Phase 1 study of romidepsin plus erlotinib in advanced non-small cell lung cancer.

Abstract Purpose Preclinical studies demonstrated anti-tumor efficacy of the combination of the histone deacetylase (HDAC) inhibitor romidepsin plus erlotinib in non-small cell lung cancer (NSCLC) models that were insensitive to erlotinib monotherapy. We therefore studied this combination in a phase 1 clinical trial in previously treated advanced NSCLC. Methods Romidepsin (8 or 10mg/m 2 ) was administered intravenously on days 1, 8, and 15 every 28 days in combination with erlotinib (150mg orally daily), with romidepsin monotherapy lead-in during Cycle 1. Correlative studies included peripheral blood mononuclear cell HDAC activity and histone acetylation status, and EGFR pathway activation status in skin biopsies. Results A total of 17 patients were enrolled. Median number of prior lines of therapy was 3 (range 1–5). No cases had a sensitizing EGFR mutation. The most common related adverse events were nausea, vomiting, and fatigue (each 82%), diarrhea (65%), anorexia (53%), and rash (41%). Dose-limiting nausea and vomiting occurred at the romidepsin 10mg/m 2 level despite aggressive antiemetic prophylaxis and treatment. Among 10 evaluable patients, the best response was stable disease ( n =7) and progressive disease ( n =3). Median progression-free survival (PFS) was 3.3 months (range 1.4–16.5 months). Prolonged PFS (>6 months) was noted in a KRAS mutant adenocarcinoma and a squamous cell cancer previously progressed on erlotinib monotherapy. Romidepsin monotherapy inhibited HDAC activity, increased histone acetylation status, and inhibited EGFR phosphorylation. Conclusions Romidepsin 8mg/m 2 plus erlotinib appears well tolerated, has evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population.