Original studyProspective Study of Gefitinib Readministration After Chemotherapy in Patients With Advanced Non–Small-Cell Lung Cancer Who Previously Responded to Gefitinib
Introduction
Gefitinib, an oral small-molecule agent that acts as an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first molecular targeted agent to be approved for the treatment of patients with advanced non–small-cell lung cancer (NSCLC). The extremely high response rate (RR) for gefitinib is associated with the presence of active EGFR mutations in tumor cells, such as in-frame deletions in exon 19 or point mutations in exon 21 (eg, L858R).1, 2, 3, 4, 5, 6, 7 Two phase III trials that compared chemotherapy with gefitinib in a first-line setting demonstrated that gefitinib could produce improved progression-free survival (PFS) compared with chemotherapy in patients who harbor EGFR-activating mutations.6, 7 EGFR-TKI in second-line treatment after chemotherapy showed similar activity as the first-line treatment in sensitive patients with EGFR mutations.4, 8, 9 Furthermore, as second-line chemotherapy, a phase III study demonstrated superior PFS with gefitinib than docetaxel for unselected patients in Korea.10 Thus, gefitinib is useful for the first- and second-line treatment of NSCLC.
Tumors initially responded to EGFR-TKI, but most patients with NSCLC eventually showed a progressive disease (PD). Although several possible mechanisms of secondarily acquired EGFR mutations11, 12 or other unrelated pathways to EGFR genotypes13 were reported, successful strategies for overcoming the resistance to EGFR-TKI have yet to be established.14, 15, 16 Thus, the development of a novel and possible therapeutic strategy for patients with resistance to EGFR-TKI is an important clinical issue in medical oncology. Several case reports and retrospective clinical analyses have indicated that the patients with NSCLC who responded to gefitinib in the initial treatment were successfully controlled by readministration of gefitinib.17, 18 However, there were a few prospective studies to evaluate the efficacy of gefitinib readministration in patients with NSCLC.14 In the present study, we prospectively investigated the efficacy of gefitinib readministration in 20 patients with NSCLC who initially responded well to gefitinib. The subjects received at least a cytotoxic chemotherapy after progression to initial gefitinib. The enrolled patients then were treated with readministration of gefitinib after progression to the chemotherapy.
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Patients and Methods
Subjects with histologically or cytologically confirmed NSCLC and recurrent or metastatic NSCLC (stage IV) were enrolled in this study. Patients with the following treatment histories were eligible: (1) responded to initial gefitinib treatment (complete response, partial response [PR], or stable disease [SD] over 6 months), (2) documented PD to the initial gefitinib according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines,19 and (3) then received at least 1 subsequent
Statistical Analysis
The objective RR with gefitinib readministration was taken as the primary endpoint in the present study. The Simon 2-stage MiniMax design was used to determine the sample size. We set RR at 25% with enrolled patients and a rate of 5% as the lower limit of interest, with α = .1 and β = .1. The estimated minimum sample size for was 20 cases. Secondary endpoints were disease-control rate (DCR), PFS, overall survival (OS), and toxicity. DCR was defined as the sum of the rate of RR plus SD. PFS and
Patient Characteristics
Twenty patients were enrolled between April 2007 and May 2011. The clinical characteristics are summarized in Table 1. The median age of patients was 61 years (range, 41-81 years). Seventeen (85%) patients were women, 18 (90%) were nonsmokers, and all the patients had adenocarcinoma. One patient initially received nonplatinum chemotherapy (docetaxel) because of advanced age, whereas, the other patients were treated with platinum doublet regimens, including, eg, cisplatin (CDDP) plus docetaxel
Discussion
We conducted a prospective study to evaluate the efficacy of gefitinib readministration in patients with a previous response to initial gefitinib therapy. The subjects treated with cytotoxic chemotherapies between the initial and second course of gefitinib therapy were enrolled in the present study. Fifteen percent of patients had PR to gefitinib readministration, although the interval of response was transient. Several retrospective studies or case reports suggested that gefitinib
Conclusion
Gefitinib readministration after a certain interval should be considered as one of the therapeutic options for selected patients who showed a good response to initial gefitinib treatment. New therapeutic approaches for identifying molecular markers that affect resistance to EGFR-TKI are required to break through the development of resistance to EGFR-TKI.
Disclosure
The authors have stated that they have no conflicts of interest.
Acknowledgments
We thank the patients and their families for their support and participation in this study.
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2017, Clinical Lung CancerCitation Excerpt :Some studies have prospectively examined the efficacy of gefitinib readministration in patients with NSCLC and acquired resistance after an initial response to gefitinib. These studies demonstrated a median PFS of 2.0 to 3.4 months.11-13 EGFR-TKI readministration appears to be effective after an EGFR-TKI–free interval that includes some treatment with cytotoxic drugs.14,15
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2016, Lung CancerCitation Excerpt :Indeed, ORR ranged from 0% [34] to 25% [37] and CBR from 44% [34] to approximately 65% [36,37]. PFS was 2 [35] and 2.5 months [34] and OS 10 [37] and 14.7 months [34]. The low ORR of 4.9% observed upon third-line gefitinib may be partly explained by the regrowth of EGFR-TKI-sensitive cells, reported in <10% of cases.
Rationale and study design of the IRENE-Trial (NVALT-16): A phase II trial to evaluate iressa rechallenge in advanced nsclc patients with an activating egfr mutation who responded to an EGFR-TKI used as first-line or previous treatment
2015, Clinical Lung CancerCitation Excerpt :Moreover, development of resistance along the course of the disease is not well understood. The treatment strategy of reinitiating EGFR-TKI treatment after a TKI-free period has been described various times15-25 and there is a biological rationale available to explain this phenomenon. Nevertheless, the strategy has never been evaluated prospectively.