Entinostat for Lung Cancer

Syndax’s lead product, entinostat, is in development for patients with non-small cell lung cancer (NSCLC), a disease in which malignant cells form in the tissues of the lungs and the most common type of lung cancer which is the leading cause of cancer deaths. The three main types of NSCLC are squamous cell carcinoma, large cell carcinoma and adenocarcinoma. Each year there are more than 200,000 cases of newly diagnosed advanced NSCLC. About 60% of patients present with advanced NSCLC, meaning it has already spread beyond the lung at the time they are seen by a doctor. The five-year survival rate is less than ten percent for patients with advanced NSCLC.

Targeted therapies such as epidermal growth factor receptor inhibitors (EGFRi) have greatly improved the treatment of those NSCLC patients that harbor the appropriate targets. Unfortunately all patients develop resistance due in part to epigenetic changes in the tumor which reduce the sensitivity to EGFRi such as erlotinib (Tarceva®). Entinostat has been shown to delay the emergence of erlotinib resistance by maintaining a sensitive tumor phenotype1.

Using a biomarker to select patients based on the tumor biology can improve patient outcomes versus treating an unselected patient population. Restoring E-cadherin (a molecular marker of epithelial tumors) expression has been shown preclinically to increase sensitivity to epidermal growth factor receptor inhibitors (EGFRi) thereby restoring sensitivity to the standard of care treatment. Therefore, E-cadherin, which represents 40 percent of the population, is a potentially relevant clinical biomarker to select patients for treatment with erlotinib (Tarceva®), an EGFRi, plus entinostat.

In preclinical studies entinostat was shown to synergize with certain EGFRi’s to enhance gene re-expression and inhibit cancer cell growth2. ENCORE 401, a randomized, phase 2 clinical trial recently presented, demonstrated a survival advantage in the subset of patients with elevated E-cadherin receiving entinostat in combination with erlotinib. Further evaluation of entinostat with erlotinib in randomized studies will be initiated next year in a selected patient population of NSCLC patients with high levels of E-cadherin.

In addition, in collaboration with the National Cancer Institute, Syndax is using a dual epigenetic therapy approach to treating advanced lung cancer.