Phase II trial of dose-dense chemotherapy followed by dose-intense erlotinib for patients with newly diagnosed metastatic non-small cell lung cancer

W Jeffrey Petty, Jennifer Laudadio, Lynsay Brautnick, James Lovato, Travis Dotson, Nathan P Streer, Kathryn E Weaver, Antonius A Miller, W Jeffrey Petty, Jennifer Laudadio, Lynsay Brautnick, James Lovato, Travis Dotson, Nathan P Streer, Kathryn E Weaver, Antonius A Miller

Abstract

This phase II study investigated dose-intense erlotinib maintenance after dose-dense chemotherapy for patients with metastatic non-small cell lung cancer and examined two cell cycle biomarkers. Patients with newly diagnosed metastatic non-small cell lung cancer received docetaxel 75 mg/m² and cisplatin 75 mg/m² on day 1 and pegfilgrastim on day 2 every 14 days for four cycles. Patients then received erlotinib with initial doses based on smoking status. Doses were increased in 75 mg increments every two weeks depending on toxicities until each patient's maximal tolerable dose (MTD) was achieved. Cyclin D1 and D3 biomarkers were measured by immunohistochemistry. The objectives of the study were to evaluate time to progression (TTP) and overall survival (OS) for the entire population and biomarker subgroups. Forty-five patients were enrolled. Intra-patient erlotinib MTD ranged from 0 to 525 mg. Median MTD achieved in smokers was higher than in non-smokers (300 vs. 150 mg; P=0.019). TTP for the entire cohort was not significantly improved compared to historical controls. Patients with high cyclin D1 expressing tumors demonstrated improved TTP on erlotinib (8.2 vs. 4.7 months; hazard ratio, 4.1; 95% CI, 1.6-0.6; P=0.003) and improved OS (20.5 vs. 8.0 months; hazard ratio 2.8; 95% CI, 1.2-6.3; P=0.016). Intratumoral cyclin D3 expression did not impact clinical outcomes. Current smokers but not former smokers exhibit a higher erlotinib MTD. High cyclin D1 expression was associated with favorable TTP and OS.

Trial registration: ClinicalTrials.gov NCT00723138.

Figures

Figure 1.
Figure 1.
Impact of smoking status on the maximal tolerable dose (MTD) of erlotinib. MTD achieved for each patient is shown. Horizontal lines indicate mean values and standard error bars are shown. *Significant difference (P

Figure 2.

Kaplan-Meier graph and log-rank statistics…

Figure 2.

Kaplan-Meier graph and log-rank statistics based on biomarker expression. (A) Time to progression…

Figure 2.
Kaplan-Meier graph and log-rank statistics based on biomarker expression. (A) Time to progression (TTP) and overall survival (OS) for all patients. (B) TTP on erlotinib for patients based on cyclin D1 expression. (C) OS for patients based on cyclin D1 expression.

Figure 2.

Kaplan-Meier graph and log-rank statistics…

Figure 2.

Kaplan-Meier graph and log-rank statistics based on biomarker expression. (A) Time to progression…

Figure 2.
Kaplan-Meier graph and log-rank statistics based on biomarker expression. (A) Time to progression (TTP) and overall survival (OS) for all patients. (B) TTP on erlotinib for patients based on cyclin D1 expression. (C) OS for patients based on cyclin D1 expression.

Figure 2.

Kaplan-Meier graph and log-rank statistics…

Figure 2.

Kaplan-Meier graph and log-rank statistics based on biomarker expression. (A) Time to progression…

Figure 2.
Kaplan-Meier graph and log-rank statistics based on biomarker expression. (A) Time to progression (TTP) and overall survival (OS) for all patients. (B) TTP on erlotinib for patients based on cyclin D1 expression. (C) OS for patients based on cyclin D1 expression.
Figure 2.
Figure 2.
Kaplan-Meier graph and log-rank statistics based on biomarker expression. (A) Time to progression (TTP) and overall survival (OS) for all patients. (B) TTP on erlotinib for patients based on cyclin D1 expression. (C) OS for patients based on cyclin D1 expression.
Figure 2.
Figure 2.
Kaplan-Meier graph and log-rank statistics based on biomarker expression. (A) Time to progression (TTP) and overall survival (OS) for all patients. (B) TTP on erlotinib for patients based on cyclin D1 expression. (C) OS for patients based on cyclin D1 expression.
Figure 2.
Figure 2.
Kaplan-Meier graph and log-rank statistics based on biomarker expression. (A) Time to progression (TTP) and overall survival (OS) for all patients. (B) TTP on erlotinib for patients based on cyclin D1 expression. (C) OS for patients based on cyclin D1 expression.

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