In patients with aggressive gastroenteropancreatic neuroendocrine tumors, first-line treatment with the mTOR inhibitor everolimus and the somatostatin analog lanreotide more than doubled the median progression-free survival for patients vs everolimus alone, in the phase III JCOG1901 (STARTER-NET) trial conducted in Japan.¹

“Everolimus plus lanreotide has the potential to become a new standard first-line treatment of patients with unresectable or recurrent gastroenteropancreatic neuroendocrine tumors in the poor-prognostic population.”

— SUSUMU HIJIOKA, MD, PhD

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“Everolimus plus lanreotide has the potential to become a new standard first-line treatment of patients with unresectable or recurrent gastroenteropancreatic neuroendocrine tumors in the poor-prognostic population,” said Susumu Hijioka, MD, PhD, of the Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo.

Background

ASCO expert Laura B. Vater, MD, MPH, Assistant Professor of Clinical Medicine at Indiana University School of Medicine, explained that for patients with metastatic, well-differentiated grade 1 and 2 tumors and a low tumor burden, careful observation or somatostatin analogs are considered. For those with a clinically significant tumor burden, somatostatin analogs or alternative front-line therapies are standard. Typically, in the United States, everolimus is used in the second-line setting. There are currently no data to support a specific sequence of systemic therapy options.

Laura B. Vater, MD, MPH

Dr. Hijioka noted that monotherapy with everolimus has been shown to prolong progression-free survival in patients with advanced gastroenteropancreatic neuroendocrine tumors, although median progression-free survival is less than 1 year. For patients with poor prognostic factors, treatment is even less effective. The use of lanreotide has similarly been shown to extend remission. Whether these drugs given together might improve upon these outcomes has been unclear. STARTER-NET was designed to address that question.

Study Details and Results

This trial enrolled 178 patients with unresectable or recurrent grade 1 or 2 gastroenteropancreatic neuroendocrine tumors with poor prognostic factors, primarily high Ki67 levels (5%–20% or < 5% with diffuse liver metastases), and no prior treatment. Patients were randomly assigned to receive everolimus monotherapy (10 mg/d) or everolimus plus lanreotide (120 mg every 28 days) until disease progression or unacceptable toxicity.

At a preplanned interim analysis in June 2024, median progression-free survival was 11.5 months with monotherapy vs 29.7 months with the combination therapy. Based on the efficacy results, the trial was terminated early. The final outcome, as of November 2024, showed a median progression-free survival of 29.7 months with everolimus plus lanreotide vs 13.6 months with the single agent (hazard ratio = 0.44; P = .00016). Outcomes were consistently better with the combination therapy in key subgroups, including by primary tumor site (pancreatic or gastrointestinal tract), age, and Ki67 index.

For everolimus plus lanreotide vs everolimus alone, the response rates were 23.0% and 8.3% (P = .011), respectively, with disease control rates of 92.0% and 84.5%, respectively. Overall survival is immature, with the medians not reached in either arm; 1-year overall survival rates were 96.2% with the combination and 97.0% with monotherapy.

Safety Profile

The combination was associated with more adverse events; the grade ≥ 3 nonhematologic toxicity rate was 35.6% vs 14.9%, respectively. Hyperglycemia, oral mucositis, and fatigue were among the most common toxicities associated with the combination, but severe adverse events were similar; grade ≥ 3 stomatitis rates were 15% and 10%, and interstitial lung disease occurred in 5% and 3%, respectively. Overall, Dr. Hijioka said, the toxicities associated with everolimus plus lanreotide were manageable and “within acceptable limits.”

DISCLOSURE: Dr. Hijioka has received honoraria from Novartis and Teijin Pharma Ltd. Dr. Vater disclosed a financial relationship with GoodRx and MDLinx.

REFERENCE

1. Hijioka S, Honma Y, Machida N, et al: A phase III study of combination therapy with everolimus plus lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumor (JCOG1901, STARTER-NET). 2025 ASCO Gastrointestinal Cancers Symposium. Abstract 652. Presented January 24, 2025.

EXPERT POINT OF VIEW

Discussant of the STARTER-NET trial, Shagufta Shaheen, MD, Clinical Assistant Professor of Medicine at Stanford University School of Medicine, described the key clinical trials of the various treatments of gastroenteropancreatic neuroendocrine tumors, noting that the differences in study populations, line of treatment, and other factors make direct comparisons among treatments challenging. Looking generally at the outcomes achieved with everolimus and lanreotide, she called STARTER-NET “a promising study but not practice-changing.”

Shagufta Shaheen, MD

Dr. Shaheen noted that the greatest effect with the combination therapy was in patients with Ki67 > 10%. However, for those with a lower Ki67 index, the somatostatin analog achieved “comparable or better progression-free survival.”

The combination in the study was associated with more grade ≥ 3 hyperglycemia (9% vs 1%), fatigue (6% vs 1%), oral mucositis (8% vs 5%), and pneumonitis (3% vs 1%) as well as more diarrhea and anorexia of any grade. “Even if [the combination] improved progression-free survival, since adverse events are worse, its true value in the first-line setting is unknown,” she said. “Even if progression-free survival is improved, when we do a risk/benefit analysis in choosing therapy, we always consider adverse events and especially quality of life, which is missing in this study.”

Dr. Shaheen proposed that this combination might best be considered in high-risk patients, including those with a Ki67 level higher than 10% to 20%, and in patients for whom a tumor response is the objective. Among these patients could be those with nonpancreatic or hindgut neuroendocrine tumors.

DISCLOSURE: Dr. Shaheen has served as a consultant or advisor to Crinetics Pharmaceuticals and Exelixis and has received reimbursement for travel from DAVA Oncology.