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

Lung Cancer. 2013 Mar;79(3):276-82.

Kazuhiro Asamia, Tomohisa Okumab, Tomonori Hirashimac, Masaaki Kawaharad, Shinji Atagia, Tomoya Kawaguchia, Kyoichi Okishioa, Naoki Omachia, Naoko Takeuchia

aDepartment of Clinical Oncology, National Hospital Organization Kinki-chuo Chest Medical Center, Sakai, Japan

bDepartment of Radiology, National Hospital Organization Kinki-chuo Chest Medical Center, Sakai, Japan

cDepartment of Clinical Oncology, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Japan

dDepartment of Clinical Oncology, Federation of National Public Service Personnel Mutual Aid Associations, Otemae Hospital, Osaka, Japan



Background: Gefitinib is an effective treatment for patients suffering from non-small cell lung cancer (NSCLC) and harboring activating epidermal growth-factor receptor (EGFR) mutations. However, no optimal strategies have 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 [CI]: 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 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.

Copyright © 2012 Elsevier Ireland Ltd.

PMID: 23261231


Supplement: New treatment strategy for EGFR-mutated NSCLC patients

Gefitinib elicits a remarkable response in patients with non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutation. However, all patients acquire resistance to gefitinib and eventually present tumor progression. After confirmation of tumor progression during gefitinib treatment, a decision needs to be made regarding whether the present therapy should be continued; treatment should be changed to other molecular targeting agents such as erlotinib, afatinib, and dacomitinib; or treatment should be changed to chemotherapy. Subsequent treatment by switching to other therapies including other molecular targeting and chemotherapeutic agents after tumor progression during gefitinib therapy is considered standard treatment. Confirmed resistance to gefitinib therapy poses a major clinical problem. What is the best time to discontinue gefitinib therapy? Tumor progression with clinical deterioration, the appearance of new metastatic lesions, and recurrence before initiation of gefitinib may be indications of the time to change therapy. Rapid tumor progression was observed in some cases after the discontinuation of gefitinib therapy. Subsequent treatment with other molecular targeting agents with higher biological activity such as erlotinib, afatinib, and dacomitinib after discontinuation of gefitinib therapy may inhibit rapid tumor progression, and an early switch to these molecular targeting agents may confer benefits on gefitinib responders. Subsequent treatment with more effective agents after gefitinib failure would be considered reasonable. In LUX-Lung 4, a phase II study on subsequent afatinib therapy in NSCLC patients who acquired resistance to gefitinib or erlotinib, afatinib showed very good efficacy; the response rate was 8%, stable disease was observed in 57% of patients, and the duration of response was 24 weeks [1]. However, a prospective study is needed to assess whether subsequent treatment with other molecular targeting agents would confer a survival benefit in patients after gefitinib failure compared to initial treatment with these agents as EGFR-tyrosine kinase inhibitor therapy. With regard to the survival benefit of continuing gefitinib therapy after disease progression, continuing therapy with gefitinib with the addition of chemotherapy may be a new strategy for EGFR-mutated NSCLC patients who demonstrate acquired resistance to gefitinib. The treatment strategy after progressive disease (PD) with gefitinib is a key clinical topic in the field of EGFR-mutated NSCLC. Currently, several prospective clinical trials on the treatment strategy after PD with gefitinib are ongoing. These include “A Study of IRESSA Treatment Beyond Progression in Addition to Chemotherapy Versus Chemotherapy Alone” ( [, Identifier NCT01544179) and “A randomized phase II trial of docetaxel with or without gefitinib in elderly advanced non-small cell lung cancer” (UMIN-CTR [, identification number UMIN000007765]). These trials may lead to develop new treatment strategy for patients who failed gefitinib.

[1]    Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K et al: LUX-Lung 4: A Phase II Trial of Afatinib in Patients With Advanced Non-Small-Cell Lung Cancer Who Progressed During Prior Treatment With Erlotinib, Gefitinib, or Both. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013.


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