Elsevier

Lung Cancer

Volume 79, Issue 3, March 2013, Pages 276-282
Lung Cancer

Continued treatment with gefitinib beyond progressive disease benefits patients with activating EGFR mutations

https://doi.org/10.1016/j.lungcan.2012.11.022Get rights and content

Abstract

Background

Gefitinib is an effective treatment for patients with non-small cell lung cancer who harbor activating epidermal growth factor receptor (EGFR) mutations. However, no optimal strategy has been established for these patients after gefitinib fails. The aim of this retrospective study was to assess the survival benefit of continued gefitinib treatment in these cases.

Patients and methods

We analyzed gefitinib responders with activating EGFR mutations who developed progressive disease (PD) during the course of therapy. Prognostic variables were analyzed using a Cox proportional-hazards model.

Results

A total of 134 patients were retrospectively reviewed. Exon-19 deletion mutations and L858R point mutations were detected in 71 and 63 patients, respectively. Median survival time after PD with gefitinib was 14.3 months (95% confidence interval: 11.7–16.9). The median duration of continued gefitinib therapy beyond PD was 3.2 months. Statistical analysis showed that good performance status (0–1) (hazard ratio [HR]: 0.6), progression of a previously evaluated lesion (HR: 0.6), and at least 3 months of continued treatment (HR: 0.4) were independent prognostic factors.

Conclusion

Continuation of gefitinib beyond PD is an effective optional treatment in EGFR-mutated patients.

Introduction

Lung cancer is a leading cause of cancer-related deaths worldwide [1], [2]. More than 70% of lung-cancer patients are diagnosed with advanced non-small cell lung cancer (NSCLC), and prognosis remains poor [3]. Gefitinib is an oral EGFR tyrosine-kinase inhibitor (EGFR-TKI) with reported efficacy in limited populations harboring EGFR mutations, including activating mutations such as exon-19 deletion mutations and L858R point mutations [4], [5], [6]. Several clinical trials in EGFR-mutated patients with advanced NSCLC have demonstrated that, compared to chemotherapy, gefitinib results in significantly higher response rates (55–80%) with longer progression-free survival [7], [8]. However, despite these benefits, a majority of patients ultimately develop resistance to gefitinib therapy after 8 to 12 months [9] through amplification of the MET oncogene and secondary EGFR T790M mutations [10], [11]. Although the lack of established standard treatments markedly hampers the management of patients who develop resistance to gefitinib, data that assess the course of the disease and optimal therapy once gefitinib has failed are sorely lacking.

Indeed, several studies have demonstrated that among those who develop resistance to first-generation EGFR-TKIs (including gefitinib and erlotinib), secondary T790M mutation occurs in nearly 50%, while MET amplification occurs in nearly 20% [12], [13], [14], [15], [16]. Additionally, overexpression of hepatocyte growth factor (HGF) accounts for more than half of all cases of EGFR-TKI-acquired resistance [17]. Further, several studies report secondarily acquired resistance to EGFR-TKIs, but the timing of such acquired resistance is unknown [18], [19].

In general, once tumor exacerbation is observed, patients are treated with another agent or the best supportive care available [20]. In patients receiving gefitinib, however, treatment is often continued rather than promptly discontinued, as some patients have shown rapid tumor progression on cessation [21]. Although gefitinib has been provided beyond progressive disease (PD) in some cases, information regarding the subsequent disease course is markedly lacking, and the usefulness of continuing gefitinib beyond PD has not been investigated.

We hypothesized that it may be useful for gefitinib patients harboring EGFR mutations to continue therapy even after the progressive disease (PD) stage has been reached, and conducted this retrospective study to assess the usefulness of continuing gefitinib treatment for more than a certain period beyond PD. We did this by examining the disease course and survival benefits of such a course of action.

Section snippets

Patients and methods

We retrospectively reviewed the records of patients with activating EGFR mutations (exon-19 deletion or L858R) who were histopathologically diagnosed with non-small cell lung cancer and who received gefitinib treatment between September 2002 and February 2011 at the Kinki-chuo Chest Medical Center and Osaka Prefectural Medical Center for Respiratory and Allergic Diseases. All records reviewed were from patients whose condition changed from non-PD to PD after the initial assessment. EGFR

Patient characteristics

Activating EGFR mutations were found in 308 of 1172 patients (26%) screened, with no patients having both an exon-19 deletion mutation and an L858R point mutation. Of these 308 patients, 151 received gefitinib as the initial EGFR-TKI. Among these patients 17 were excluded; 7 because they were confirmed as PD at initial assessment, 3 because they received clinical trial treatment that combined the use of pemetrexed with gefitinib after gefitinib failed, and 7 because they received gefitinib as

Discussion

Here, we investigated the survival benefit and disease course of patients with activating EGFR mutations and NSCLC who continued gefitinib treatment after developing progressive disease. Along with good PS (0–1) and progression of previously evaluated lesions, continuing gefitinib treatment for at least 3 months beyond PD was a key prognostic factor, suggesting that continuing this therapy should be considered even after PD has been confirmed.

We define short-/long-term as the period between

Conflict of interest statement

None declared.

Funding

None.

Acknowledgements

We are grateful to the staff of Kinki-Chuo Chest Medical Center and Osaka Prefectural Medical Center for Respiratory and Allergic Diseases for their helpful comments. We are especially indebted to Dr. Masahiko Ando of Nagoya University for his assistance with statistical analyses.

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