Clinically meaningful survival advantage with 177Lu-DOTATATE in advanced midgut neuroendocrine tumours
The randomised, controlled NETTER-1 trial previously established the efficacy and safety of lutetium-177 (177Lu)–DOTATE in patients with advanced, progressive, somatostatin-receptor–positive midgut neuroendocrine tumours. After a median follow-up of more than 6.3 years, the prespecified final overall survival analysis of this trial revealed a clinically meaningful difference of 11.7 months for patients treated with 177Lu-DOTATATE plus long-acting octreotide compared to high-dose long-acting octreotide alone.
Midgut neuroendocrine tumour (NETs), also known as carcinoid tumours, are the most common subtype of advanced, well-differentiated gastro-entero-pancreatic NETs (GEP-NETs). The majority of these GEP-NETs express somatostatin receptors, which can be used as a therapeutic target. 177Lu-DOTATATE is a beta-emitting radionuclide coupled to a high-affinity somatostatin analogue. In the primary analysis of the phase III NETTER-1 trial, 177Lu-DOTATATE significantly prolonged progression-free survival (PFS) compared to high-dose long-acting octreotide (HR[95%CI]: 0.18[0.11-0.29], p< 0.0001) in patients with advanced, progressive and well-differentiated somatostatin receptor-positive midgut NETs. Five years after the last patient was randomised, mature overall survival (OS) and long-term safety data were presented at the 2021 ESMO World Congress on Gastrointestinal World Cancer.
NETTER-1 study design
NETTER-1 is open-label, comparator-controlled, phase III trial that randomised (1:1) 231 patients with advanced, inoperable, well-differentiated midgut NETs to receive four administrations of 177Lu-DOTATATE 7.4 GBq (200mCi) every eight weeks (Q8W) plus long-acting octreotide (30 mg) Q4W, or high-dose long-acting octreotide (60 mg) Q4W. Eligible patients were also required to have somatostatin receptor-positive tumours, radiographic progression of disease while taking a fixed dose of long-acting octreotide 20 or 30 mg every 3-4 weeks and a Karnofsky performance status ≥60. The primary endpoint was progression-free survival (PFS) by independent central review, with key secondary endpoints including OS and safety. Following disease progression or completion of an 18-month treatment period, patients entered long-term follow-up. Access to additional anti-cancer therapy, including cross-over, was permitted during this period.
At a median follow-up of 76.3 months in the 177Lu-DOTATATE arm and 76.5 months in the control arm, a total of 142 deaths had occurred. In the intent-to-treat population, treatment with 177Lu-DOTATATE plus octreotide resulted in a numerically superior median OS compared to octreotide alone (48.0 months vs. 36.3 months; HR[95%CI]: 0.84[0.60-1.17], p= 0.30). This difference was not statistically significant, and was likely impacted by the high rate (36%) of cross-over of patients in the control arm to radioligand therapy after progression. Although statistically untested, when accounting for this cross-over, the median OS was found to be 48.0 months with the combination, compared to 30.9 months with octreotide alone (HR[95%CI]: 0.73[0.40-1.34]). With respect to subsequent systemic anti-cancer treatments during long-term follow-up, 21.4% of patients in the 177Lu-DOTATATE and 26.3% of patients in the control arm received anti-neoplastic agents. However, patients in the control arm received radioligand therapy during follow-up at a higher rate, compared to patients in the 177Lu-DOTATATE arm (36% vs. 12%).
Throughout the entire study, the rate of ≥ grade 3 nephrotoxicity in the 177Lu-DOTATATE arm was low and similar to the control arm (5.4% vs. 3.6%, respectively). No patients in the 177Lu-DOTATATE arm reported ≥ grade 3 nephrotoxicity during long-term follow-up. No new cases of myelodysplastic syndrome (MDS) were reported during long-term follow-up. In total, 1.8% of patients treated with 177Lu-DOTATATE developed MDS, including one case of unilineage dysplasia and one case of refractory cytopenia with multilineage dysplasia.
With a median follow-up of more than 6.3 years, the prespecified final OS analysis did not reach statistical significance. However, this was likely impacted by a variety of confounding factors, including 36% cross-over to radioligand therapy in the control arm. The median OS was reported at 48.0 months in the 177Lu-DOTATATE arm as compared to 36.3 months in the control arm and this difference of 11.7 months can be considered clinically meaningful. No new safety signals emerged during long-term follow-up.
Strosberg J, 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 the 2021 ESMO World Congress on Gastrointestinal Cancer; Abstract O2.