trial has shown an approximate 12-month benefit with the addition of lutetium-177 (Lu-177) dotatate to long-acting octreotide in patients with midgut neuroendocrine tumors, although the difference did not achieve statistical significance.

The trial supported the January 2018 approval of Lu-177 dotatate in this setting based on the primary analysis of progression-free survival. At this analysis, median progression-free survival was not reached in the Lu-177 dotatate group vs 8.5 months in the high-dose long-acting octreotide control group; median overall survival at an updated analysis was not reached vs 27.4 months.

Jonathan R. Strosberg, MD

Study Details

The open-label trial included 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. They 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.

The primary endpoint was progression-free survival. Final analysis of overall survival was prespecified to occur after the first of either occurrence: 158 deaths, or 5 years after random assignment of the last patient.

Overall Survival

The final analysis occurred 5 years after the last patient was randomly assigned (142 deaths). Median follow-up was 76.3 months (range = 0.4–95.0 months) in the Lu-177 dotatate group and 76.5 months (range = 0.1–92.3 months) 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 analysis adjusting for survival among the 36% of control group patients who crossed over to receive radioligand therapy with peptide receptor radionuclide therapy, adjusted median overall survival was 30.9 months in the control group.

Restricted mean survival times were 21.2 vs 19.3 months at 2 years, 29.7 vs 26.0 months at 3 years, 36.2 vs 31.5 months at 4 years, and 41.2 vs 36.1 months at 5 years.

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 (3%) of 111 patients, with no new treatment-related serious adverse events being reported after the safety analysis cutoff (June 2016). Myelodysplastic syndrome developed in 2 (2%) of 111 patients; 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.

 The investigators concluded, “Lu-177 dotatate treatment did not significantly improve median overall survival vs 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 vs high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up.”

Dr. Strosberg, of Moffitt Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Advanced Accelerator Applications, a Novartis company. For full disclosures of the study authors, visit thelancet.com.