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 » Introduction
 »  Materials and Me...
 » Results
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Table of Contents 
ORIGINAL ARTICLE
Year : 2013  |  Volume : 19  |  Issue : 1  |  Page : 48-53

The role of Gefitinib in patients with non-small-cell lung cancer in India


1 Department of Pulmonary Medicine, Cancer Institute and Institute of Molecular Medicine, Amrita Institute of Medical Sciences, AIMS Ponekkara P.O. Kochi, Kerala, India
2 Department of Medical Oncology and Hematology, Cancer Institute and Institute of Molecular Medicine, Amrita Institute of Medical Sciences, AIMS Ponekkara P.O. Kochi, Kerala, India
3 Cancer Institute and Institute of Molecular Medicine, Amrita Institute of Medical Sciences, AIMS Ponekkara P.O. Kochi, Kerala, India

Date of Web Publication8-Apr-2013

Correspondence Address:
Asmita Anilkumar Mehta
Department of Pulmonary Medicine, Cancer Institute and Institute of Molecular Medicine, Amrita Institute of Medical Sciences, AIMS Ponekkara P.O. Kochi, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1075.110237

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 » Abstract 

Background: Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor, represents a new treatment option for patients with advanced non-small-cell lung cancer (NSCLC). We analyzed the data of patients who received Gefitinib for NSCLC in a tertiary care center in South India.
Materials and Methods: Sixty-three patients with advanced NSCLC who had received Gefitinib either after failure of conventional chemotherapy or were previously not treated as they were unfit or unwilling for conventional treatment were included in the analysis.
Results: The median follow-up for the cohort was 311 days (range 11-1544 days). Median time to progression was 161 (range 9-883) days. Complete and partial remission was seen in 1 (2%) and 6 (9%) patients, respectively, with overall response rate of 11%. Twenty-four (38%) patients had stable disease. Gefitinib was well tolerated with no significant side effects.
Conclusion: Gefitinib shows anti-tumor activity in pretreated or previously untreated patients with advanced NSCLC. It has a favorable toxicity profile and is well tolerated. Gefitinib should be considered as a viable therapy in patients with NSCLC.


Keywords: Epidermal growth factor-tyrosine kinase inhibitor, Gefitinib, Non-small-cell lung cancer


How to cite this article:
Mehta AA, Jose WM, Pavithran K, Triavadi GS. The role of Gefitinib in patients with non-small-cell lung cancer in India. Indian J Palliat Care 2013;19:48-53

How to cite this URL:
Mehta AA, Jose WM, Pavithran K, Triavadi GS. The role of Gefitinib in patients with non-small-cell lung cancer in India. Indian J Palliat Care [serial online] 2013 [cited 2019 Aug 23];19:48-53. Available from: http://www.jpalliativecare.com/text.asp?2013/19/1/48/110237



 » Introduction Top


Lung cancer is the leading cause of cancer among men in India. According to International Agency for Research on Cancer, 43,500 Indian patients are diagnosed with lung cancer every year and 37,500 die of the disease. [1] Indian patients present with the disease at an earlier age than Western patients. [2] Chemotherapy is beneficial for patients with locally advanced and metastatic disease. [3] Adjuvant chemotherapy is generally indicated for patients with resected stages IB through IIIA non-small-cell lung cancer (NSCLC). [4],[5],[6] Elderly patients may have a poor tolerance to chemotherapy due to impaired organ function and frequent co-morbidities. Patients with poor performance status (PS ≥2 due to NSCLC and/or coexisting illnesses) are often considered unfit for conventional chemotherapy.

Alteration of the major cell-signaling and regulatory pathways either by overexpression or gene mutation is a frequent event in lung cancer. These patients may benefit from novel, relatively nontoxic treatment modalities like targeted therapies. The epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy because it is overexpressed in a variety of tumors, including NSCLC. [7] The EGFR is overexpressed in 40-80% of patients with NSCLC, and is associated with poor prognosis. [8] High levels of EGFR expression and deregulation promote tumor growth by increasing cell proliferation, motility, adhesion, invasive capacity, and by evading apoptosis, and therefore have been associated with poorer prognosis in several studies. [9] EGFR-tyrosine kinase inhibitors (TKIs) inhibit the intracellular tyrosine kinase domain of the EGFR, and therefore block the signal transduction pathways implicated in the proliferation and survival of cancer cells. [10] There was lack of correlation with EGFR overexpression and response to EGFR inhibitors. In a landmark study, it was shown that patients whose tumors demonstrated a mutation in the kinase domain of EGFR responded to such inhibitors. The mutations in the kinase domain render the EGFR protein constitutively active. The patients whose tumors harbor an EGFR mutation response well to TKIs.

Gefitinib is an EGFR-TKI and has recently been approved in several countries for use in advanced or metastatic NSCLC. [11] Gefitinib monotherapy in patients with advanced NSCLC has been investigated in two large, multicenter, randomized phase II trials: "Iressa" Dose Evaluation in Advanced Lung cancer (IDEAL) 1 and 2 and The Iressa Survival Evaluation in Lung cancer study (ISEL). [11],[12],[13] The study showed an increased efficacy with Gefitinib in the subgroup of patients of Asian origin and those who were non-smokers. However, there is very little data about the efficacy of the drug in patients of Indian origin. We analyzed patients receiving oral Gefitinib for advanced NSCLC to understand the clinical response in the Indian patients.


 » Materials and Methods Top


The study included all patients with histology-proven NSCLC, who had failed previous chemotherapy regimens, or those chemotherapy-naive patients who were either not willing or unfit for conventional chemotherapy. Gefitinib was administered at 250 mg/day until disease progression, unacceptable toxicity, or death occurred. Patients who were diagnosed from January 2006 to January 2010 were included, and they were studied till January 2011. Data were collected on demographics, smoking status, type of tumor, tumor stage at the time of diagnosis, Eastern Cooperative Oncology Group (ECOG) PS, previous local treatment, previous chemotherapy status and response, time of starting Gefitinib from the time of diagnosis, duration of Gefitinib treatment, time to progression, symptom improvement (SI) and outcome after Gefitinib. Detailed information about previous chemotherapy was included, i.e., number of lines, drugs administered, and duration of treatment, treatment-free intervals, and best objective response to each line. Response was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) parameters. Patient's initial evaluation of response was performed after the first month of treatment by chest X-ray and/or computed tomography (CT) scan of thorax. SI was evaluated according to the clinical judgment of the treating physician.

Statistical analysis

The relationship between patients' characteristics and likelihood of response or disease control (i.e., response or stabilization) was tested using a Chi-square test in the univariate analysis. Overall survival was defined as the period between the date of diagnosis and the date of last follow-up or date of death. Time to progression was defined as the period between initiation of Gefitinib treatment and the date of progression or date of last follow-up. The relationship with survival was studied by Kaplan-Meier analysis. A P value of <0.05 was considered to be statistically significant. The data were analyzed with SPSS software (version 11).


 » Results Top


Patient characteristics and initial treatment

Sixty-three patients with NSCLC, diagnosed from January 2006 to January 2010, were included in this study. The median age of patients was 63 years (range 39-86 years). There were 35 (56%) men and 28 (44%) women. Thirty-four (54%) of the patients were never smokers. Majority of the patients (n = 55, 87%) had advanced disease [Table 1]. The ECOG PS was ≤2 in 41 (65%) patients. The most common histopathology type was adenocarcinoma (AD; 71%), followed by squamous cell carcinoma (18%) and bronchoalveloar carcinoma (BAC; 11%).
Table 1: Patients' demographics

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Response

Complete remission was observed in 1 (1.6%) patient. There were 5 (7.9%) patients with partial remission. Twenty-four (38%) patients had stable disease. Progressive disease was observed in 28 (42.8%) patients. There were five patients who were lost to follow-up in our hospital and their response was unknown.

Toxicity

The most common toxicity observed in the study patients was skin rash (32%). Among the patients with this, one had severe skin rash, leading to discontinuation of treatment. Gefitinib was otherwise well tolerated with no reported hepatotoxicity.

Survival and prognostic factors

The median duration of Gefitinib treatment was 183 days (range 9-1094 days). The median duration of follow-up was 311 days (range 11-1544 days). The progression-free survival (PFS) was 161 days (95% CI: 124-200). The overall response rate (OR) which included complete remission (CR) and partial remission (PR) was 11%, and disease control rate (CR + PR + stable disease (SD)) was 49%. Twenty-seven (42.86%) patients had progression of disease. Five patients were lost to follow-up. Univariate analysis of different variables with outcome is shown in [Table 2]. The response was better among females (P = 0.028), nonsmokers (P = 0.065): [Figure 1] and [Figure 2] and previously untreated patients (P = 0.053). Median time to progression was 162 days. Variables associated with longer PFS were again female sex and non-smokers. There was no statistically significant difference found with regard to PFS between patients who received Gefitinib as first-line chemotherapy and those who received it as subsequent chemotherapy. On multivariate analysis, none of the variables showed statistically significant difference in relation to OR or PFS [Table 3].
Figure 1: Survival according to sex of the patients (female, ---; male, -)

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Figure 2: Survival according to smoking status of the patients (nonsmoker, ---; smoker, __)

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Table 2: Univariate analysis

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Table 3: Multivariate analysis

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 » Discussion Top


This single-center study was an analysis of the patients with advanced disease NSCLC, who received treatment with Gefitinib either as first-line or as subsequent line of treatment. The drug was prescribed when conventional chemotherapy was felt to be not feasible or as too toxic for the individual in the first- and second-line setting.

Objective response rate in our study was 11%. Response rate of IDEAL 1 was 18.4, [14] IDEAL 2 was 12%, [15] single agent Gefitinib (SIGN) study was 13.2%, [16] and Iressa survival evaluation in lung cancer (ISEL) India was 14%. Thus, our studies' OR was comparable to that of previous studies which were conducted in an unselected group of patients.

Activating mutations in the EGFR gene contribute to tumor progression, and also therefore confer hypersensitivity to the TKIs, Gefitinib and Erlotinib, in patients with advanced NSCLC. Mutations in EGFR and KRAS are the most commonly observed alterations in NSCLC. As per previous studies, Gefitinib cannot be given to the patients with KRAS mutation. [17]

Response rates in EGFR mutation-positive patients receiving Gefitinib after previous chemotherapy have been reported to be between 76% and 91% in Asian studies [14],[18],[19],[20],[21],[22],[23] and between 58% and 70% in non-Asian patients. [24] This study was conducted in unselected patients, and response rate (RR) was 11%. It may have been better if EGFR status was evaluated as shown in other studies in selected patients. [25],[26]

There was no survival benefit noted in our study, which was similar to the results obtained in ISEL and Iressa pan Asia Study (IPASS). [27] The median duration of treatment with Gefitinib was 6.1 months (range 9-1094 days).

Improvement in symptoms was reported in 80% of the patients, the majority of such symptoms being dyspnea, cough, effort tolerance, and general well-being. Patients of Asian origin, never-smoking status, AD histology, and female sex have been reported to be the predictors of improved response in previous randomized trials of TKIs. [5],[16],[21],[28]

The nonsmoker status of lung cancer patients is the strongest indicator of activity of Gefitinib in Western populations. [12],[29],[30] In our study, on univariate analysis, female sex and nonsmoker status were associated with an improved outcome. In previous studies, AD histology, especially the AD-BAC subtype, is usually associated with higher likelihood of response. [16],[17],[18],[31],[32],[33],[34],[35],[36] In our study, patients with AD or bronchoalveolar type had a higher OR when compared with non-adenocarcinoma patients (44% vs. 19%). However, the difference was not statistically significant (P = 0.611). The reason for this is probably the small number of patients. [Table 4] shows comparison of the present study data with the results of previously conducted clinical trials. Our study showed median survival time of 10.4 months and 1-year survival of 44% (28/63). The median survival and PFS was comparable with other studies conducted in Asia. [7],[17],[21] It was also comparable to IDEAL 1 and 2 studies. [20],[17],[32] The response rate (11%) in the present study was lower than that obtained in the Chinese study (27%) and Taiwanese study (33.3%). [7],[22] This could be attributed to different frequency of mutation in EGFR in Indian patients compared to studied populations. There is no published data available for EGFR mutation in NSCLC patients from India.
Table 4: Summary of phase II/III Gefitinib 250 mg/day efficacy data on "unselected" patients with advanced NSCLC and comparison with the present study data

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The strength of the study is its adequately large sample size to say the results were statistically significant. This is the first Indian study in which Gefitinib was evaluated in unselected patients with NSCLC.

The data of the study may be helpful for planning future multicenter studies for more appropriate documentation of role of Gefitinib in Indian population. It will also be interesting to see the incidence of EGFR mutation rate in tumors (NSCLC). There are more improved drugs that inhibit EGFR, in addition to Erlotinib and Gefitinib that are in trial. It is now possible to initiate treatment in a patient with an EGFR inhibitor as primary chemotherapy if the tumor is positive for a mutation and has a wild k-Ras.


 » Conclusion Top


EGFR mutation ?positive status highly correlates with a favorable response, and in case of NSCLC patients, -positive status highly correlates with a favorable response, and in case of NSCLC patients, it should be done. But in resource-limited countries like India, where the test is not easily available, in case of advanced NSCLC patients, treatment with Gefitinib is still a viable option. Female sex and nonsmoking status are the variables related to positive response in the present study. Gefitinib therapy of 250 mg/day has a favorable toxicity profile and is well tolerated.

 
 » References Top

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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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