Drug Combo for Common Neuroendocrine Tumor: A New Standard?

Adding the somatostatin analog lanreotide to the mTOR inhibitor everolimus significantly prolonged progression-free survival in patients with unresectable or recurrent gastroenteropancreatic neuroendocrine tumors compared with everolimus alone. 

This combination has “the potential to become a new standard first-line treatment” for well-differentiated grade 1/2 gastroenteropancreatic neuroendocrine tumors with poor prognostic factors, said Susumu Hijioka, MD, from the Department of Hepatobiliary and Pancreatic Oncology at the National Cancer Center, Tokyo, Japan.

Once considered rare, these tumors are becoming more common, said Hijioka, who reported the results of the phase 3 STARTER-NET trial at the 2025 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco. 

The standard treatment for grade 1 or 2 nonfunctional, unresectable gastroenteropancreatic neuroendocrine tumors is monotherapy with a targeted therapy, everolimus, or a somatostatin analog.

Earlier reports have suggested a benefit to combining everolimus with a somatostatin analog in this patient population.

However, the combination of lanreotide and everolimus has not previously been studied, ASCO exert Laura Vater, MD, MPH, with Indiana University Simon Cancer Center, Indianapolis, said in a statement.

“Establishing this new treatment option benefits patients by expanding their therapeutic choices and potentially improving their prognosis and quality of life,” Vater said. 

At the meeting, Hijioka reported an interim analysis of 145 patients from STARTER-NET. Patients had histologically proven grade 1 or 2 unresectable metastatic or recurrent gastroenteropancreatic neuroendocrine tumors. Additional inclusion criteria included an ECOG performance status of 0 to 2, and Ki-67 index of 5% to 20% or Ki-67 index less than 5% with diffuse liver metastases. 

Patients were randomly allocated (1:1) to everolimus monotherapy (10 mg/d) or to the combination of everolimus (10 mg/d) and lanreotide (120 mg every 28 days). 

Median progression-free survival (the primary outcome) was 29.7 months in the everolimus plus lanreotide group vs 11.5 months in the everolimus monotherapy group (stratified hazard ratio, 0.38). The predictive probability of showing superiority of combination therapy was 98.1%. Based on the efficacy results, the trial was terminated early. 

The objective response rate was 23.0% with the combination vs 8.3% with everolimus monotherapy, and the disease control rate was 92% and 84.5%, respectively, in the two groups.

The 1-year survival rate was similar between the two groups — 96.2% in the everolimus plus lanreotide group and 97.0% in the everolimus monotherapy group.

Toxicities and Adverse Events

A total of 13 events were observed; there were 11 deaths from the primary disease, one death from another disease, and one from an unknown cause, but no treatment-related deaths were reported.

Both hematologic and nonhematologic toxicities tended to be more frequent in the combination group. 

Adverse events of grade 3 or higher occurred in 35.6% of patients in the everolimus plus lanreotide group and 14.9% of patients in the everolimus group. The most common of these were hyperglycemia (9.1% with combination therapy and 1.1% with monotherapy), oral mucositis (8.0% and 4.6%, respectively), and fatigue (5.7% and 1.1%, respectively). 

Briefing moderator Julie Gralow, MD, ASCO chief medical officer, said this is a “very nice study and an advancement for these cancers.”

She noted that lanreotide and everolimus are both separately approved by the US Food and Drug Administration for use in gastroenteropancreatic neuroendocrine tumors. Now with this study showing a benefit of combined use, “the question will be whether the combination will be covered by payers.”

Hijioka had no disclosures. Vater disclosed relationships with GoodRx and MDLinx. Gralow has had consulting or advisory roles in Genentech/Roche.