Study of Axitinib in Patients With Recurred or Metastatic Adenoid Cystic Carcinoma

Adenoid cystic carcinoma (ACC) is a rare variant of adenocarcinoma that occurs in secretory glands such as in salivary glands. Although ACC is histologically low grade and slow-growing, more than half of patients eventually have recurrent and/or metastatic disease.

The natural course of metastatic disease with ACC is relatively indolent; however, most patients with metastatic disease ultimately die from their cancer. The management of recurred / metastatic ACC is a distinct therapeutic challenge because of its insidious local growth pattern, propensity for perineural involvement, tendency for distant metastasis, and pronounced ability to recur over a prolonged period.

1. Current treatment

The role of systemic chemotherapy in ACC is very limited and objective response to any cytotoxic or molecular targeted agent is infrequent, and the optimum regimen is unclear. Because of the rarity of ACC, there are few clinical trials investigating the efficacy of systemic chemotherapy. Recurrent/metastatic ACC is an incurable disease with no standard treatments.

VEGF is highly expressed in ACC and its expression correlates with stage, tumor size, vascular invasion, recurrence and metastasis. High expression of VEGF and Ki-67 were independent poor prognostic factors in ACC. MYB/NFIB translocation has recently identified in ACC and MYB protein over expression was found in ACC. MYB over-expression in ACC has been correlated to the increased expression of genes involved in vascular endothelial growth factor (VEGF), KIT . More than 70% of ACCs highly express the oncogenic transcription factor c-myb, which drives expression of genes that activate VEGFR and c-kit pathways.

Several lines of evidence suggest a function for VEGF, PDGFR signaling in ACC progression. The expressions of NF-kappaB p65, iNOS, and VEGF were related with microvessel density. In vitro, the inhibition of VEGF expression via iNOS gene induced apoptosis of ACC cell lines.

Axitinib (AG-013736; Pfizer) is a multi-targeted small-molecule inhibitor of the receptor tyrosine kinases involved in tumor proliferation and angiogenesis, including VEGFR-1, VEGFR-2 and VEGFR-3, c-kit, platelet-derived growth factor receptor (PDGFR)-α and PFGFR-β. Axitinib (AG-013736) has demonstrated a partial response lasting 4 months in one patient with ACC in a phase I trial . In that aspect, Ho et al. conducted phase II study with axitinib in ACC. Interestingly, response rate was 9.1% and tumor shrinkage was observed in 66.7%

Besides of axitinib, other antiangiogenic agents such as sutene or dovitinib showed promising activity in ACC. Dovitinib, which is pan FGFR , VEGF, PDGFR inhibitor showed one confirmed partial response PR (3.1%) and three unconfirmed PR (9.3%). Interestingly, hyperphosphatemia was not observed in this study, and one PR patients showed strong PDGFR beta positivity, which suggests that antiangiogenic pathway is more important than FGFR pathway.

1. Gap, issue or problem that needs to be addressed

Based on these evidences which suggest a function for VGFR, PDGFR signaling in ACC tumorigenesis and progression, the use of axitinib is reasonable and valuable.

However, the huge gap in ACC trial is lack of randomization trial. Until now, there is no randomized trial in ACC because of its rarity. Hence there is no confirmatory trial in ACC. Without randomization trial, we can not say the real efficacy of axitinib.

So we design multicenter randomized trial of axtinib in ACC to confirm the efficacy of axitinib in this orphan disease.