Erlotinib as Neoadjuvant Therapy in Stage IIIA (N2) EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Prospective, Single-Arm, Phase II Study

Liwen Xiong, Rong Li, Jiayuan Sun, Yuqing Lou, Weiyan Zhang, Hao Bai, Huiming Wang, Jie Shen, Bo Jing, Chunlei Shi, Hua Zhong, Aiqin Gu, Liyan Jiang, Jianxing Shi, Wentao Fang, Heng Zhao, Jie Zhang, Junyuan Wang, Junyi Ye, Baohui Han, Liwen Xiong, Rong Li, Jiayuan Sun, Yuqing Lou, Weiyan Zhang, Hao Bai, Huiming Wang, Jie Shen, Bo Jing, Chunlei Shi, Hua Zhong, Aiqin Gu, Liyan Jiang, Jianxing Shi, Wentao Fang, Heng Zhao, Jie Zhang, Junyuan Wang, Junyi Ye, Baohui Han

Abstract

Lessons learned: The findings of this prospective, single-arm, phase II study showed that neoadjuvant erlotinib was well tolerated and might improve the radical resection rate in patients with stage IIIA-N2 epidermal growth factor receptor mutation-positive non-small cell lung cancer (NSCLC).Erlotinib shows promise as a neoadjuvant therapy option in this patient population.Next-generation sequencing may be useful for predicting outcomes with preoperative tyrosine kinase inhibitors (TKIs) in patients with NSCLC.Large-scale randomized controlled trials investigating the role of TKIs in perioperative therapy, combining neoadjuvant and adjuvant treatments to enhance personalized therapy for patients in this precision medicine era, are warranted.

Background: Information on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as neoadjuvant therapy in non-small cell lung cancer (NSCLC) is scarce. We evaluated whether neoadjuvant erlotinib improves operability and survival in patients with stage IIIA-N2 EGFR mutation-positive NSCLC.

Methods: We conducted a prospective, single-arm, phase II study. Patients received erlotinib 150 mg per day for 56 days in the neoadjuvant period. The primary endpoint was the radical resection rate.

Results: Nineteen patients were included in the final analysis. After erlotinib treatment, 14 patients underwent surgery. The radical resection rate was 68.4% (13/19) with a 21.1% (4/19) rate of pathological downstaging. The objective response rate was 42.1%; 89.5% (17/19) of patients achieved disease control, with a 10.3-month median disease-free survival among patients who underwent surgery. Among all 19 patients who received neoadjuvant therapy, median progression-free survival (PFS) and overall survival were 11.2 and 51.6 months, respectively. Adverse events (AEs) occurred in 36.8% (7/19) of patients, with the most common AE being rash (26.3%); 15.8% experienced grade 3/4 AEs. Quality of life (QoL) improvements were observed after treatment with erlotinib for almost all QoL assessments. Effects of TP53 mutation on prognosis were evaluated in eight patients with adequate tissue samples. Next-generation sequencing revealed that most patients had a TP53 gene mutation (7/8) in addition to an EGFR mutation. No TP53 mutation, or very low abundance, was associated with longer PFS (36 and 38 months, respectively), whereas high abundance was associated with short PFS (8 months).

Conclusion: Neoadjuvant erlotinib was well tolerated and may improve the radical resection rate in this patient population. Next-generation sequencing may predict outcomes with preoperative TKIs.

Trial registration: ClinicalTrials.gov NCT01217619.

© AlphaMed Press; the data published online to support this summary are the property of the authors.

Figures

Figure 1.
Figure 1.
Waterfall plot of response to erlotinib neoadjuvant therapy. Bars show data from individual patients. Negative values suggest tumor shrinkage and positive values suggest PD; the dashed lines show the thresholds for a partial response (shrinkage by 30%) or for progressive disease (growth by 20%) according to RECIST criteria. Abbreviation: PD, progressive disease.
Figure 2.
Figure 2.
Patient flowchart. Abbreviations: EBUS, endobronchial ultrasound; EGFR, epidermal growth factor receptor; NGS, next‐generation sequencing; PD, progressive disease; SAE, serious adverse event.
Figure 3.
Figure 3.
Kaplan‐Meier curves of disease‐free survival (DFS), progression‐free survival (PFS), and overall survival (OS). (A): DFS for 14 patients who underwent surgery (calculated from the date of oral EGFR tyrosine kinase inhibitor to the first date of disease progression). (B): The DFS time of 14 patients who had surgery (calculated from the date of operation to the first date of disease progression). (C): PFS for all 19 patients. (D): OS for all 19 patients. (E): PFS for patients who were smokers. (F): PFS for patients who were nonsmokers. Abbreviation: CI, confidence interval.
Figure 4.
Figure 4.
Next‐generation sequencing analysis of mutation abundance and CEA level for eight cases (A)–(D). Abbreviations: CEA, carcinoembryonic antigen; EGFR, epidermal growth factor receptor.

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