Elsevier

Clinical Lung Cancer

Volume 13, Issue 6, November 2012, Pages 458-463
Clinical Lung Cancer

Original study
Prospective Study of Gefitinib Readministration After Chemotherapy in Patients With Advanced Non–Small-Cell Lung Cancer Who Previously Responded to Gefitinib

https://doi.org/10.1016/j.cllc.2012.01.006Get rights and content

Abstract

Introduction

Salvage treatment for acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor in patients with non–small-cell lung cancer is a matter of clinical concern. Several retrospective reports have indicated the usefulness of epidermal growth factor receptor tyrosine kinase inhibitor readministration; however, there have been few prospective studies.

Materials and Methods

This study was designed to prospectively evaluate the clinical efficacy of gefitinib readministration in patients with advanced or metastatic non–small-cell lung cancer who responded well to initial gefitinib treatment. The subjects received at least 1 regimen of cytotoxic chemotherapy after progressive disease with the initial gefitinib therapy. Gefitinib administration (250 mg/d, orally) was started after progressive disease with the previous chemotherapeutic regimen. The primary endpoint in the present study was the response rate.

Results

Twenty patients were enrolled between April 2007 and May 2011. Three patients achieved partial response, and 6 showed stable disease. Thus, the overall response rate and disease control rate of gefitinib readministration were 15% (95% CI, 3.21-37.9) and 45% (95% CI, 23.1-68.5), respectively. Median progression-free survival and overall survival from the start of gefitinib readministration were 2.0 months (95% CI, 0.9-3.1 months) and 12.0 months (95% CI, 8.0-16.0 months), respectively.

Conclusion

These results suggest that gefitinib readministration may be an option, albeit with a low response rate and short progression-free survival, for patients who responded well to initial gefitinib followed by systemic chemotherapy. These findings provide valuable information for the management of previous gefitinib responders.

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.

Section snippets

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.

References (24)

  • A. Inoue et al.

    Prospective phase II study of gefitinib for chemotherapy-naïve patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations

    J Clin Oncol

    (2004)
  • S. Morita et al.

    Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations

    Clin Cancer Res

    (2009)
  • Cited by (27)

    • Response to the Combination of Osimertinib, Dabrafenib, and Trametinib in Leptomeningitis From EGFR-Mutant NSCLC With Acquired BRAF V600E Mutation: A Case Report

      2021, JTO Clinical and Research Reports
      Citation Excerpt :

      This treatment sequence may have modified the subclonal heterogeneity of the tumor and resensitized it to EGFR inhibition, by prompting the proliferation of the sensitive EGFR-mutated clone after removing the selective pressure from the EGFR TKI.3 However, experience gained from patients rechallenged with first-generation EGFR TKIs reflects that, despite an interesting initial disease control rate (45%), the median PFS remains short (around 2.0 mo).4 The relative long-term response (at least 1 y) achieved using O+D+T argues in favor of the efficacy of this treatment combination.

    • Phase II Study of the EGFR-TKI Rechallenge With Afatinib in Patients With Advanced NSCLC Harboring Sensitive EGFR Mutation Without T790M: Okayama Lung Cancer Study Group Trial OLCSG 1403

      2017, Clinical Lung Cancer
      Citation 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

    • Efficacy and safety of rechallenge treatment with gefitinib in patients with advanced non-small cell lung cancer

      2016, Lung Cancer
      Citation 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 Cancer
      Citation 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.

    View all citing articles on Scopus
    View full text