177Lu-DOTATATE prolongs progression-free survival in previously treated advanced GEP-NETs

As presented at the ESMO Asia Congress 2025 (Singapore, 5–7 December), the LUMINET-1 study reported highly positive findings, confirming that ¹⁷⁷Lutetium (Lu)-DOTATATE has a place in the treatment not just of grade 2 or 3 gastroenteropancreatic neuroendocrine tumours (GEP-NETs) – as reported in the NETTER-2 combination trial in mainly Western patients (Lancet. 2024;403:2807–2817) – but also in lower grade GEP-NETs (LBA3).

In the study, peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE led to a 94% improvement in the primary endpoint – progression-free survival (PFS) – compared with high-dose long-acting octreotide (hazard ratio [HR] 0.06; 95% confidence interval [CI] 0.03–0.13; p<0.001) among 203 treated patients with unresectable advanced grade 1 or 2 somatostatin receptor-positive GEP-NETs who had progressed on standard-dose octreotide.

“NETs used to be thought of as a rare disease in Asia, but today the incidence is rising and many new cases are GEP-NETs,” says Prof. Stephen Chan from the Chinese University of Hong Kong, Hong Kong SAR, China. “The trial demonstrates convincingly that ¹⁷⁷Lu-DOTATATE is effective as monotherapy, the results being particularly impressive given the hazard ratio of 0.06.” Median PFS was only 5.6 months in the control arm at a 9-month median follow-up, but was not reached after a median of 10.6 months in the experimental arm.

The PFS benefit of ¹⁷⁷Lu-DOTATATE was evident across pre-specified demographic and prognostic subgroups, including age, sex, primary tumour location and number of prior lines of therapy. ¹⁷⁷Lu-DOTATATE also improved rates of objective response (40.0% versus 2.0%) and disease control (93.3% versus 62.2%). While overall survival data are immature, there was a trend towards a considerable reduction in the risk of death with ¹⁷⁷Lu-DOTATATE (HR 0.17; 95% CI 0.04–0.79; p=0.0106).

Tolerability results did not reveal any unexpected findings. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 39.0% of patients receiving ¹⁷⁷Lu-DOTATATE and 4.1% receiving octreotide. The most common TRAEs with PRRT were haematological events, including reductions in the counts of white blood cells (53.3%), lymphocytes (44.8%) and platelets (43.8%).

Chan points out some of the challenges facing PRRT in the clinic, including the practicalities of implementing therapy, which requires close collaboration between oncologists and nuclear medicine specialists along with a high degree of expertise, and the need for more information on the absolute magnitude of survival benefit and long-term toxicity. Looking to future radionuclide therapies, he notes: “Investigation of alpha particle-emitting agents, such as ²²⁵Actinium (²²⁵Ac), which have the potential for greater tumour penetration than beta-emitting agents like ¹¹⁷Lu, is a very exciting direction for PRRT.” Preliminary completion of the phase III ACTION-1 study of ²²⁵Ac-DOTATATE in patients progressing on ¹⁷⁷Lu-based PRRT is expected by the end of 2025 (NCT05477576). Targeted therapies, such as the multitargeted tyrosine kinase inhibitor zanzalintinib, which is under phase III investigation in the STELLAR-311 trial (NCT06943755), may be another possible option for patients whose tumours progress on previous treatment.