A phase II/III randomized double-blind study of octreotide acetate LAR with axitinib versus octreotide acetate LAR with placebo in patients with advanced G1-G2 NETs of non-pancreatic origin (AXINET trial-GETNE-1107).

Abstract

360 Background: 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 NETs. Methods: Eligible pts were randomized (1:1) to receive octreotide LAR (30 mg IM q4w) with axitinib (5 mg BID) or placebo BID until disease progression or unacceptable toxicity. Pteswere stratified by time from diagnosis to study entry ( > or < 12m), primary tumor site (GI tract vs non-GI) and Ki-67 index (< 5% vs > 5%). Prior therapy with SSA, IFN and up to 2 lines of systemic treatment was allowed, but not prior VEGF- or VEGFR-targeted drugs. Clinical and/or radiological disease progression within 12 months prior to study entry was required. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), time to progression, overall response rate (ORR), duration of response, biochemical response and safety. Results: 256 pts were randomized (106 in the Phase II part, and 150 additional pts in the Phase III part), 126 to axitinib and 130 to placebo. The main characteristics of the study population were: median age 61 years (range: 21-85), 52% male, PS 0-1 (64-35%), G1-2 (29%-71%), primary tumor site GI (40%)-Lung (17%)-Other (32%). Prior therapies included: SSA (46%), everolimus (13%), chemotherapy (13%), TACE (5%) and PRRT (2%). ORR was significantly higher in axitinib- vs placebo-treated patients (17.5% vs 3.8%, p = 0.0004). PFS per investigator assessment also favored axitinib vs placebo-treated patients, although the difference did not reach statistical significance (median PFS 17.2 vs 12.3 months, respectively, HR 0.816, p = 0.169). Grade 3-4 treatment-related AEs occurred more frequently in the axitinib vs placebo arm (52% vs 13.8%), and included 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%). There were 3 treatment-related deaths, 1 in the axitinib arm (cardiac failure) and 2 in the placebo arm (myocardial infarction and hepatorenal syndrome). Conclusions: 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. Data base cleaning and central blinded radiological PFS assessment are currently ongoing. Clinical trial information: NCT01744249.

Cardiovascular Toxicities Secondary to Biotherapy and Molecular Targeted Therapies in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials

“…Significant heterogeneity was observed across the subset of studies on TKI (I 2 = 89.8%, p -value < 0.0001; Figure 2 ). A funnel plot was also produced demonstrating asymmetry ( Figure S1A ), that was mainly attributed to the recent studies on novel TKIs by Xu et al on surufatinib in pancreatic NENs and by Carbonero et al on axitinib in extra-pancreatic NENs (Galbraith’s plot; Figure S1B ) [ 29 , 30 ]. Egger’s test showed no indication of publication bias across the included studies ( p -value > 0.05).…”

Personalized functional profiling using ex-vivo patient-derived spheroids points out the potential of an antiangiogenic treatment in a patient with a metastatic lung atypical carcinoid

“… 19–21 These investigations led to the FDA approval of sunitinib in treating progressive, well-differentiated pancreatic NET for patients with locally advanced or metastatic disease. 22 Although no antiangiogenic drugs have been granted FDA approval for NET of pulmonary origin yet, several clinical trials have already demonstrated their activity in this indication, as illustrated by the results of studies investigating surufatinib, 20 axitinib, 23 pazopanib, 24 and bevacizumab 25 in NET. Nevertheless, no general treatment recommendation can be issued at this stage regarding the use of antiangiogenic drugs in NET of pulmonary origin.…”

Bronchial Carcinoids: From Molecular Background to Treatment Approach

“…The efficacy of surufatinib in the US population was assessed in pancreatic NETs and in the European population is currently under research in an open-label phase 2 study (NCT04579679) with different cohorts of patients (Cohort A: NETs of lung origin; Cohort B: NETs of small bowel origin; Cohort C: NETs of non-small bowel, non-pancreas, and non-lung origin; Cohort D: NETs of any origin, DDI substudy) [104] (Table 3). The role of axitinib has been assessed in the AXINET phase II/III study [92] conducted in patients with advanced G1-G2 non-pancreatic NETs, including 71 patients with lung NETs. Patients were randomized (1:1) to receive octreotide LAR with axitinib or placebo.…”