Randomized Phase II Study of Axitinib Versus Observation in Patients with Recurred or Metastatic Adenoid Cystic Carcinoma

Abstract

BACKGROUND: Adenoid cystic carcinoma (ACC) does not respond to cytotoxic chemotherapy. While several anti-angiogenic agents have been evaluated in single-arm phase II trials, the role of chemotherapy is still controversial because ACC is usually stable without chemotherapy and lack of randomized trials. Here, we conducted the first randomized trial to evaluate the efficacy of axitinib as compared to observation in ACC. \n \nMETHODS: In this multicenter, prospective phase II trial, we enrolled recurred, metastatic ACC patients who had progressed within the past 9 months. Patients were randomly assigned to either axitinib (5 mg twice daily) or observation at a 1:1 ratio. Crossover from observation to axitinib was permitted for patients who showed progression. The primary endpoint was a 6-month progression-free survival (PFS) rate. The secondary endpoints included objective response rate (ORR), overall survival (OS), PFS, duration of response, and adverse events. \n \nFINDINGS: Sixty patients were randomly allocated to axitinib or observation, with response evaluation conducted in 54 patients. With a median follow-up of 25.4 months, the 6-month PFS rate was 73.0% with axitinib and 23.0% with observation. Median PFS was significantly different ( P < 0.001) between the two arms. The ORR of axitinib was 0.0%. The disease control rate was 100.0% with axitinib and 51.9% with observation. After crossover, ORR of axitinib in the observation arm was 11.5%. Median OS was not reached with axitinib versus 27.2 months with observation ( P = 0.226). The most frequently reported adverse events for axitinib were oral mucositis and fatigue. \n \nINTERPRETATION: In this first randomized trial in patients with recurred or metastatic ACC, axitinib significantly increased the 6-month PFS rate as compared to observation. \n \nTRIAL REGISTRATION: (ClinicalTrials.gov number, NCT02859012) \n \nFUNDING STATEMENT: Adenoid Cystic Carcinoma Research Foundation, and National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1720150). \n \nDECLARATION OF INTERESTS: BK received research funding from MSD, AstraZeneca, and Ono Pharmaceutical and served as an advisor for AstraZeneca, MSD, Handok, CBS Bio and Genexine outside of the current work. M-J A received research funding from AstraZeneca and received honoraria from AstraZeneca, Lilly, Novartis, MSD, TAKEDA, Alpha pharmaceutical, Roche, Ono Pharmaceutical and served as an advisor or consultancy for AstraZeneca, Lilly, Novartis, MSD, TAKEDA, Alpha Pharmaceutical, Roche and Ono pharmaceutical. K-W L received honoraria from BMS, Lilly, Genexine and received research funding from Macrogenics, MSD, Ono Pharmaceutical, Green Cross Corp. ASLAN Pharmaceuticals and AstraZeneca/MedImmune, Five Prime Therapeutics, LSK BioPharma, Merck, Array BioPharma, Pharmacyclics, Pfizer, ALX Oncology, Zymeworks, BeiGene, Daiichi Sankyo, Taiho Pharmaceutical, and served as an advisor or consultancy for Bayer. S-BK received research funding from Novartis, Sanofi- Genzyme, Dongkook Pharmaceutical Co., Ltd and served as an advisor or consultancy for Novartis, Astrazeneca, Lilly, Enzychem, Dae Hwa Pharmaceutical Co.,Ltd, ISU Abxis and Daiichi-Sankyo.YY served as an advisor or consultancy for Lilly.MKK received honoraria from Janssen Korea. All other authors declare no competing interests. \n \nETHICS APPROVAL STATEMENT: The study protocol was approved by the Institutional Review Board of each participating institution.