Everolimus Plus Lanreotide Demonstrates Potential as First-Line Treatment for Grade 1/2 GEP-NETs

Because limited evidence exists on the benefit of combining somatostatin analogs with molecular targeted agents for the treatment of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs), the phase III STARTER-NET study presented at the American Society of Clinical Oncology 2025 Gastrointestinal Cancers Symposium sought to compare everolimus plus lanreotide (EVE/LAN) with everolimus alone in the first-line setting for patients with unresectable or recurrent GEP-NETs.

A total of 178 patients with grade 1 or 2 nonfunctioning GEP-NETs with poor prognostic factors (defined as a Ki-67 labeling index of 5%-20% or diffuse liver metastasis) were enrolled in the study between April 2020 and June 2024, with a data cutoff date of November 2023. The planned interim analysis was conducted with 145 patients in June 2024. A total of 72 patients received EVE, 10 mg/day, and 73 patients received EVE/LAN, 120 mg, every 28 days.

The primary endpoint was progression-free survival (PFS), and the key secondary endpoint was overall survival (OS). Other secondary endpoints measured included objective response rate (ORR), disease control rate (DCR), and safety. The study was formulated based on the hypothesis of an assumed median PFS of 11 months for EVE and a 4-month improvement with EVE/LAN (hazard ratio [HR], 0.73).

The median PFS was 11.5 months in the EVE arm and 29.7 months in the EVE/LAN arm (HR, 0.38 [99.91% CI, 0.15-0.96]; P=.00017 < prespecified significance level of 0.00046, by stratified log-rank test). The HR for OS was 0.97 (95% CI, 0.24-3.90).

The ORR and DCR were 8.7% (6/69) and 87.0% (60/69) in the EVE arm and 26.8% (19/71) and 91.5% (65/71) in the EVE/LAN arm, respectively. Hematologic and nonhematologic toxicities were found to occur more frequently in the EVE/LAN arm than in the EVE monotherapy arm. No treatment-related deaths occurred in either arm.

The combination of EVE/LAN can significantly prolong PFS in patients with well-differentiated grade 1/2 GEP-NETs with poor prognostic factors compared with EVE alone. With a manageable safety profile, EVE/LAN may serve as a new standard first-line treatment for this patient population.