177Lu-Dotatate Yields Clinically Relevant But Non-Significant OS Benefit for Midgut NETs

Despite not yielding a significant improvement in median overall survival (OS) among patients with advanced midgut neuroendocrine tumors, treatment with ¹⁷⁷Lu-Dotatate (Lutathera) resulted in a potential clinically relevant improvement vs the control arm, high-dose long-acting octreotide (Sandostatin), according to results from the phase 3 NETTER­1 trial (NCT01578239) published in Lancet Oncology.

Although the secondary end point of OS was not met, the median OS was 48.0 months (95% CI, 37.4-55.2) in the ¹⁷⁷Lu-Dotatate group at a median follow-up of 76.3 months compared and 36.3 months (95% CI, 25.9-51.7) in the control group at a median follow-up of 76.5 months (HR, 0.84; 95% CI, 0.60-1.17; P = .30).

“Final analysis of the NETTER­1 study showed that treatment with ¹⁷⁷Lu­Dotatate did not lead to a significant improvement in overall survival versus high­dose long­acting octreotide; however, an arguably clinically relevant difference in median overall survival of 11.7 months with ¹⁷⁷Lu­-Dotatate was recorded, and was accompanied by a favourable long­term safety profile, in patients with advanced, progressive, well­differentiated, grade 1 and grade 2 midgut neuroendocrine tumors,” the investigators wrote.

Eligible patients were 18 years and older, and had advanced, well­differentiated midgut neuroendocrine tumors with positive uptake on 111In­DTPA­octreotide scintigraphy on all target lesions. Patients also had confirmed disease progression per RECIST 1.1 criteria.

Patients were randomly assigned 1:1 to receive ¹⁷⁷Lu­-Dotatate at 7.4 GBq intravenously every 8 weeks for 4 cycles plus concomitant long­acting octreotide at 30 mg administered intramuscularly, or high­dose long­acting octreotide at 60 mg given intramuscularly every 4 weeks.

The primary end point of the NETTER-1 study was progression-free survival, which was previously reported.

A total of 101 patients in the ¹⁷⁷Lu­-Dotatate group and 99 patients in the control group entered long-term follow up. Yearly survival rates for the ¹⁷⁷Lu­Dotatate and control groups, respectively, were 91.0% (95% CI, 84.0%-95.1%) and 79.7% (95% CI, 70.8%-86.1%) at 1 year; 76·0% (95% CI, 66.7%-83.0%) and 62.7% (95% CI, 52.6%-71.2%) at 2 years; 61.4% (95% CI, 51.4%-69.9%) and 50.1% (95% CI, 40.0%-59.4%) at 3 years; 49.5% (95% CI, 39.5%-58.6%) and 41.8% (95% CI, 31.8%-51.4%) at 4 years; and 37.1% (95% CI, 27.8%-46.4%) and 35.4% (95% CI, 25.7%-45.2%) at 5 years.

Six percent of patients in the ¹⁷⁷Lu­-Dotatate group had grade 3 or higher serious treatment-related adverse effects (TRAEs) during the whole study. During long-term follow up, 3% of patients experienced serious AEs. A single patient died from grade 5 myelodysplastic syndrome and another patient had grade 3 respiratory infection and refractory cytopenia with multilineage dysplasia leading to treatment discontinuation. After the safety analysis cutoff, no new serious TRAEs were reported.

“These results highlight the challenges in demonstrating a significant [OS] benefit in patients with advanced, well-differentiated neuroendocrine tumors, given the extended survival in this indolent tumour type, heterogeneity of previous treatments, potential for crossover within the trial, and the availability of other further therapeutic options,” the investigators concluded.

Reference

Strosberg JR, Caplin ME, Kunz PL, et al. 177Lu-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. 2021;22(12):1752-1763. doi:10.1016/S1470-2045(21)00572-6