Everolimus Plus Octreotide LAR Is Effective in Advanced Neuroendocrine Tumors

Combination therapy with the oral mammalian target of rapamycin (mTOR) inhibitor everolimus and the somatostatin analogue octreotide long-acting repeatable (LAR) increases the median progression-free survival (PFS) in patients with advanced neuroendocrine tumors associated with carcinoid syndrome, according to the results of the multicenter, phase III RADIANT-2 study.

Marianne E. Pavel, MD, with the Charité-Universitätsmedizin Berlin in Germany, and colleagues elsewhere randomized 429 patients to treatment with 10 mg everolimus once daily or matching placebo, both in conjunction with intramuscular injection 30 mg octreotide LAR every 28 days. Treatment continued until disease progression, withdrawal from treatment because of adverse events, or withdrawal of consent.

Study participants had low- or intermediate-grade advanced neuroendocrine tumors with a history of symptoms due to carcinoid syndrome and radiologically confirmed disease progression within the previous 12 months. Tumors were located in the small intestine in about half of patients in both treatment groups; the rest of the patients had tumors at different sites in the gut and lung.

“Treatment of advanced neuroendocrine tumors remains a clinical challenge because of the lack of effective options and the absence of well-controlled randomized clinical trial data to support evidence-based practice,” according to the authors. “With few exceptions, chemotherapeutic drugs are not active in advanced non-pancreatic neuroendocrine tumors and are associated with substantial toxic effects. Thus, there is a need for new treatment options.”

Everolimus had shown promising antitumor activity in patients with advanced neuroendocrine tumors in 2 phase II studies.

The median PFS by central review was 16.4 months (95% CI, 13.7-21.2) in the everolimus plus octreotide LAR group and 11.3 months (95% CI, 8.4-14.6) in the placebo plus octreotide LAR group (hazard ratio, 0.77; 95% CI, 0.59-1.00; 1-sided log-rank test; P = .026).

While the study did not meet its prespecified significance boundary on the P-value scale of .0246, the 5.1-month prolongation in PFS observed with everolimus plus octreotide LAR is “clinically meaningful,” the researchers noted.

In addition, patients in the everolimus group demonstrated a reduction in circulating chromogranin A and 5-hydroxyindoleacetic acid, which are neuroendocrine markers of carcinoid.

Drug-related adverse events were usually grade 1 or 2. Adverse events of all grades in the everolimus plus octreotide LAR group versus the placebo plus octreotide LAR group included: stomatitis (62% vs 14%, respectively); rash (37% vs 12%, respectively); fatigue (31% vs 23%, respectively); and diarrhea (27% vs 16%, respectively).

Pavel and colleagues said that their findings, when coupled with the results of the RADIANT-3 trial of everolimus in patients with advanced pancreatic neuroendocrine tumors, demonstrated the efficacy of everolimus in a broad spectrum of advanced neuroendocrine tumors.