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Keywords:

  • gefitinib;
  • chemonaive;
  • epidermal growth factor receptor;
  • nonsmall cell lung cancer

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND.

Chemonaive patients had higher response rates than chemotherapy-treated patients in previous analyses of East Asian patients with advanced nonsmall cell lung cancer. The survival outcome and the predictors for antitumor activity in chemonaive patients who received gefitinib as first-line treatment are unclear.

METHODS.

Clinicopathologic predictive factors, objective tumor responses, and the survival of consecutive patients with advanced, chemonaive nonsmall cell lung cancer who received gefitinib as first-line treatment were collected and analyzed. Multivariate analysis was conducted to determine independent predictive factors for gefitinib antitumor efficacy.

RESULTS.

One hundred ninety-six patients (112 males and 84 females) were analyzed. Ninety-six patients (49%) were never smokers. One hundred forty-four patients (73%) had adenocarcinoma or bronchioloalveolar carcinoma histology. One hundred twenty patients had an Eastern Cooperative Oncology Group performance status 0 to 2. Eighty-three patients (42%; 95% confidence interval, 36–49%) had an objective tumor response. An additional 35 patients had stable disease (disease control rate, 61%). The tumor response rate was 52% in patients who had a good performance status. Female gender, nonsmoking status, and adenocarcinoma histology all were independent predictors of response or disease control in multivariate analysis. The median survival was 11.1 months, and the 1-year survival rate of patients who had a good performance status was 47.5%.

CONCLUSIONS.

The response rate to gefitinib was high in East Asian chemonaive patients with advanced nonsmall cell lung cancer. Female gender, adenocarcinoma histology, and nonsmoking status all were independent predictors of gefitinib response. The survival outcome of these patients was similar to that of patients who initially received chemotherapy. Cancer 2006. © 2006 American Cancer Society.

Gefitinib was the first targeted agent to be approved for the treatment of patients with advanced nonsmall cell lung cancer (NSCLC) who failed on previous chemotherapy.1 Despite the observation that gefitinib can be beneficial in terms of response in patients NSCLC who already have received 1 or 2 regimens of chemotherapy,2 a recent report of a large, placebo-controlled, randomized study indicated that gefitinib failed to increase survival in chemotherapy-resistant patients.3 However, in the same study, a statistically significantly improvement in overall survival was demonstrated in gefitinib-treated patients over placebo-treated patients with East Asian ethnicity. These findings were consistent with the good response rate reported in Japanese patients in the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 study.4 Many other reports from East Asia also demonstrated that chemotherapy-treated patients with NSCLC from this region had high response rates and longer survival when they received gefitinib.5–10

In our previous analysis of 428 Taiwanese patients with advanced NSCLC who received treatment with gefitinib, no previous chemotherapy was associated with a better response to gefitinib in multivariate analysis.11 Several small, single-arm studies in East Asians have demonstrated the effectiveness of gefitinib in chemonaive patients with NSCLC.12–14 However, because of the small size or preselected nature of those studies, the estimated response rates for chemonaive East Asian patients who had different clinicopathologic predictive factors were unknown.

Patients who receive gefitinib rarely suffer from extreme fatigue, anorexia, emesis, or profound myelosuppression, which frequently are encountered in patients who receive systemic chemotherapy. Given the effectiveness and low side-effect profile of gefitinib in East Asia, it seems reasonable to replace chemotherapy with gefitinib as first-line treatment in patients with advanced NSCLC who have only limited life expectancy. Therefore, gefitinib often has been given to chemonaive patients who have a poor performance status and are not candidates to receive any chemotherapy or to patients who refuse to receive chemotherapy a priori. However, currently, there is no information on the survival outcome in a large patient population that received gefitinib as first-line treatment to justify the drugs as routine treatment.

For the current study, we retrospectively analyzed the response and survival of patients with advanced NSCLC who received gefitinib as first-line treatment from 2 medical centers in Taiwan. In this relatively unselected population, predictive indicators for gefitinib response and survival after gefitinib treatment were identified.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patients

All patients with Stage IIIB or IV NSCLC patients who received gefitinib as first-line treatment between October 2002 and December 2004 (National Taiwan University Hospital) or between October 2002 and May 2005 (Taichung Veterans General Hospital) in Taiwan were identified and included in this analysis. Medical charts, imaging reports, and films were reviewed. Patients were required to meet the following criteria to be included in these analyses: The diagnosis of NSCLC had to be confirmed histologically or cytologically. Patients must have had advanced Stage IIIB or Stage IV disease that was not curable with surgery or radiotherapy. Patients must not have received any chemotherapy for their advanced NSCLC. Clinical data were collected prospectively in each medical center's registry and included the patient's age; gender; Eastern Cooperative Oncology Group (ECOG) performance status; tumor histology; disease stage; smoking status (nonsmoking was defined as patients who had never smoked); dates of diagnosis, treatment, progression, and death or last follow-up; best response to gefitinib treatment; and any chemotherapy after failure to gefitinib. Some patients were included from our previous analysis,11 but the survival of those patients was updated in this analysis. These patients either refused the initial offer of chemotherapy and asked for gefitinib as their first-line treatment, or they had a poor performance status, and chemotherapy was not recommended. This study was approved by the Institutional Review Board.

Efficacy Assessments

In the clinical practice of both institutions, chest X-rays were obtained every month, and computed tomography scans of the chest and tumor metastatic sites were obtained at 2 to 3 months intervals for tumor size assessments in these patients. Imaging studies were reviewed retrospectively, and World Health Organization criteria were used to assess objective tumor response.15 If patients did not have adequate imaging studies available for tumor response evaluation, then they were counted as nonevaluable patients. Predictive factors, such as gender, performance status, smoking history, and disease stage, were recorded prospectively in the medical charts. Progression-free survival was measured from Day 1 of treatment until the first objective or clinical sign of disease progression. Overall survival was measured from Day 1 of treatment until the date of death.

Statistical Analysis

All patients who fulfilled the criteria described above were included in the intent-to-treat analysis to determine their response and survival. Potential predictive factors, such as gender, smoking status, adenocarcinoma versus nonadenocarcinoma histology, and disease stage, were tested in univariate models (with chi-square tests or the Fisher exact test) and in multivariate models (logistic regression) to predict response or disease stabilization to gefitinib. Kaplan–Meier analysis was used to estimate patient survival outcome. The log-rank test was used to compare the survival of patients with different predictive factors. A Cox proportional-hazards model was used to determine the effects of gender, smoking status, histology, disease stage, and postgefitinib chemotherapy on patient survival.

Epidermal Growth Factor Receptor Expression

Tissue blocks with histologically confirmed NSCLC were derived from the tissue block archive after informed consent was obtained. The mutational analysis of the epidermal growth factor receptor (EGFR) gene from formalin fixed, paraffin embedded diagnostic tissues was described previously.16 DNA was extracted from thin sections and subjected to nested polymerase chain reaction (PCR) amplification. Sequences of exons 18, 19, 20, and 21 of EGFR were derived from analyzing the purified, nested PCR amplicons in an automatic ABI Prism 3700 DNA analyzer.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patient Demographics and Treatment

Patient characteristics are summarized in Table 1. Approximately 50% of the population was male and 50% smoked. Approximately 75% of patients had adenocarcinoma or bronchioloalveolar carcinoma histology. For further evaluation, all patients were divided according to their performance status into a group with good performance status (ECOG performance status, 0–2; eligible for chemotherapy, n = 120 patients) and a group with poor performance status (ECOG performance status, 3–4; ineligible for chemotherapy; n = 76 patients). The characteristics of the patients are listed in Table 1. Patients received 500 mg or 250 mg of gefitinib on Day 1 and 250 mg every day thereafter. Treatment was continuous unless the patient developed intolerable toxicity or progressive disease. Some patients continued gefitinib treatment and refused chemotherapy even when there were clinical or radiologic signs of disease progression. Forty-six patients continued on gefitinib for > 1 month, 31 patients continued for > 2 months, 14 patients continued for > 6 months, and 4 patients continued for > 12 months after they had documented evidence of progressive disease. The duration of treatment ranged from 1 day to 33 months (median, 3.0 months).

Table 1. Characteristics of 196 Chemonaive Patients
CharacteristicNo. of patients (%)
TotalECOG PS 0-2ECOG PS 3-4
  1. ECOG PS indicates Eastern Cooperative Oncology Group performance status; BAC, bronchioloalveolar carcinoma.

All patients19612076
Age, y
 Median716874
 Range20–9120–8526–91
Gender
 Male112 (57)65 (54)47 (62)
 Female84 (43)55 (46)29 (38)
Smoking
 Yes100 (51)54 (45)46 (61)
 No96 (49)66 (55)30 (39)
Histology
 Adenocarcinoma and BAC144 (73)87 (73)57 (75)
 Squamous30 (15)17 (14)13 (17)
 Others22 (11)16 (13)6 (8)
Stage
 Stage III30 (15)19 (16)11 (14)
 Stage IV166 (85)101 (84)65 (86)

Tumor Response to Gefitinib Treatment

One hundred eighty-five patients were evaluable for response. There were 11 nonevaluable patients. They either had very short survival and evaluation imaging studies were not performed or their tumor could not be evaluated objectively on imaging studies. One patient had a complete response, and 82 patients had a partial response to gefitinib (response rate, 42%; 95% confidence interval [95% CI], 36–49%). An additional 35 patients had stable disease (disease control rate, 60%; 95% CI, 53–67%). The response rate was higher in patients who were eligible to receive chemotherapy than in patients who were ineligible to receive chemotherapy (52% vs. 28%). The response rates in each subset of patients with different predictive factors are listed in Table 2.

Table 2. Treatment Response of 196 Chemotherapy-Naive Patients
CharacteristicNo. of patients (%)
Total (n = 196)ECOG PS 0-2 (n = 120)ECOG PS 3-4 (n = 76)
ResponseStabilizationResponseStabilizationResponseStabilization
  • ECOG PS indicates Eastern Cooperative Oncology Group performance status; BAC, bronchioloalveolar carcinoma.

  • *

    Chi-square test.

  • Fisher exact test.

All patients83 (42)118 (60)62 (52)84 (70)21 (28)34 (45)
Gender
 Male33 (30)55 (49)25 (38)40 (62)8 (17)15 (32)
 Female50 (60)63 (75)37 (67)44 (80)13 (45)19 (66)
 P*.0001.0002.0017.0279.0085.0042
Smoking
 Yes28 (28)50 (50)20 (37)33 (61)8 (17)17 (37)
 No55 (57)68 (71)42 (64)51 (77)13 (43)17 (57)
 P*.0001.0029.0037.0546.0134.0912
Histology
 Adenocarcinoma and BAC70 (49)95 (66)50 (57)66 (76)20 (35)29 (51)
 Others13 (25)23 (44)12 (36)18 (55)1 (5)5 (26)
 P*.0031.006.0388.0229.0158.0622
Stage
 Stage III13 (43)17 (57)12 (63)14 (74)1 (9)3 (27)
 Stage IV70 (42)101 (61)50 (50)70 (69)20 (31)31 (48)
 P*.9054.6671.2746.7025.2720.3269

Overall Survival and Progression-Free Survival

One hundred thirty-seven patients (69.9%) had died at the time of the current analysis. Two patients were lost to follow-up after failure on gefitinib treatment. The median follow-up for 59 patients who remained alive was 13.4 months (range, 4.1–33 months). The Kaplan–Meier survival curves for each subset of patients are shown in Figure 1. The median overall survival for all patients was 8.4 months, and the 1-year survival rate was 36.2%. Overall survival was better in patients who had a good performance status (median survival, 11.1 months; 1-year survival rate, 47.5%) compared with patients who had a poor performance status (median survival, 2.4 months; 1-year survival rate, 18.3%). Although the survival probability generally was poor in patients who had a poor performance status, survival was remarkably good in 29 female patients who had an ECOG performance status of 3 or 4 (median survival, 9.1 months; 1-year survival rate, 37.0%). The median survival and overall survival for each subset of patients are listed in Table 3. One hundred seventy-three patients (88.3%) had disease progression at the time of this analysis. The median response duration for 83 responders was 8.5 months (95% CI, 6.9–10.0 months). The longest response duration in 1 patient was > 25 months. Seventy-five patients received postgefitinib chemotherapy after they developed disease progression. Among 120 patients who had a good performance status, 105 patients had developed progressive disease at the time of the current analysis. Fifty-nine of those patients received chemotherapy after gefitinib treatment, and their median survival was 14.0 months. Forty-six patients did not receive chemotherapy, and their median survival was 7.2 months. In 72 patients who had a poor performance status, 68 patients had developed progressive disease at the time of the current analysis. Twelve of those patients were able to receive chemotherapy when their performance status improved after gefitinib treatment. Their median survival was 9.2 months. Five of those patients lived for >18 months, and 4 of them remained alive at the time of this analysis.

thumbnail image

Figure 1. (A) This Kaplan–Meier curve illustrates the overall survival of all 196 patients. (B) These survival curves compare patients who had a good performance status (PS) (n = 120 patients) with patients who had a poor PS (n = 96 patients). (C and D) These survival curves illustrate gender in (C) patients with a good PS and (D) patients with a poor PS. (E and F) These survival curves illustrate smoking status in (E) patients with a good PS and (F) patients with a poor PS. N-smoker indicates nonsmoker. (G and H) These survival curves illustrate histology in (G) patients who had a good PS and (H) patients who had a poor PS. Adeno indicates adenocarcinoma histology; N-adeno, nonadenocarcinoma histology.

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Table 3. Overall Survival in Each Patient Subset
CharacteristicOverall survival
Total (n = 196)ECOG PS 0-2 (n = 120)ECOG PS 3-4 (n = 120)
Median, months1-year, %Median, months1-year, %Median, months1-year, %
  • ECOG PS indicates Eastern Cooperative Oncology Group performance status; BAC, bronchioloalveolar carcinoma.

  • *

    Log-rank test.

  • Cox regression analysis.

All patients8.436.211.147.52.418.3
Gender
 Male5.124.79.437.81.23.4
 Female11.649.215.155.39.137.0
 P*<.0001 .0096 <.0001 
 P.0716 .2690 .0015 
Smoking
 Yes4.819.98.427.11.811.4
 No14.051.118.260.74.626.9
 P*<.0001 <.0001 .0103 
 P.0022 .0007 .6163 
Histology
 Adenocarcinoma and BAC9.442.915.056.83.821.8
 Others4.318.17.024.10.87.9
 P*.0002 .0003 .0031 
 P.0223 .0192 .3898 
Stage
 Stage III8.445.715.161.42.018.2
 Stage IV8.234.310.944.62.618.1
 P*.5413 .2616 .3857 
 P.0308 .1152 .2245 
Chemotherapy
 Yes14.053.814.054.411.941.7
 No4.825.29.439.91.511.8
 P*<.0001 .0863 .0011 
 P<.0001 .0053 .0091 

Predictive Factors for Response

In univariate analysis, female gender, nonsmoking status, and adenocarcinoma histology were strong predictors of a tumor response or disease stabilization from gefitinib (Table 2). Logistic regression was used to test the independent contribution of these factors to tumor response or disease stabilization. The odds ratios with P values from the analysis are listed in Table 4. In that analysis, 3 factors remained strong independent predictors of a gefitinib-induced tumor response. When patients with a good performance status and patients with a poor performance status were analyzed separately, these 3 factors still were strong predictors of a tumor response to gefitinib treatment.

Table 4. Odds Ratio of Response or Disease Stabilization for Each Predictive Factor in All Patients
Patient subsetResponseDisease stabilization
OR (95% CI)P*OR (95% CI)P*
  • OR, odds ratio; 95% CI, 95% confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status.

  • *

    Logistic regression.

All patients (n = 196)
 Gender3.52 (1.94–6.39)<.00013.11 (1.68–5.76).0003
 Smoking3.45 (1.90–6.25)<.00012.43 (1.35–4.38).0032
 Histology2.84 (1.40–5.76).00392.44 (1.28–4.67).0068
 Stage1.049 (0.48–2.30).90520.84 (0.38–1.85).6673
ECOG PS 0–2 (n = 120)
 Gender3.29 (1.55–6.98).00192.50 (1.09–5.72).0302
 Smoking2.98 (1.41–6.27).00422.16 (0.98–4.79).0568
 Histology2.37 (1.03–5.41).04132.62 (1.13–6.09).0252
 Stage1.75 (0.64–4.80).27841.24 (0.41–3.75).7029
ECOG PS 3–4 (n = 76)
 Gender3.96 (1.38–11.38).01064.05 (1.52–10.81).0052
 Smoking3.63 (1.27–10.38).01612.23 (0.87–5.70).0937
 Histology9.73 (1.21–78.31).03252.90 (0.92–9.12).0685
 Stage0.23 (0.03–1.88).16830.41 (0.10–1.69).2179

Predictive Factors for Overall Survival

The log-rank test was used to compare overall survival in each subset of patients (Table 3). Female patients, patients who never smoked, and patients who had adenocarcinoma histology had better survival after gefitinib treatment. Because female gender and nonsmoking status were indicated previously as good prognostic factors in some studies, the contributions of gefitinib treatment on survival in patients with different clinical factors were not clear. Cox regression analysis was used to test the contributions of gender, smoking status, histology type, disease stage, and postgefitinib chemotherapy on the overall survival of patients. Patients who had a good performance status, nonsmoking status, adenocarcinoma histology, and postgefitinib chemotherapy were associated with a better survival outcome. Conversely, in patients who had a poor-performance status, female gender and postgefitinib chemotherapy were predictors of a better survival outcome.

Response and Survival Outcome of Patients with Wild Type or Mutated EGFR

Tumor samples were available from 37 patients. Nineteen samples tested positive for EGFR mutation (mutation rate, 51.3%). One patient had an exon 20, T790M-resistant type mutation,17 The clinical characteristics and types of mutation of these 19 patients are listed in Table 4. Thirteen of 19 patients with mutated EGFR responded (response rate, 68.4%). Seven of 18 patients with wild type EGFR responded (response rate, 38.9%), 3 patients had stable disease, 6 patients had progressive disease, and 2 patients had nonevaluable disease. The median survival of patients who had mutated and wild type EGFR was 15.0 months and 9.7 months, respectively (P = .29; log-rank test). Responders with wild type EGFR included 1 male smoker, 1 female smoker, and 5 female nonsmokers.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

In the current analysis, we demonstrated the high response rates of gefitinib monotherapy in chemonaive patients from Taiwanese with NSCLC (Table 5). These response rates were much higher than the earlier reported response rate (15.2–35.5%) and the reported 25.8% to 50% disease stabilization rate in chemotherapy-treated patients from East Asian countries.5, 8 Furthermore, in our previous analysis on 428 NSCLC patients who received gefitinib, no prior chemotherapy was among the independent predictive factors for a greater gefitinib-induced response in tumors.11 One of the factors that may account for the differences in the reported response to gefitinib is the percentage of patients with favorable predictive factors in the whole population. The contribution of preselection factors in this retrospective analysis is minimal because of the large population studied and the fact that response rates in each subset of patients with different predictive factors all were higher than that expected in chemotherapy-treated patients. Because all consecutive patients who were treated at these 2 medical centers during these periods were included in the current analysis, it is likely that the response rates to gefitinib in chemonaive patients in East Asia are as high as those reported here.

Table 5. Clinicopathologic Features, Gefitinib Response, and Survival Outcomes of Patients with Epidermal Growth Factor Receptor Mutations in Tumor Samples
Age, yearsGenderSmoking status*Pathologic cell typeGefitinib responseEGFR mutation exonNucleotide alternationAmino acid A iternationSurvival, months
  • EGFR indicates epidermal growth factor receptor; PR, partial response; Del, deletion; SD, stable disease; PD, progressive disease; Ins, insertion;

  • *

    Plus signs indicate that the patient remained alive at the time of the current report.

77MaleAdenocarcinomaPR19Del 2236–2250Del E746-A75018.7
45FemalePoorly differentiated carcinomaPR19Del 2236–2250Del E746-A7508.6
33FemaleAdenocarcinomaPD19Del 2236–2250Del E746-A750>13.4
54Male+AdenocarcinomaSD19Del 2236–2250Del E746-A7504.3
65Female+AdenocarcinomaPD19Del 2236–2250Del E746-A7503.8
77FemaleAdenocarcinomaPR19Del 2238–2252Del L747-T751>12.9
76FemaleAdenocarcinomaPR19Del 2239–2247, 2248 G[RIGHTWARDS ARROW]CDel L747-A750, Ins P>25.0
57FemaleAdenocarcinomaPR19Del 2240–2257Del 747-P753, Ins S>10.2
71Male+AdenocarcinomaSD192225 T[RIGHTWARDS ARROW]CV742A7.4
73FemaleAdenocarcinomaPR212573 T[RIGHTWARDS ARROW]GL858R11.0
77FemaleAdenocarcinomaPR212573 T[RIGHTWARDS ARROW]GL858R>17.4
76FemaleAdenocarcinomaPR212573 T[RIGHTWARDS ARROW]GL858R>16.0
55FemaleAdenocarcinomaPR212573 T[RIGHTWARDS ARROW]GL858R>16.3
54FemaleAdenocarcinomaPR212573 T[RIGHTWARDS ARROW]GL858R>9.4
75FemaleAdenocarcinomaPR212573 T[RIGHTWARDS ARROW]GL858R>16.4
70Male+AdenocarcinomaSD212573 T[RIGHTWARDS ARROW]GL858R3.9
74Male+Poorly differentiated carcinomaPR19, 212273 A[RIGHTWARDS ARROW]G, 2573 T[RIGHTWARDS ARROW]GE758G, L858R14.0
55Female AdenocarcinomaPD20, 212369 C[RIGHTWARDS ARROW]T, 2573 T[RIGHTWARDS ARROW]GT790M, L858R>10.4
78Male+AdenocarcinomaPR212520 C[RIGHTWARDS ARROW]T, 2527 G[RIGHTWARDS ARROW]AA848A, V843I15.0

One small study of gefitinib treatment in 37 chemonaive, never-smoking, and predominantly female patients with NSCLC demonstrated a high response rate (69%) and disease stabilization rate (80%) in Korea.13 However, that encouraging observation was not confirmed by another Phase II study from Japan that showed a response rate of only 30% in 40 unselected chemonaive patients who were treated with gefitinib.12 Another study on 30 chemonaive patients showed that the response rate of gefitinib was 33.3%. The median survival was 10.6 months, and the 1-year survival rate was 43.3%.14 The response rates to gefitinib treatment from several small studies in chemonaive patients with NSCLC in the western world were low.18, 19 Therefore, a more definitive clinical trial on a large number of chemonaive NSCLC patients with different predictive factors in East Asians is warranted. We have initiated 1 such study to include 106 patients with a good performance status using gefitinib as first-line treatment. The interim analysis on the first 44 patients demonstrated a response rate of 54.5%.20 This preliminary result confirmed our observation that the response rate of chemonaive patients is high in East Asian patients.

Because of the high effectiveness of gefitinib in East Asian patients with NSCLC, sometimes, it is given to patients who have not received any chemotherapy. If gefitinib is to be recommended to chemonaive patients with a good performance status, then the efficacy of gefitinib should be compared against standard combination chemotherapy. Platinum-based combination chemotherapy is the treatment of choice for patients with advanced, inoperable NSCLC. A survival benefit has been documented for patients who have a good performance status (ECOG performance status, 0–1), who received platinum plus a new drug, or patients with compromised performance status (ECOG performance status, 2), and who received monotherapy.21 The median survival was 11.1 months, and the 1-year survival rate was 47.5% in 120 patients who had a good performance status in this retrospective analysis. The survival outcome of these patients was similar to that of patients who received chemotherapy in our previous reports.22 The median survival was 18.8 months, and the 1-year survival rate was 65% in 43 female, nonsmoking patients with adenocarcinoma and a good performance patients in the current study. The expected survival was similar to the 78% 1-year survival rate in a Korean study.13 Although the survival outcome of these patients was much better than the average median survival of patients with NSCLC in our population,22 it should be noted that good predictive factors for response to gefitinib, such as female gender, were good prognostic factors for longer survival in patients who received chemotherapy.23, 24 A direct comparison of gefitinib with chemotherapy as first-line treatment in the East Asian population in a Phase III study to test the value of gefitinib in chemonaive patients who have a good performance status is indicated.

The use of EGFR-tyrosine kinase inhibitors as initial treatment for patients with a poor performance status is less controversial, because chemotherapy is not an option for these patients. In Western study of gefitinib treatment in 72 chemonaive patients with NSCLC who had a performance status of 2 or 3, the objective response rate was only 4%. Forty-six percent of patients in that study had stable disease, and the median survival was 6.3 months.19 Hotta et al. indicated that gefitinib should be given cautiously to patients with NSCLC who have a poor performance status.25 In these patients, the effectiveness of gefitinib probably is related to the time course for achieving a response. Patients who have tumors that respond slowly to gefitinib may not have time to improve before their disease deteriorates. In the current analysis, only approximately 33% of male patients or smokers with a poor performance status had their disease controlled by gefitinib, whereas 66% of female or nonsmoking patients had their disease controlled. Furthermore, > 40% of those patients who had a good predictive factor had an objective tumor response after gefitinib treatment. The median survival of female patients and of nonsmoking patients with a poor performance status who received gefitinib was 9 months and 5 months, respectively. Therefore, gefitinib may be recommended as initial treatment for these East Asian patients with a poor performance status.

The presence of mutations of exons 18, 19, or 21 of EGFR in clinical specimens from patients with NSCLC were correlated with a good response to gefitinib and long-term survival in previous studies.26, 27 The rates of mutations in the NSCLC samples from patients in East Asian countries ranged from 18.9% to 61.1%.16, 28–34 The response rates of East Asian patients with mutated EGFR ranged from 64.7% to 83% and the response rates of patients with wild type EGFR ranged from 0% to 30.8%.16, 28, 30–34 The response rate of 18 chemonaive patients with wild type EGFR expression in the current study was 38.9%: much higher than expected. The responding patients also had long survival after treatment. Most of the patients who responded were female nonsmoking patients. It is possible that, because of the heterogeneity of tumor tissue, mutated EGFR may not be detected in some small specimens from responding patients.35 Because of the limitation of tumor tissue acquisition for sequencing analysis, mutations of the EGFR gene determined by conventional sequencing technique may not be a good predictive biomarker for gefitinib treatment response in chemonaive patients with NSCLC.

The response rate to gefitinib in chemotherapy-treated patients was not affected by the receipt of 1 or 2 previous regimens.4 Conversely, we have demonstrated that the response rate was higher in chemonaive patients than in chemotherapy-treated patients. This finding, taken together with the differences in the independent predictive factors between chemonaive and chemotherapy-treated patients in our population, prompted us to hypothesize that there are fundamental biologic differences between chemonaive and chemotherapy-treated NSCLC cells. Comparison studies on prechemotherapy and postchemotherapy biopsy samples, especially in genes or proteins that demonstrate involvement in gefitinib sensitivity, should be carried out. In addition, patients should be stratified into a chemotherapy-treated group and a chemonaive group whenever receptor tyrosine kinase inhibitor sensitivity linked to the expression of genes is reported.

In summary, the survival outcome of patients who received gefitinib as initial treatment was similar to the survival outcome of patients who initially received chemotherapy. The response rate of gefitinib treatment was higher in chemonaive patients than in chemotherapy-treated patients. Female gender, nonsmoking status, and adenocarcinoma histology all are independent predictive factors for gefitinib response when it is given as first-line treatment. Gefitinib is indicated for patients who have a poor performance status and good predictive factors at initial treatment. The use of gefitinib in good-performance, chemonaive patients should be explored in randomized controlled studies. There may be fundamental biologic differences in terms of responsiveness to EGFR tyrosine kinase inhibitors between chemonaive patients and chemotherapy-treated patients with NSCLC.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We thank Dr. Ronald Freund for editing the article.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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