A phase 2/3 randomized, double-blind study of axitinib in combination with octreotide acetate has shown activity and tolerable safety in patients with grade 1 or 2 gastric neuroendocrine tumors (NETS) of non-pancreatic origin, according to a study presented by Rocio Garcia-Carbonero MD, PhD, Hospital Universitario Doce de Octubre, Madrid, Spain, at the virtual 2021 ASCO Gastrointestinal Cancers Symposium (J Clin Oncol. 2021;39[suppl 3]:abstr 360).

“Angiogenesis plays an important role in NET development and progression. Axitinib is a potent and selective VEGFR-1,2,3 inhibitor, with proven activity against several vascular-dependent solid tumors. The aim of this randomized, double-blind phase II/III study was to assess the efficacy of axitinib in patients with advanced G1-2 extra-pancreatic NET,” explained Dr Garcia-Carbonero and colleagues.

Researchers randomized eligible patients in a 1:1 ratio to receive octreotide LAR (30 mg IM q4w) with axitinib (5mg twice daily) or with a placebo twice daily until they experienced disease progression or unacceptable toxicity. Patients were arranged by time from diagnosis to study entry ( > or <12 m), primary tumor site (GI tract vs non-GI) and Ki-67 index (< 5% vs >5%).

Although prior vascular endothelial growth factor (VEGFR)- or VEGFR-targeted drugs were not allowed, prior therapy with somatostatin analog (SSA), interferon therapy (IFN), and up to 2 lines of systemic treatment were. Another requirement included clinical and/or radiological disease progression within 12 months before study entry.

The primary end point was progression-free survival (PFS), while secondary end points included overall survival (OS), time to progression, overall response rate (ORR), duration of response, biochemical response, and safety. 

A total of 256 patients were included in this study (106 from phase 2 and 150 additional patients in the phase 3 part) 126 were randomized to axitinib and 130 to placebo. The median age in patients was 61 years (range: 21-85), over half of whom were male; 29% and 71% were grades 1 and 2, respectively, the most common primary tumor site was gastrointestinal (40%), and prior therapies included: SSA (46%), everolimus (13%), chemotherapy (13%), TACE (5%) and PRRT (2%).

Although results showed that PFS per investigator assessment favored axitinib over placebo-treated patients, the difference was not enough to reach statistical significance (median PFS, 17.2 vs 12.3 months, respectively, HR, 0.816; P = .169). Howbeit, the ORR was significantly higher in the axitinib group compared to the placebo-treated group (17.5 vs 3.8%; P = .0004).

Treatment-related AEs of grades 3 and 4 were more common in the axitinib arm versus the placebo arm (52% vs 13.8%), with the most common being hypertension (21% vs 6 %), cardiac disorders (3.2% vs 0.7%), diarrhoea (13% vs 1.5 %), asthenia (9% vs 3%) and nausea/vomiting (2% vs 0.7%). Treatment-related deaths did occur, 1 in the axitinib arm as a result of cardiac failure, and 2 in the placebo arm due to myocardial infarction and hepatorenal syndrome.

“Although the study failed to demonstrate a significant PFS benefit per investigator assessment, axitinib in combination with octreotide LAR demonstrated activity and had a tolerable safety profile in patients with advanced G1-2 extra-pancreatic NETs. Database cleaning and central blinded radiological PFS assessment are currently ongoing,” concluded Dr Garcia-Carbonero et al. —Alexandra Graziano