A phase I, pharmacokinetic, and pharmacodynamic study of panobinostat, an HDAC inhibitor, combined with erlotinib in patients with advanced aerodigestive tract tumors

Abstract

Purpose: Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer.

Experimental design: Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre and posttherapy tumor biopsies for checkpoint kinase 1 (CHK1) expression were assessed.

Results: Of 42 enrolled patients, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1-3), and rash and anorexia (grades 1-2). Disease control rates were 54% for NSCLC (n = 26) and 43% for head and neck cancer (n = 7). Of 7 patients with NSCLC with EGF receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P = 0.43) and overall survival was 41 (estimated) versus 5.2 months (P = 0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat's pharmacodynamic effect in blood, FPB, and tumor samples. Low CHK1 expression levels correlated with PFS (P = 0.006) and response (P = 0.02).

Conclusions: We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore the benefits of HDAC inhibitors in patients with EGFR-mutant NSCLC, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1's predictive role.

Figure 1

Pharmacokinetic analyses. A, Erlotinib exposure (AUC_0-24hr) with and without the presence of panobinostat in the dose escalation cohorts. Includes only those patients who completed all 3 days of pharmacokinetic blood draws. B, Panobinostat time versus mean plasma concentration (+/− standard deviation) in the dose escalation cohorts. Includes only those patients who completed all 3 days of pharmacokinetic blood draws. SS, steady state.

Figure 2

Best percent change in target lesions based on RECIST v1.0. +Erlotinib-naïve, EGFR mutant; ^#EGFR mutant with prior erlotinib exposure; *Progressive disease based on new lesions.

Figure 3

Progression-free survival (PFS) and overall survival (OS) for the intent-to-treat population. A, No difference in PFS or OS for NSCLC versus head and neck cancer patients. B, Excluding the head and neck patients (see Table 1 for number of patients), when comparing squamous cell lung cancer (SQCLC) versus non-SQCLC, no significant differences in PFS or OS were observed. C, OS was not yet reached for the EGFR-mutant NSCLC group but in a post-hoc analysis was estimated to be 41 months (P = 0.0087) compared with the other groups. EGFR+, EGFR mutant adenocarcinoma of the lung; EGFR-, EGFR wild-type NSCLC; Head/Neck, head and neck cancer; Unknown, EGFR mutation status unknown.

Figure 4

A, CHK1 score inversely correlates with E-cadherin expression, percent decrease in tumor size, and PFS in NSCLC. Adenoca, adenocarcinoma; Large cell NE, large cell neuroendocrine carcinoma; AS: Allred score. B, Panobinostat plus erlotinib therapy induces tubulin acetylation in tumor cells as well as histone H4 acetylation (ac H4) in subcutaneous fat tissue and PBMC, as assessed by Western blot analysis. β-Actin was used as a loading control.