The combination of everolimus (Afinitor) and lanreotide (Somatuline) has demonstrated a significant improvement in progression-free survival (PFS) compared to everolimus monotherapy in patients with unresectable or recurrent gastroenteropancreatic neuroendocrine tumors (GEP-NETs). These findings from the phase 3 STARTER-NET trial (jRCT1031200023) were presented at a press briefing prior to the 2025 Gastrointestinal Cancers Symposium, potentially establishing a new first-line treatment option for this patient population.
Improved Progression-Free Survival
The interim analysis, conducted in June 2024, revealed a median PFS of 29.7 months (95% CI, 20.5-not evaluable) in the everolimus plus lanreotide group, compared to 11.5 months (95% CI, 9.0-19.8) in the everolimus monotherapy group. This represents a significant difference, with a stratified hazard ratio of 0.38 (99.91% CI, 0.15-0.96; one-sided P = .00017).
Overall Survival and Response Rates
While the median overall survival (OS) analysis conducted in November 2024 was not evaluable in either group, the 1-year survival rate was 96.2% (range, 88.8%-98.8%) in the combination group and 97.0% (range, 88.4%-99.2%) in the everolimus group. The hazard ratio for OS was 0.74 (95% CI, 0.25-2.24).
The objective response rate (ORR) was also significantly higher in the combination group, with 23.0% (95% CI, 14.6%-33.3%) compared to 8.3% (95% CI, 3.4%-16.4%) in the everolimus group (P = .011). The disease control rate (DCR) was 92.0% (95% CI, 84.1%-96.7%) and 84.5% (95% CI, 75.0%-91.5%), respectively (P = .16).
Expert Commentary
According to Susumu Hijioka, MD, from the Department of Hepatobiliary and Pancreatic Oncology at the National Cancer Center, the combination of lanreotide and everolimus significantly prolonged PFS in a poor prognostic population of grade 1 or 2 gastroenteropancreatic neuroendocrine tumors, with a manageable toxicity profile. He stated that this combination has the potential to become a new standard first-line treatment for patients with unresectable or recurrent GEP-NETs.
Laura Vater, MD, MPH, assistant professor of clinical medicine at Indiana University Simon Cancer Center, noted that while lanreotide and everolimus have each previously demonstrated the ability to extend PFS in patients with GEP-NETs, the combination treatment was previously unstudied. She added that establishing this new treatment option benefits patients by expanding their therapeutic choices and potentially improving their prognosis and quality of life.
Trial Design and Patient Population
The STARTER-NET trial randomly assigned 250 patients in a 1:1 ratio to either everolimus at 10 mg/day plus lanreotide at 120 mg every 28 days or everolimus monotherapy at 10 mg/day. Patients were required to be 20 years or older with histologically proven grade 1 or 2 GEP-NETs that were unresectable, metastatic, or recurrent. Additional criteria included an ECOG performance status of 0 to 2, no prior history of treatment for metastatic or recurrent disease, and a Ki-67 index of 5% to 20% or a Ki-67 index of less than 5% with diffuse liver metastases.
Safety Profile
Adverse events (AEs) of grade 3 or higher occurred in 35.6% of patients in the everolimus and lanreotide group and 14.9% in the everolimus group. The most common AEs of any grade were oral mucositis (62.1% and 67.8%, respectively), hyperglycemia (62.1% and 33.3%), and diarrhea (36.8% and 26.4%). The most common grade 3 or higher AEs were hyperglycemia (9.1% and 1.1%), oral mucositis (8.0% and 4.6%), and fatigue (5.7% and 1.1%). The trial was terminated early due to efficacy.
