Our lung cancer program is focused on advancing three combination approaches shown in preclinical studies to inhibit lung cancer cell growth. The first approach combines entinostat with erlotinib, an approved epidermal growth factor receptor inhibitor; the second approach combines entinostat with azacitidine, a DNA methyltransferase inhibitor; and the third approach combines entinostat as an immunomodulatory agent with antibodies targeting programmed cell death protein 1 (PD1) or programmed cell death ligand 1 (PDL1). We believe that successful treatment of NSCLC and introduction of novel therapeutic approaches will be dependent on the identification of biomarkers that allow patient selection for the optimization of response.
- Encore 401: Phase 2b Clinical Trial. We conducted a randomized, double-blind, placebo-controlled Phase 2b clinical trial of entinostat in combination with erlotinib compared to erlotinib plus placebo. The trial enrolled 132 patients with metastatic NSCLC who experienced disease progression after one or two prior regimens of therapy or within six months of completion of chemotherapy following surgery. Patients were randomized on a one-to-one basis and stratified according to the patients’ smoking status. Patients in the trial received treatment with erlotinib in a 150 mg dose daily with entinostat or placebo in a 10 mg dose on days 1 and 15 of a 28-day cycle. Patients could receive up to six cycles of therapy, subject to discontinuation in the event of disease progression or unacceptable toxicity. In the overall trial population, there were no statistically significant differences in the primary or secondary endpoints of the trial. However, in a subset of 26 patients with elevated levels of epithelial cadherin (E-cadherin), we observed extended overall survival with entinostat combined with erlotinib versus erlotinib alone using a predefined, retrospective analysis. As a follow up to the ENCORE 401 clinical trial and to further study the E-cadherin patient biomarker enrichment strategy, we have planned a randomized, Phase 2 clinical trial of 200 NSCLC patients selected prior to randomization based on expression of high levels of the E-cadherin biomarker in their tumor.
- NCI-7759: Phase 2 Clinical Trial. Preclinical studies in lung cancer models have indicated that a dual epigenetic therapy approach of combining entinostat with azacitidine resulted in a greater inhibition of cancer cell growth than either agent alone. Based on these findings, investigators at Johns Hopkins University and the NCI conducted a single-arm, two-stage, open-label clinical trial of the combination of entinostat and azacitidine in patients with recurrent metastatic NSCLC. All of these patients had been heavily pre-treated with a median of three prior regimens for metastatic disease and had shown no meaningful response to such treatment. Although this population was heavily pre-treated, patients given the combination of entinostat and azacitidine achieved objective responses, including a complete response, a partial response with complete resolution of multiple liver metastases, and several patients with durable stable disease.
The following trials of entinostat combinations planned by investigators at Johns Hopkins University are designed to build on the initial NCI-funded trial data in metastatic NSCLC to further validate the observation that dual epigenetic therapy can augment the clinical activity of cytotoxic or immune therapy in these patients.
- NCI-9253: Epigenetic Priming to Chemotherapy Trial. This NCI-funded Phase 2 clinical trial is currently enrolling up to 165 metastatic NSCLC patients in three different arms, (i) chemotherapy alone, (ii) chemotherapy preceded by injectable azacitidine plus entinostat, or (iii) chemotherapy preceded by oral azacitidine plus entinostat. The primary objective of the trial is to determine the percent of patients without disease progression at six months. We expect to see the proof-of-concept data for this trial in late 2015.
- J1353: Epigenetic Priming to Immunotherapy Trial. This investigator-sponsored Phase 2 clinical trial, funded by Stand Up To Cancer, is currently enrolling up to 120 patients with metastatic NSCLC and is designed to test the ability of epigenetic therapy—either oral azacitidine alone or the entinostat and azacitidine combination—to enhance the response of NSCLC patients to nivolumab, a type of immunotherapy. We expect to see the proof-of-concept data for this trial in late 2015.
In order to fully understand the potential for entinostat to potentiate the activity of immune therapies, we plan to work with our collaborators to initiate a series of clinical studies in combination with targeted immune therapies in melanoma, breast cancer, lung cancer and other solid tumors. Data from a completed Phase 2 NSCLC clinical trial with entinostat combined with azacitidine suggest that entinostat may prime tumors to be more responsive to subsequent immune therapy targeting PD1 or its ligand, PDL1. Further, preclinical studies have indicated that entinostat works to enhance the activity of immune therapy by inhibiting the activity of host immune cells that function to suppress the activity of anti-tumor immune responses.
- ENCORE 601: Phase 1b Clinical Trial. Based on these findings and emerging preclinical data demonstrating synergistic combined anti-tumor effects of entinostat and immune therapy, we are currently planning a Phase 1b clinical trial to examine the combination of entinostat with antibodies targeting PD1 to characterize the safety, define a recommended Phase 2 dose and assess the preliminary clinical activity of this combination. The trial will combine entinostat with an anti-PD1 antibody in patients with metastatic NSCLC or melanoma. We anticipate initiating this trial in the first half of 2015 with safety, recommended Phase 2 dose, preliminary activity and correlative data available in mid-2016.