Carcinomas of the salivary glands (SGCs) are rare, (less than 1% of all cancers of the head and neck and include more than 20 malignant histotypes). They can occur both in major and minor salivary glands, are locally aggressive, demonstrating invasiveness that leads to involvement of the facial nerve, skin, bone and surrounding soft tissue. The standard treatment is surgical excision, followed by radiotherapy in selected cases such as high-grade histotypes, advanced disease and neck nodes diffusion. Loco-regional recurrence occurs in 16% to 85%, it can be managed in very selected cases with further surgery and/or radiotherapy, although the prognosis of these patients remains poor. Adenoid cystic cancer (ACC) is the most common SGC histotype observed in metastatic subjects (60%), while the other histotypes (non-ACC) such as mucoepidermoid cancer (MEC), salivary duct gland cancer, adenocarcinoma, myoepithelial carcinoma are more uncommon. Distant metastases are the principal cause of failure, being diagnosed in 25-55% of the patients. Only 20% of the patients with distant metastases is alive at 5 years. First-line treatment is palliative chemotherapy that is typically not associated with solid data showing any benefit neither in response rate nor in outcome. Very recently a phase II trial with sorafenib has been carried out in 37 subjects (19 ACC and 18 non-ACC) with recurrent and/or metastatic SGCs. Interestingly, a response rate of 16% (95% CI 6,2-32,0) was observed, 11% in ACC and 22% in non-ACC cases with two outstanding responses in patients with an high-grade MEC. In one case the metastatic lesion evolved in a cavitation as observed with antiangiogenic agents. In preclinical models, VEGF seems to contribute to tumor aggressiveness as well as to distant metastatization of SGCs, in particular in ACC and MEC. Remarkably three confirmed partial responses, one ACC, one renal cancer and one lung cancer, on 36 patients were observed in a phase I study with Inlyta®. These results prompted a phase II study to test the activity of axitinib in relapsed and/or metastatic and progressive ACC patients. Results were 9% of partial responses and 75% of stable disease as best overall response. Inlyta®, a potent VEGFR specific-inhibitor, has been approved by FDA as second line treatment for renal cancer. Based on preclinical and clinical data, we believe that targeting VEGFR might represent a rational basis to further test Inlyta® in patients with relapsed and/or metastatic ACC but also in subjects with recurrent/metastatic non-ACC .

Open-label, monocentric, single arm phase II study evaluating the activity and safety of axitinib in recurrent and/or metastatic tumors of salivary gland. 26 patients with histologically proven relapsed or metastatic SGC, progressed within 6 months at study entry will be enrolled over two years. A 2-stage Simon design will be applied: 15 patients enrolled into step one and if a least 1/15 response is observed, 11 additional patients will be enrolled into second step. Axitinib will be administered orally at 5 mg twice daily to patients for the first two weeks. Patients who tolerate axitinib with no adverse events axitinib-related should have a dose increased until to 10 mg twice. The drug will be taken until progression of disease or intolerable toxicity. Tissue paraffin block from primary lesion or metastasis will be collected for CRTC1-MAML2 translocation analysis in MEC; MYB-NFIB translocation analysis in ACC; androgen receptor and HER2 analysis in SDC and adenocarcinoma NOS.