Amrubicin for the treatment of advanced lung cancer

Abstract

Although the advancement of the chemotherapy of non-small cell lung cancer and small cell lung cancer is remarkable in recent years, it is still unsatisfactory. Therefore, some new agents or a new treatment strategy for lung cancer is required. Amrubicin is a totally synthetic anthracycline anticancer drug that acts as a potent topoisomerase II inhibitor. Recently, amrubicin has been approved in Japan for the treatment of small-and non-small cell lung cancers and some clinical trials about amrubicin were conducted in Japan, and promising results have been reported for the treatment of small cell lung cancer in particular. The preclinical, pharmacology and clinical data of amrubicin for the treatment of advanced lung cancer are reviewed. OverviewLung cancer is the leading cause of cancer-related death in many countries. The disease can be classified into two types, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with NSCLC accounting for 80 -85% of all cases.Approximately 50% of the patients with NSCLC have advanced disease. The standard therapy for patients with good performance status (PS) is systemic chemotherapy. Based on the results of a meta-analysis, cisplatin (CDDP)-based doublets are considered the best available therapy for patients with metastatic NSCLC, with a 10% improvement in the 1-year survival rate compared to the best supportive care [1] . As several new agents with significant activity against NSCLC have been introduced, such as paclitaxel, docetaxel, vinorelbine and gemcitabine, any of these agents used in combination with a platinum agent has improved outcomes compared to older agents [2] and each regimen provides a similar survival outcome [3,4] . However, unfortunately, almost all patients recur. Relapsed patients who still have a good PS receive second-line chemotherapy, which is considered a standard of care. Docetaxel, pemetrexed and EGFR inhibitor, erlotinib, are used in this setting. Recently, some molecular targeted agents have been developed in the treatment of NSCLC. A large, randomised Phase III study showed clear survival benefit by adding bevacizumab, an angiogenesis inhibitor, to the combination chemotherapy of carboplatin (CBDCA) and paclitaxel [5] . In addition, EGFR inhibitors, such as erlotinib and gefitinib, were very effective in a special molecularly defined population of patients harbouring EGFR somatic mutations [6,7] . For these reasons, much interest is concentrated on the development of molecular targeted agents. However, as the strategy of combination therapy with molecular targeted agents and cytotoxic agents is becoming more important, the development of cytotoxic agents is also similarly growing in importance.

Pharmacokinetic Characterization of Amrubicin Cardiac Safety in an Ex Vivo Human Myocardial Strip Model. II. Amrubicin Shows Metabolic Advantages over Doxorubicin and Epirubicin

“…Amrubicin myocardial accumulation was limited primarily by formation of amrubicin metabolites, such as 9-deaminoamrubicin and 9-deaminoamrubicinol, that diffused from the strips in plasma . These findings correlated with reports of amrubicin cardiac tolerability in preclinical models or in approved or investigational clinical settings that adopted cumulative doses of amrubicin in the treatment of refractory/relapsed non-small-cell lung carcinoma or small cell lung carcinoma (Kurata, 2009;Ogawara et al, 2010). However, a global preclinical assessment of the risk of cardiotoxicity associated with the clinical use of amrubicin requires that amrubicin conversion to ROS or secondary alcohol metabolite be investigated.…”