Final overall survival and long-term safety results of the phase 3 NETTER-1 trial were presented during the World Congress on Gastrointestinal Cancer 2021.
There is no doubt that survival outcomes for patients with progressive midgut NETs have improved dramatically [with 177Lu-Dotatate],” according to Jonathan R. Strosberg, MD, head of the Neuroendocrine Tumor Division and Department of Gastrointestinal Oncology Research Program at Moffitt Cancer Center, Tampa, Florida.
Strosberg presented final overall survival (OS) and long-term safety results of the phase 3 NETTER-1 trial (NCT01578239) during the 2021 World Congress on Gastrointestinal Cancer.1 The NETTER-1 trial compared lutetium Lu 177 dotatate (177Lu-Dotatate; Lutathera) with high-dose octreotide in patients with progressive midgut NETs.
Preliminary analysis from the study revealed that 177Lu-Dotatate significantly prolonged progression-free survival (PFS) versus high-dose long-acting octreotide (HR, 0.18; 95% CI, 0.11-0.29; P < .0001).2 The final report showed similar success regarding OS.1
“Median overall survival was 11.7 months longer with 177Lu-Dotatate compared to high-dose octreotide,” noted Strosberg.
The primary end point for the study was PFS by blinded independent central review with OS a key secondary end point. The final intention-to-treat analysis of OS was prespecified to take place after 158 deaths or 5 years after the last patient was randomized, whichever occurred first.
Eligibility criteria included advanced, inoperable, well-differentiated (Ki67 index ≤ 20%) midgut NETs; somatostatin receptor positivity on all target lesions; radiographic disease progression (RECIST v1.1) while taking a fixed dose of long-acting octreotide 20 or 30 mg every 3 to 4 weeks; and Karnofsky performance status ≥ 60.
Selected patients (n = 231) were randomized into 2 arms: 117 in the 177Lu-Dotatate arm and 114 in the high-dose long-acting octreotide arm. Those in the 177Lu-Dotatate arm received 7.4 GBq (200 mCi) every 8 weeks plus 30 mg long-acting octreotide every 4 weeks. Those in the octreotide-only arm received 60 mg every 4 weeks. After disease progression or completion of an 18-month treatment period, patients in both arms entered long-term follow-up and could receive further treatment as recommended by their physicians.
In the 177Lu-Dotatate arm, 101 patients (86.3%) entered follow-up and 99 (86.8%) in the control arm. During this period, 41 patients (36%) in the control arm received subsequent radioligand therapy or crossed over to receive 177Lu-Dotatate treatment.
Median study follow-up was 76.3 months (range, 0.4-95.0) in the 177Lu-Dotatate arm and 76.5 months (range, 0.1-92.3) in the control arm.
Median OS was 48 months (95% CI, 37.4-55.2) in the 177Lu-Dotatate arm and 36.3 months (95% CI, 25.9-51.7) in the control arm (HR, 0.84; 95% CI, 0.60-1.17; log-rank P = .30). Thirty-six percent of patients in the control arm crossed over to receive the radioligand; when accounting for crossover, the risk of death was reduced by 27% (HR, 0.73; 95% CI, 0.40-1.34).
Subsequent therapy consisted of radioligand therapy in 12.0% of patients and anti-neoplastic agents in 21.4% of patients from the investigational arm, as compared with 36.0% and 26.3% of patients, respectively, in the control arm.
Regarding safety, no new cases of myelodysplastic syndrome (MDS) or acute leukemia were reported during long-term follow-up. Although, 2 patients (1.8%) in the 177Lu-Dotatate arm did develop MDS. One developed unilineage dysplasia, confirmed as MDS; another developed refractory cytopenia with multilineage dysplasia.
During the study, the rate of grade 3 or higher nephrotoxicity in the 177Lu-Dotatate arm was low and similar to the control arm (5.4% and 3.6%, respectively). No additional patients in the 177Lu-Dotatate arm had grade 3 or higher nephrotoxicity during long-term follow up.
Overall, Strosberg noted that the median OS of 48 months in the 177Lu-Dotatate arm versus 36.3 months in the control arm “a difference of 11.7 months may be considered clinically meaningful.” However, the prescribed final analysis of OS, with a median follow-up of more than 6.3 years, did not reach statistical significance, which, Strosberg concluded, was “most likely impacted by a variety of cofounding factors, including 36% cross-over to radioligand therapy in the control arm (primarily 177Lu-Dotatate).”
1. Strosberg J, Caplin M, Ruszniewski P, et al. Overall survival and long-term safety data from the NETTER-1 trial: 177-Lu-Dotatate vs. high-dose octreotide in patients with progressive midgut NETs. Presented at: 2021 World Congress on Gastrointestinal Cancer; June 30-July 3, 2021; Virtual. Abstract O-2.
2. Strosberg J, El-Haddad G, Wolin E, et al; NETTER-1 Trial Investigators. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376:125-135. doi:10.1056/NEJMoa1607427