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 10 mg/m2) was administered intravenously on days 1, 8, and 15 every 28 days in combination with erlotinib (150 mg 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 10 mg/m2 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 8 mg/m2 plus erlotinib appears well tolerated, has evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population.

High prevalence of malnutrition and nutrition impact symptoms in older patients with cancer: Results of a Brazilian multicenter study

“…Previous findings showed that no appetite is a predicter of weight loss and consequent nutritional risk or malnutrition in adults and older patients . This is in line with findings from 2 recent studies conducted in Japan, which showed that no appetite was the most prevalent symptom in patients with cancer, with a prevalence ranging from 20% to 24.4% . However, in 2 other studies conducted in patients with advanced cancer, the prevalence of no appetite varied between 53% and 57%, which is even higher than that found in our study …”

“…34 This is in line with findings from 2 recent studies conducted in Japan, which showed that no appetite was the most prevalent symptom in patients with cancer, with a prevalence ranging from 20% to 24.4%. 35,36 However, in 2 other studies conducted in patients with advanced cancer, the prevalence of no appetite varied between 53% and 57%, which is even higher than that found in our study. [37][38][39] Nausea was higher in patients with gynecological cancer, and similar findings were reported in a conductive study at Aga Khan University Hospital, Pakistani, where 1 of the most common adverse effects was nausea (33.3%) in patients who received pelvic radiotherapy for gynecological cancer.…”

A histone deacetylase inhibitor enhances expression of genes inhibiting Wnt pathway and augments activity of DNA demethylation reagent against nonsmall-cell lung cancer

“…These topoisomerase II inhibitors or DNA damage reagents could gain accessibility to target DNA thus increasing the efficacy since TMU‐35435 induces open chromatin structure. In addition, it warrants further investigation whether TMU‐35435 alone or in combination with other drugs could be used for overcoming the acquired resistance seen in most NSCLC patients who initially respond to EGFR TKI therapy or chemotherapy . It is likely that combined epigenetic therapy could result in increased antitumor activity in comparison to the use of single‐agent inhibitor of DNMTs or HDACs, but this needs validation in randomized studies.…”

Inhibition of histone deacetylases sensitizes EGF receptor‐TK inhibitor‐resistant non‐small‐cell lung cancer cells to erlotinib in vitro and in vivo

“…Furthermore, the addition of an HDAC inhibitor (such as SAHA and SNDX‐275) to erlotinib or SAHA combined with gefitinib has become a novel clinical strategy to treat EGFR‐TKI resistance in patients suffering from NSCLC (NCT00503971, NCT00750698 and NCT02151721; https://www.clinicaltrials.gov/; accessed: April 11, 2017). The combination of romidepsin and erlotinib also exhibited inhibitory effects on relevant molecular targets in an unselected advanced NSCLC phase 1 clinical trial (Gerber et al, ). These findngs have led to the notion that HDAC inhibitors are promising drugs to potentiate the therapeutic efficacy of EGFR‐TKIs.…”