Treatment of relapsed non-small cell lung cancer (NSCLC) remains discouraging. Results from clinical trials yield median survivals that range from 6 to 9 months, and rates of toxicities, particularly with the use of cytotoxic agents, are not negligible (1-4). Investigation of more effective, or at least less toxic, agents and combinations remains paramount.
Histone deacetylases (HDACs) represent an emerging therapeutic target in NSCLC and other malignancies since the extent of histone acetylation impacts gene expression, including those genes involved in the pro-survival signaling cascades, regulation of apoptosis, and control of the cell cycle (5-7). Histone deacetylase inhibitors effect cell death by activating apoptotic pathways, mitotic failure, or autophagic cell death (5,8,9). Normal cells are relatively resistant to cell death induced by HDAC inhibitors. This specificity may be related to protection from generation of reactive oxygen species found in the normal cell. As such, HDAC inhibitors may offer an appealing therapeutic index in cancer therapy (10).
Vorinostat (suberoylanilide hydroxamic acid, SAHA, Zolinza™, NSC# 701852) is a small molecule inhibitor of class I and II HDACs. It has yielded anti-proliferative and pro-apoptotic results in multiple cancer cell lines (including NSCLC) and xenograft mouse models (11-13). Preclinical studies using NSCLC and other cell lines confirmed the ability of vorinostat to enhance the cytotoxicity of radiation, targeted agents, and traditional DNA-directed chemotherapeutics (14-16).
Phase I trials with oral vorinostat identified the maximum tolerated dose to be 400 mg once daily or 200 mg twice daily in patients with solid tumors or hematologic malignancies, or 300 mg twice daily for 3 consecutive days per week for patients with solid tumors (17,18). Dose limiting toxicities included anorexia, dehydration, diarrhea, and fatigue. Drug-related adverse events were constitutional (fatigue), gastrointestinal (anorexia, diarrhea, nausea, and vomiting), metabolic (hyperglycemia and hypocalcemia), and hematologic (thrombocytopenia, anemia, and some neutropenia). Antitumor activity was seen in patients with Hodgkin's and non-Hodgkin's lymphoma, mesothelioma, differentiated thyroid cancer, bladder cancer, and laryngeal cancer. Accumulation of acetylated histones H3 and H4 was demonstrated 4 hours after treatment with vorinostat in peripheral blood mononuclear cells and in 3 of 5 paired tumor biopsies (17,18).
Two schedules of vorninostat (400 mg once daily for 14 days and 300 mg twice daily for 7 days) were tolerated well when combined with carboplatin and paclitaxel (19). This phase I combination study yielded surprisingly robust antitumor activity in patients with advanced NSCLC: 10 of 19 patients obtained a partial response (19). Vorinostat obtained Food and Drug Administration (FDA) approval in refractory cutaneous T cell lymphoma resulting from a nearly 30% response rate (20,21). Disease activity has also been seen in a phase II trial of mesothelioma, such that a randomized trial is underway for patients who have progressed through pemetrexed (22). Phase II trials in advanced ovarian cancer, head and neck cancers, and relapsed diffuse large-B-cell lymphoma were negative (23-25).
The objective of our multicenter phase II trial was to establish the single agent activity of vorinostat in the second line setting of advanced NSCLC. Additional objectives included examining the safety profile of vorinostat in this population, and estimating survival of treated patients.