Erlotinib plus capecitabine as first-line treatment for older Chinese patients with advanced adenocarcinoma of the lung (C-TONG0807): an open-label, single arm, multicenter phase II study

Hong-Yun Zhao, Gong-Yan Chen, Yan Huang, Xiao-Li Li, Ji-Feng Feng, Mei-Qi Shi, Ying Cheng, Li-Xia Ma, Yi-Ping Zhang, Cui-Ping Gu, Xiang-Qun Song, Da Zhou, Li Zhang, Hong-Yun Zhao, Gong-Yan Chen, Yan Huang, Xiao-Li Li, Ji-Feng Feng, Mei-Qi Shi, Ying Cheng, Li-Xia Ma, Yi-Ping Zhang, Cui-Ping Gu, Xiang-Qun Song, Da Zhou, Li Zhang

Abstract

Preclinical studies have shown synergism between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and antifolates in solid tumors. This study is to investigate the efficacy and tolerability of erlotinib plus capecitabine as first-line treatment in older Chinese patients (≥ 65 years) with lung adenocarcinoma. This is an open-label, single arm, multicenter phase II clinical trial. Sixty- two patients with previously untreated stage IIIB/IV adenocarcinoma and age 65 years or above were enrolled at four tertiary teaching hospitals and 2 provincial hospitals in China; 58 patients fulfilled the study requirements. Erlotinib (150 mg/day) and capecitabine (1000 mg/m2 twice daily on days 1-14) were administered during every 21-day cycle. The primary endpoint was the non-progression rate at 12 weeks. EGFR and K-ras mutation rates were determined using PCR. Tumor expression of different biomarkers was assessed using immunohistochemistry. In a cohort of 58 patients, 34 patients had no disease progression at 12 weeks following treatment. The objective response rate was 29.3%, and the disease control rate was 75.9%. The objective response rate was significantly higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with thymidine phosphorylase-negative tumors had significantly longer overall survival after one year than patients with thymidine phosphorylase-positive tumors. Forty-four patients had at least one primary adverse events (AEs), including skin rash (n = 30), grade 3 AEs (n = 17), and grade 4 AEs (n = 7). This is the first phase II clinical trial to assess erlotinib plus capecitabine combination therapy as first-line treatment in older patients with lung adenocarcinoma. Erlotinib/capecitabine chemotherapy was significantly better in patients with EGFR mutations and in those with thymidine phosphorylase-negative tumors. The use of fluorouracil derivatives for the treatment of lung adenocarcinoma warrants further study.

Trial registration: ClinicalTrials.gov NCT00816868.

Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Flow diagram of patient participation.
FIGURE 2
FIGURE 2
The secondary endpoints OS (A) and PFS (B).
FIGURE 3
FIGURE 3
Immunohistochemical staining of human NSCLC tissues (200× magnification). (A and B) Carcinoma with positive and negative thymidylate synthase expression. (C and D) Carcinoma with positive and negative dihydropyrimidine dehydrogenase expression. (E and F) Carcinoma with positive and negative orotate phosphoribosyltransferase expression. (H and I) Carcinoma with positive and negative thymidine phosphorylase expression. Scale bar, 50 μm.
FIGURE 4
FIGURE 4
Survival analysis for OS by EGFR (A) and K-ras (B) mutation status, and thymidylate synthase (TS) (C), dihydropyrimidine dehydrogenase (DPD) (D), thymidine phosphorylase (TP) (E), and orotate phosphoribosyltransferase (OPRT) (F) expression status.
FIGURE 5
FIGURE 5
Survival analysis for PFS by EGFR (A) and K-ras (B) mutation status, and thymidylate synthase (TS) (C), dihydropyrimidine dehydrogenase (DPD) (D), thymidine phosphorylase (TP) (E), and orotate phosphoribosyltransferase (OPRT) (F) expression status.
FIGURE 6
FIGURE 6
Survival analysis for OS and PFS according to EGFR mutation status and expression of thymidylate synthase (TS) (1), thymidine phosphorylase (TP) (2), and dihydropyrimidine dehydrogenase (DPD) (3).
FIGURE 7
FIGURE 7
Survival analysis for OS by thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyltransferase expression (OPRT) in 37 patients with wild-type EGFR.

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