Phase Ib Study of Chemoprevention with Green Tea Polyphenon E and Erlotinib in Patients with Advanced Premalignant Lesions (APL) of the Head and Neck

Abstract

Purpose: On the basis of synergistic effects between green tea polyphenon E (PPE) and EGFR-tyrosine kinase inhibitor in preclinical studies, we conducted a phase Ib study of the PPE and erlotinib combination in patients with advanced premalignant lesions (APL) of the oral cavity and larynx.

Patients and methods: Patients were treated with a fixed dose of PPE (200 mg three times a day) and dose escalation of erlotinib (50, 75, 100 mg daily) for 6 months with tissue biopsy at baseline and 6 months. Primary endpoints were safety and toxicity; secondary endpoints were evaluation of pathologic response, cancer-free survival (CFS), overall survival (OS), and biomarker modulation.

Results: Among 21 enrolled patients, 19 began treatment and 17 completed 6 months of treatment with PPE and erlotinib. Main characteristics of treated patients: 15 severe dysplasia or carcinoma in situ and 17 oral cavity. Only skin rash was associated with dose-limiting toxicity and MTD. Recommended doses for phase II studies are PPE 600 mg daily plus erlotinib 100 mg daily for 6 months. Pathologic responses in 17 evaluable patients: pathologic complete response (47%) and pathologic partial response (18%). The 5-year CFS and OS were 66.3% and 93%, respectively. Among tested biomarkers, only phosphorylated ERK was correlated with response to treatment.

Conclusions: Treatment with PPE and erlotinib combination was well tolerated in patients with APLs of the head and neck, and showed a high rate of pathologic response with excellent CFS. This combination deserves further investigation for the chemoprevention and/or prevention of second primary tumors in early-stage head and neck cancer.

Figure 1:

Three example cases of pathologic responses of premalignant lesions of the oral cavity before treatment (Pre-Tx) and after 6 months of treatment (Post-Tx) with green tea PPE and erlotinib. Case #16 was moderate dysplasia before treatment (Pre-Tx) that became mild dysplasia (pathologic partial response) after treatment (Post-Tx). Case #3 was mild dysplasia Pre-Tx and improved to no dysplasia Post-Tx (pathologic complete response). Case #24 was severe dysplasia/carcinoma in situ (CIS) Pre-Tx that also improved to no dysplasia Post-Tx (pathologic complete response) (200X Magnification).

Figure 2:

The figure represents duration (months) of response for each responder among 17 pathologically evaluable patients: 8 CRs, 3 PRs and 3 SDs. Five patients developed progressive disease during the follow-up: * Indicates progressive disease without developing invasive cancer (3 cases) and ** indicates progressive disease with developing invasive cancer (2 cases).

Figure 3:

Kaplan-Meier plots of overall survival (OS) (A) and cancer free survival (CFS) (B) of the 19 patients. The 5-year OS was 93% (95% CI, 59.1%−99%) and median OS was not reached. The 5-year CFS was 66.3% (95% CI, 29.0%−87.2%) and median CFS was not reached. The median follow up was 44.2 months.

Figure 4:

Biomarker modulation of Case #24 (severe dysplasia/CIS) at baseline (Pre-Tx) became no dysplasia (pathologic complete response). pERK was highly expressed in the baseline (BL) tissue which was downregulated after 6 months of treatment (6-M). PS6 was not expressed at baseline but increased after 6 months, while Ki-67 was highly expressed at baseline (BL) and was downregulated after 6 months of treatment (6-M) (200X Magnification).