TOPLINE:

Axitinib combined with octreotide long-acting release (LAR) significantly improved progression-free survival (PFS) per blinded independent central review (BICR) and objective response rate in patients with advanced extrapancreatic neuroendocrine tumors (epNETs). But the primary endpoint of investigator-assessed progression-free survival was not met.

METHODOLOGY:

• NETs often have a rich vascular network, and aberrant Von Hippel-Lindau/hypoxia inducible factor signaling has been involved in NET pathogenesis, providing rationale for investigating antiangiogenic tyrosine kinase inhibitors. Axitinib is a potent and selective inhibitor of vascular endothelial factor receptor-1 (VEGFR-1), VEGFR-2, and VEGFR-3, with a phase II study suggesting activity in epNETs.
• Researchers conducted an international, randomized, double-blind, placebo-controlled, phase II/III trial (AXINET, GETNE 1107) in 27 hospitals across Spain, Italy, and Germany from October 2011 to May 2019, enrolling 256 patients with unresectable or metastatic grade 1-2 epNETs.
• Patients were randomly assigned 1:1 to receive either axitinib 5 mg orally twice daily or matching placebo, both combined with octreotide LAR 30 mg intramuscularly once every 28 days until disease progression or unacceptable toxicity.
• Randomization was stratified by primary tumor site (gastrointestinal vs other locations), Ki-67 index (≤ 5% or > 5%), and time from diagnosis (≤ 12 months or > 12 months).
• The primary endpoint was investigator-assessed PFS, with secondary endpoints including BICR-assessed PFS, objective response rate, duration of response, biochemical response, overall survival, and safety.
• Tumor assessments using computed tomography or magnetic resonance imaging were performed at baseline and every 12 weeks until disease progression, evaluated locally by investigators using RECIST 1.1 criteria and retrospectively by BICR in 243 patients (94.9%).

TAKEAWAY:

• BICR-assessed median PFS was significantly longer with axitinib compared with placebo (16.6 months vs 9.9 months; hazard ratio [HR], 0.71; 95% CI, 0.54-0.94; P = .017).
• Investigator-assessed median PFS showed no significant difference between axitinib and placebo groups (17.2 months vs 13.1 months; HR, 0.86; 95% CI, 0.65-1.15; P = .324).
• Objective response rate was significantly higher with axitinib than with placebo per investigator assessment (17.5% vs 4.6%; P = .001) and BICR assessment (12.8% vs 3.2%; P = .005).
• Most common grade ≥ 3 treatment-related adverse events in the axitinib group were hypertension (24.0% vs 9.2% in placebo) and diarrhea (13.6% vs 1.5% in placebo).

IN PRACTICE:

“Axitinib significantly increased PFS per BICR assessment and [objective response rate] both per investigator and BICR assessment compared with placebo, although the primary study end point was not met. Toxicity profile was manageable with no new safety concerns,” the authors of the study wrote.

SOURCE:

The study was led by Rocio Garcia-Carbonero, MD, PhD, Hospital Universitario 12 de Octubre in Madrid, Spain. It was published online on February 20 in Journal of Clinical Oncology.

LIMITATIONS:

According to the authors, the study had limited geographic representativeness, with 89% of patients from Spain, restricting generalizability to other European regions or ethnicities. The study was initiated before approval of everolimus, cabozantinib, and radioligand therapy, and octreotide LAR was chosen as backbone therapy based on the PROMID study, leading to inclusion of treatment-naive patients (44.9%) earlier in disease course, which resulted in PFS rates in the control group exceeding initial estimations and limiting statistical power. The median follow-up was relatively short for the study timeframe due to slow initial accrual and faster accrual in final years when expanded to phases II-III. Retrospective BICR assessment was conducted in 94.9% of patients rather than prospectively due to limited financial support at study initiation. The biological and clinical heterogeneity of epNETs made imbalance of relevant prognostic factors difficult to avoid despite adequate randomization stratification, with higher proportions of patients with Eastern Cooperative Oncology Group Performance Status ≥ 1, male sex, grade 2 tumors, high baseline lactate dehydrogenase or chromogranin A, and lung and colorectal primary tumors in the axitinib arm potentially negatively biasing outcomes.

DISCLOSURES:

This study received financial support from Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE) with funding provided by Pfizer. Garcia-Carbonero disclosed receiving honoraria from Ipsen, Sanofi, PharmaMar, Bayer, MSD, Takeda, Merck, Hutchmed, BMS, Boehringer Ingelheim, Esteve, Astellas Pharma, Advanced Accelerator Applications/Novartis, Crinetics Pharmaceuticals, GlaxoSmithKline, Isotopen Technologien, and Novocure; research funding from Pfizer, MSD, and BMS; and travel accommodations and expenses from Merck, MSD, Ipsen, Esteve, and Advanced Accelerator Applications/Novartis. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.