SEARCH

SEARCH BY CITATION

Keywords:

  • erlotinib;
  • pemetrexed;
  • non-small cell lung cancer;
  • second-line therapy;
  • epidermal growth factor receptor (EGFR) copy number

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

The current study was undertaken to investigate the efficacy and safety of erlotinib versus pemetrexed as second-line therapy for patients with advanced epidermal growth factor receptor (EGFR) wild-type and EGFR fluorescence in situ hybridization (FISH)-positive lung adenocarcinoma.

METHODS

In this open-label, randomized, phase 2 study, patients with EGFR wild-type and EGFR FISH-positive adenocarcinoma who had developed disease progression after 1 prior platinum-based chemotherapy were randomly assigned (1:1) to receive erlotinib or pemetrexed until the time of disease progression or death, unacceptable toxicity, or a request for discontinuation by the patient. The primary endpoint was progression-free survival (PFS).

RESULTS

A total of 123 patients were enrolled (61 in the erlotinib arm and 62 in the pemetrexed arm). The median PFS was 4.1 months (95% confidence interval [95% CI], 1.6 months-6.6 months) in the erlotinib group versus 3.9 months (95% CI, 2.7 months-5.1 months) in the pemetrexed group. The difference in PFS between the 2 treatment groups was not significant (hazard ratio, 0.92; 95% CI, 0.62-1.37 [P = .683]). The objective response rate appeared to be higher among patients receiving erlotinib compared with those receiving pemetrexed (19.7% vs 8.1%; P = .062). The 3 most commonly recorded adverse events were rash (54.1%), fatigue (19.7%), and diarrhea (16.4%) in the erlotinib group and fatigue (25.8%), nausea (24.2%), and anorexia (14.5%) in the pemetrexed group.

CONCLUSIONS

There were no significant differences noted with regard to efficacy between erlotinib and pemetrexed in the second-line setting for patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma. Both regimens appear to be effective treatment options for these patients. Cancer 2014;120:1379–1386. © 2014 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Lung cancer is the most common cancer worldwide and > 7 in 10 patients are presented with advanced-stage disease at the time of diagnosis.[1] Standard first-line treatment for these patients usually consists of platinum-based doublet chemotherapy,[2, 3] but disease progression ultimately occurs for most patients. Second-line treatment options available to patients who experience failure of first-line treatment include additional chemotherapy (docetaxel and pemetrexed) or targeted therapy.[4-7] Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been investigated in several studies in the second-line setting. The National Cancer Institute of Canada Clinical Trials Group Study BR.21 trial reported prolonged survival with erlotinib compared with placebo (median survival, 7.9 months vs 3.7 months) in patients with advanced non-small cell lung cancer (NSCLC) after the failure of previous chemotherapy,[7] whereas in the INTEREST (IRESSA Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) study and the V-15-32 study, gefitinib was found to have noninferior survival compared with docetaxel.[8, 9]

Several studies have demonstrated that a high EGFR gene copy number was associated with great sensitivity and prolonged progression-free survival (PFS) among patients with NSCLC after treatment with EGFR TKIs.[7, 10-14] However, subsequent studies indicated that a high EGFR copy number was not associated with greater PFS when comparing EGFR TKIs versus chemotherapy.[15, 16] Accordingly, biomarker analyses of the IPASS (IRESSA Pan-Asia Study) trial suggested that the apparent PFS benefit of gefitinib in patients with a high EGFR copy number was driven by overlapping with a coexisting EGFR mutation.[17] The value of the EGFR copy number as a predictive marker among patients with NSCLC who are treated with TKIs remains controversial.

Pemetrexed was approved for the second-line treatment of advanced NSCLC after the findings of a phase 3 trial by Hanna et al demonstrated equivalent outcomes to docetaxel. Pemetrexed was associated with fewer adverse events compared with docetaxel and comparable efficacy (median survival of 8.3 months vs 7.9 months).[6] However, to the best of our knowledge, no trial has been designed to date comparing EGFR TKIs with chemotherapy in patients with EGFR wild-type and EGFR fluorescence in situ hybridization (FISH)-positive (high polysomy or gene amplification) lung adenocarcinoma in the second-line setting. Although the evaluations of EGFR mutation and EGFR copy number were believed to be time-consuming and not feasible for all the patients, they are needed when there are predictive biomarkers for the efficacy of EGFR TKIs.

This phase 2 study was designed to assess the efficacy and safety of erlotinib compared with pemetrexed as second-line treatment of patients with EGFR wild-type and EGFR FISH-positive lung adenocarcinoma.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Study Procedure and Treatment Plan

This prospective, randomized, open-label, phase 2 study in which erlotinib was compared with pemetrexed as second-line therapy in patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma was conducted in Sun Yat-sen University Cancer Center. This trial was approved by the Medical Ethics Committee and Clinical Trial Review Committee of the study institution and followed the Declaration of Helsinki and Good Clinical Practice guidelines. All enrolled patients provided signed written informed consent before the study-related procedures; separate signed written consents were obtained for analyses of biomarkers. Tumor tissue was used from formalin-fixed, paraffin-embedded, archival diagnostic tumor tissue. All EGFR mutations were assessed by the amplification-refractory mutation system (ARMS) method.[18] Patients were classified as EGFR mutation-negative if they did not have an EGFR mutation. FISH positivity was defined as high polysomy or gene amplification.[10] Tumors were classified according to the 1997 International System for Staging Lung Cancer.[19] The primary endpoint was progression-free survival (PFS). Secondary endpoints were the objective response rate (ORR), overall survival (OS), and safety and tolerability.

Patients were randomly assigned in a 1:1 ratio to receive either erlotinib or pemetrexed. Randomization was stratified by sex (female vs male), Eastern Cooperative Oncology Group (ECOG) performance status (0 to 1 vs 2), and smoking history (never vs ever) with a minimization algorithm. Erlotinib was administered orally at a dose of 150 mg per day; pemetrexed was administered on day 1 of every 3-week cycle as a 10-minute intravenous infusion of 500 mg/m2. Patients in the pemetrexed treatment arm were also given vitamin B12 and dexamethasone to reduce toxicities. Treatment continued until disease progression, unacceptable toxicity, or a request for discontinuation by the patient. Poststudy treatment was based on the decision of the physicians and patients.

Patients

Patients were eligible if they were aged 18 years to 75 years, had an ECOG performance status of 0 to 2, had pathologically or cytologically confirmed stage IIIB to IV lung adenocarcinoma (including locally advanced and metastatic lung adenocarcinoma) or postoperative recurrent lung adenocarcinoma not curable by surgery or radiotherapy, had EGFR wild-type and EGFR FISH-positive disease, had received 1 prior platinum-based chemotherapy (including neoadjuvant or adjuvant chemotherapy), and had a life expectancy of ≥ 3 months. Patients with postoperative disease recurrence have to have developed recurrence within 6 months after neoadjuvant or adjuvant chemotherapy. Other inclusion criteria were adequate bone marrow function (absolute neutrophil count of > 1.0 × 109/L, platelet count > 100 × 109/L, and hemoglobin > 90 g/L), adequate liver function (bilirubin < 1.5 times upper limit of normal and serum transaminase < 2 times upper limit of normal) and renal function (creatinine < 2 mg/dL), and the presence of 2-dimensional measurable disease.

Patients were excluded if they had received prior EGFR TKIs or pemetrexed, or had concurrent uncontrolled illness. Other exclusion criteria were prior malignant disease (except for basal cell carcinomas), symptomatic brain metastases, and pregnancy.

Assessments

The baseline assessment before study entry involved a history and physical examination, hematologic and biochemical testing, chest x-ray, electrocardiogram, and radiographic imaging of all involved sites of disease (thoracic and upper abdomen computed tomography scan, brain magnetic resonance imaging, and other examination when necessary).

PFS was defined as the time from the date of randomization to the date of tumor progression or death from any cause; data were censored at the time of the last tumor assessment if disease progression or death did not occur. Tumor responses were evaluated every 6 weeks according to Response Evaluation Criteria in Solid Tumors (RECIST). OS was defined as the time from the date of randomization to the date of death from any cause; data were censored at the last time patients were known to be alive. Safety and tolerability were assessed every 3 weeks according to the National Cancer Institute Common Toxicity Criteria (version 3.0).

Statistical Analysis

Efficacy and safety analyses were performed for all the randomized patients who received at least 1 dose of the trial medication and had at least 1 safety follow-up. This trial was designed to detect a 40% decrease in the hazard of progression with erlotinib versus pemetrexed (hazard ratio [HR], 0.6). In consideration of the possibility of a deviation from assessment, a total of 120 patients (60 patients per treatment arm) were required to provide 80% power with a 1-sided significance level of 5%.

The Kaplan-Meier method was used to estimate PFS and OS. The HR of erlotinib to pemetrexed was estimated with 95% confidence intervals (95% CIs) and P values. The log-rank test was used to compare PFS and OS between the 2 treatment groups. Preplanned subgroup analysis with the Cox proportional hazards model, including sex, smoking history, ECOG performance status, and best response to the prior chemotherapy, was used to estimate the HR for PFS and OS. The chi-square test or Fisher exact test was used to compare the ORRs and adverse events (AEs) between the 2 groups. All P values were 2-sided and P values < 0.05 were considered to be statistically significant.

This study is registered at ClinicalTrials.gov (NCT01565538).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

From December 2008 to May 2012, a total of 123 patients were enrolled and randomly assigned to receive either erlotinib or pemetrexed (Fig. 1). The treatment groups were well matched for baseline characteristics including sex, ECOG performance status, stage of disease, and smoking history (Table 1). Greater than one-half of the patients were current smokers and most patients had an ECOG performance status of 0 to 1. On the date of data cutoff (May 10, 2012), the median follow-up was 14.7 months (range, 0.5 months-41.9 months). After the study, 49% of the patients in the erlotinib treatment group received no other therapy except for further erlotinib, and 23% received subsequent pemetrexed; of the patients in the pemetrexed group, 61% received subsequent erlotinib and 18% received no other therapy apart from pemetrexed (Table 2).

Table 1. Baseline Characteristics of Both Treatment Groupsa
CharacteristicsErlotinib ArmPemetrexed Arm
n = 61n = 62
  1. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; PD, progressive disease; PR, partial response; SD, stable disease.

  2. a

    Data are shown as the median (range) or number of patients (%). Some percentages may not sum to 100 due to rounding.

Age, y  
Median54.355.1
Range30-7433-75
Sex  
Male40 (65.6%)39 (62.9%)
Female21 (34.4%)23 (37.1%)
ECOG PS  
0, 157 (93.4%)59 (95.2%)
24 (6.6%)3 (4.8%)
Smoking status  
Never15 (24.6%)17 (27.4%)
Former7 (11.5%)5 (8.1%)
Current39 (63.9%)40 (64.5%)
Stage of disease  
IIIB4 (6.6%)6 (9.7%)
IV40 (65.6%)38 (61.3%)
Recurrent17 (27.9%)18 (29.0%)
Best response to first-line treatment  
PR21 (47.7%)20 (45.5%)
SD13 (29.5%)15 (34.1%)
PD10 (22.7%)9 (20.5%)
Table 2. Poststudy Treatmenta
 Erlotinib Arm (n = 61)Pemetrexed Arm (n = 62)
  1. a

    Data are shown as the number of patients (%).

Total37 (61%)52 (84%)
Erlotinib6 (10%)38 (61%)
Pemetrexed14 (23%)1 (2%)
Docetaxel15 (25%)9 (15%)
Other2 (3%)4 (6%)
image

Figure 1. The trial profile is shown. EGFR indicates epidermal growth factor receptor; FISH, fluorescence in situ hybridization; +, positive.

Download figure to PowerPoint

By the time of analysis, 100 instances of disease progression (51 in the erlotinib group and 49 in the pemetrexed group) and 89 deaths had occurred (42 in the erlotinib group and 47 in the pemetrexed group), and disease progression or death was the main reason for withdrawing from the study. The median PFS was 4.1 months (95% CI, 1.6 months-6.6 months) in the erlotinib group versus 3.9 months (95% CI, 2.7 months-5.1 months) in the pemetrexed group. The 6-month PFS rates were 45.1% and 38.8%, respectively, among the patients treated with erlotinib and those receiving pemetrexed. The difference in the primary endpoint between the erlotinib and pemetrexed groups was not statistically significant (HR, 0.92; 95% CI, 0.62-1.37 [P = .683]) (Fig. 2A). PFS results were consistent across all the preplanned subgroups (Table 3).

Table 3. Subgroup Analyses of Progression-Free Survival and Overall Survivala
VariablePFSOS
HR95% CIPHR95% CIP
  1. Abbreviations: 95% CI, 95% confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

  2. a

    The HR for erlotinib versus pemetrexed was derived from a Cox model including only treatment as a factor; an HR <1 favors erlotinib and an HR >1 favors pemetrexed.

Sex      
Male1.050.63-1.73.861.240.73-2.11.44
Female0.810.42-1.57.520.640.31-1.33.23
Smoking status      
Smoker0.920.58-1.47.741.100.68-1.80.70
Nonsmoker0.800.36-1.78.580.810.34-1.90.62
ECOG PS      
0,10.910.61-1.38.660.990.58-1.71.97
20.460.08-2.80.400.631.10-3.95.63
Response to prior chemotherapy      
PR1.120.62-2.01.721.310.70-2.43.40
SD1.090.53-2.26.810.800.35-1.80.58
PD0.370.10-1.40.140.520.21-1.33.17
image

Figure 2. Kaplan-Meier curves are shown for (A) progression-free survival and (B) overall survival in both treatment groups.

Download figure to PowerPoint

According to the investigator's assessment, 12 of 61 patients in the erlotinib arm (19.7%) and 5 of 62 patients in the pemetrexed arm (8.1%) experienced an objective response. All the objective responses were partial responses and there was no complete response reported (Table 4). In general, the ORR appeared to be higher among patients in the erlotinib arm compared with the pemetrexed arm, although the difference was not statistically significant (P = .062). The median OS was 11.7 months (95% CI, 7.5 months-15.9 months) in the patients treated with erlotinib and 13.4 months (95% CI, 9.2 months-17.7 months) among those in the pemetrexed group; and no statistically significant difference in OS was observed (HR, 1.01; 95% CI, 0.66-1.54 [P = .970]) (Fig. 2B). The OS results were consistent across all the preplanned subgroups (Table 3).

Table 4. Best Tumor Response in Both Treatment Groupsa
ResponseErlotinibPemetrexed
n = 61n = 62
  1. a

    Data are shown as the number of patients (%). Some percentages may not sum to 100 due to rounding.

Objective response12 (19.7%)5 (8.1%)
Complete response00
Partial response12 (19.7%)5 (8.1%)
Stable disease20 (32.8%)26 (41.9%)
Progressive disease23 (37.7%)27 (43.5%)
No assessment6 (9.8%)4 (6.5%)

The common AEs are listed in Table 5. The overall treatment-related AE rates were similar between the erlotinib group and the pemetrexed group (73.8% vs 69.4%). The 3 most commonly recorded AEs were rash (54.1%), fatigue (19.7%), and diarrhea (16.4%) in the erlotinib group, whereas fatigue (25.8%), nausea (24.2%), and anorexia (14.5%) were the 3 most common AEs reported in the pemetrexed arm. Patients in the erlotinib group experienced significantly higher rates of rash and diarrhea compared with those in the pemetrexed group, whereas patients receiving pemetrexed experienced significantly higher rates of nausea compared with those receiving erlotinib. The recorded AEs were generally mild (grade 1 or 2), with the exception of 4 patients in the erlotinib group (6.6%) and 3 patients in the pemetrexed group (4.8%) who developed a grade 3 or higher AE. Only 1 patient in the erlotinib group withdrew as a result of diarrhea. No cases of dose modification or death were reported as a result of study treatment in both groups.

Table 5. Treatment-Related Adverse Eventsa, b
VariableAll GradesGrades 3 or 4
ErlotinibPemetrexedErlotinibPemetrexed
(n = 61)(n = 62)(n = 61)(n = 62)
  1. a

    Adverse events were graded every 3 weeks according to the National Cancer Institute Common Toxicity Criteria (version 3.0).

  2. b

    Data are shown as the number of patients (%).

Rash33 (54.1%)4 (6.5%)2 (3.3%)0
Diarrhea10 (16.4%)2 (3.2%)1 (1.6%)0
Dry skin3 (4.9%)000
Paronychia1 (1.6%)000
Pruritus3 (4.9%)000
Anorexia6 (9.8%)9 (14.5%)1 (1.6%)0
Nausea1 (1.6%)15 (24.2%)02 (3.2%)
Constipation04 (6.5%)00
Fatigue12 (19.7%)16 (25.8%)00
Infection3 (4.9%)1 (1.6%)00
Alopecia03 (4.8%)00
Insomnia4 (6.6%)3 (4.8%)00
Headache1 (1.6%)3 (4.8%)00
Leukopenia03 (4.8%)01 (1.6%)

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

To our knowledge, the current study is the first randomized study that targeted EGFR wild-type and EGFR FISH-positive lung adenocarcinoma. This study failed to demonstrate the superiority of erlotinib over pemetrexed, and the differences with regard to PFS, OS, and the ORR were not statistically significant between erlotinib and pemetrexed when used as the second-line treatment of patients with EGFR wild-type and EGFR FISH-positive adenocarcinoma. Results from subgroup analyses for PFS and OS were consistent with overall results.

Although several phase 3 studies comparing EGFR TKIs with chemotherapy in the second-line setting have demonstrated that similar efficacy exists between EGFR TKIs and chemotherapy, to the best of our knowledge these studies were not designed to investigate the potential effect of EGFR mutational status on efficacy.[8, 9, 16, 20-22] The TAILOR (TArceva Italian Lung Optimization tRial) trial compared erlotinib with docetaxel as the second-line treatment of advanced NSCLC in patients with wild-type EGFR disease. Results of the trial demonstrated that compared with docetaxel, erlotinib was effective in patients with wild-type EGFR. The median PFS was 2.9 months and 2.4 months, respectively, in the docetaxel and the erlotinib arms (P = .02).[23] In a recent phase 3 trial, a comparison of docetaxel with erlotinib as second-line or third-line treatment in patients with advanced NSCLC who had wild-type EGFR indicated that PFS was significantly improved with docetaxel (HR, 0.69; 95% CI, 0.52-0.93 [P = .013]).[24] In another recent phase 2 study in patients with advanced, nonsquamous NSCLC who had wild-type EGFR, second-line treatment with pemetrexed was found to confer a significantly longer PFS than gefitinib (HR, 0.51; 95% CI, 0.36-0.73 [P < .001]).[25] These findings suggest that for patients presented with EGFR wild-type NSCLC, chemotherapy is superior to an EGFR TKI. However, to the best of our knowledge, none of these studies were designed to address the role of EGFR gene copy number as a predictive marker among patients with wild-type EGFR.

The IPASS trial established the role of EGFR TKIs as first-line treatment in patients with EGFR mutant NSCLC, whereas for patients with EGFR wild-type tumors, the PFS was significantly shorter among patients receiving gefitinib compared with those undergoing chemotherapy (HR, 2.85; 95% CI, 2.05-3.98 [P < .001]).[26] However, a combined analysis of the second-line/third-line National Cancer Institute of Canada Clinical Trials Group Study BR.21 trial and the maintenance setting SATURN trial (Sequential Tarceva in Unresectable NSCLC) demonstrated that for patients with wild-type NSCLC, erlotinib provided a significant improvement in PFS (HR, 0.72; 95% CI, 0.60-0.87 [P < .01]) and OS (HR, 0.71; 95% CI, 0.58-0.87 [P = .04]).[27] In the IPASS trial, although high EGFR copy number is associated with longer PFS, a high EGFR copy number without an accompanying mutation was associated with a shorter PFS with gefitinib therapy.[17] Although evidence from a meta-analysis demonstrated that a high EGFR copy number is associated with improved survival outcomes with EGFR TKIs, to the best of our knowledge the role of EGFR copy number as a predictive biomarker for the benefit of EGFR TKIs remains controversial.[14] The results of the current study demonstrated that erlotinib had efficacy similar to that of chemotherapy. In view of the evidence of the superiority of chemotherapy for patients with EGFR wild-type NSCLC,[23-25] the current study results indicate that EGFR TKIs should still be considered as an effective option for patients with EGFR wild-type and EGFR FISH-positive lung adenocarcinoma.

The PFS noted among patients in the erlotinib arm (median PFS, 4.1 months) in the current study was notably longer than those in previous, unselected, population-based studies or studies targeting wild-type EGFR, which reported PFS of 1.5 months to 3.6 months for patients on the TKI arm.[7-9, 11, 16, 22-25] Reasons for the longer PFS may largely relate to the 100% second-line setting and the 100% EGFR FISH-positive adenocarcinoma study design. Most previous studies were designed for previously treated patients with NSCLC who had failed of 1 or 2 prior chemotherapy regimens.[7-9, 11, 22, 24] In the 100% second-line setting TITAN (Tarceva In Treatment of Advanced NSCLC) trial, all the enrolled patients were those with poor prognosis (developed disease progression during 4 cycles of first-line chemotherapy).[16] Another reason might be the selection of erlotinib instead of gefitinib as second-line treatment. In the BR.21 trial, erlotinib prolonged survival for pretreated patients with EGFR wild-type NSCLC.[27] Erlotinib was approved for the second-line treatment of patients with advanced NSCLC,[7] whereas gefitinib was not. Furthermore, the longer PFS might be related to the high percentage of patients with postoperative disease recurrence. Because postoperative patients have a smaller tumor burden, their survival might be better.

The OS reported among patients in the erlotinib arm (median OS, 11.7 months) in the current study was in keeping with that demonstrated in previous studies, which reported an OS of 5.3 months to 14.8 months for patients treated with TKIs.[7-9, 11, 16, 22-25] However, the interpretation of the OS results of the current study might be confounded by the imbalance of crossover. In the current study, 61% of the patients in whom second-line pemetrexed failed crossed over to erlotinib therapy, but only 23% of the patients in whom second-line erlotinib failed crossed over to pemetrexed therapy. It is interesting to note that there was a trend toward improvement in the ORR among patients in the erlotinib arm, which is consistent with the results of previous studies.[10, 12, 13, 15] However, it is still unclear why the improved ORR did not translate into prolonged PFS or OS in the current study.

As expected, rash and diarrhea occurred more frequently with erlotinib treatment, whereas nausea and leukopenia occurred more often among the patients treated with pemetrexed. Overall, the occurrence and severity of AEs in the current study were much the same as those in previous studies and there were no unexpected toxicities in either group. In terms of convenience, compared with chemotherapy administered in the hospital setting, erlotinib can be taken orally at home. Together with its efficacy results, we believe that erlotinib should still be considered as a valid option for patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma.

Although the numbers of patients were relatively small, the results of the current study, which targeted the treatment of patients with EGFR wild-type and EGFR FISH-positive lung adenocarcinoma in the second-line setting, enrich the clinical evidence for the efficacy and safety of second-line therapy with EGFR TKIs or chemotherapy among patients with advanced NSCLC.

In conclusion, the differences in efficacy between erlotinib and pemetrexed were not found to be significant for the second-line treatment of patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma. Both erlotinib and pemetrexed appear to be effective treatment options in the second-line setting for patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
  • 1
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:6990.
  • 2
    Schiller JH, Harrington D, Belani CP, et al. Comparison of 4 chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:9298.
  • 3
    Scagliotti GV, De Marinis F, Rinaldi M, et al. Phase III randomized trial comparing 3 platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol. 2002;20:42854291.
  • 4
    Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens.The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000;18:23542362.
  • 5
    Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000;18:20952103.
  • 6
    Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:15891597.
  • 7
    Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123132.
  • 8
    Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372:18091818.
  • 9
    Maruyama R, Nishiwaki Y, Tamura T, et al. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol. 2008;26:42444252.
  • 10
    Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005;97:643655.
  • 11
    Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366:15271537.
  • 12
    Zhu CQ, da Cunha Santos G, Ding K, et al;National Cancer Institute of Canada Clinical Trials Group Study BR.21. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR. 21. J Clin Oncol. 2008;26:42684275.
  • 13
    Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol. 2006;24:50345042.
  • 14
    Dahabreh IJ, Linardou H, Kosmidis P, Bafaloukos D, Murray S. EGFR gene copy number as a predictive biomarker for patients receiving tyrosine kinase inhibitor treatment: a systematic review and meta-analysis in non-small-cell lung cancer. Ann Oncol. 2011;22:545552.
  • 15
    Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol. 2010;28:744752.
  • 16
    Ciuleanu T, Stelmakh L, Cicenas S, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012;13:300308.
  • 17
    Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29:28662874.
  • 18
    Newton CR, Graham A, Heptinstall LE, et al. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res. 1989;17:25032516.
  • 19
    Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest. 1997;111:17101717.
  • 20
    Lee DH, Park K, Kim JH, et al. Randomized Phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010;16:13071314.
  • 21
    Sun JM, Lee KH, Kim SW, et al. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012;118:62346242.
  • 22
    Karampeazis A, Voutsina A, Souglakos J, et al. Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer. 2013;119:27542764.
  • 23
    Garassino MC, Martelli O, Broggini M, et al;TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013;14:981988.
  • 24
    Okano Y, Ando M, Asami K, et al. Randomized phase III trial of erlotinib (E) versus docetaxel (D) as second- or third-line therapy in patients with advanced non-small cell lung cancer (NSCLC) who have wild-type or mutant epidermal growth factor receptor (EGFR): Docetaxel and Erlotinib Lung Cancer Trial (DELTA) [abstract]. J Clin Oncol. 2013;31(suppl 15):8006.
  • 25
    Yang JJ, Cheng Y, Zhao MF, et al. A phase II trial comparing pemetrexed with gefitinib as the second-line treatment of nonsquamous NSCLC patients with wild-type EGFR (CTONG0806) [abstract]. J Clin Oncol. 2013;31(suppl 15):8042.
  • 26
    Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947957.
  • 27
    Osarogiagbon R, Cappuzzo F, Ciuleanu T, Leon L. Erlotinib after initial platinum-doublet chemotherapy in patients with epidermal growth factor receptor (EGFR) wild-type (WT) non-small cell lung cancer (NSCLC): results of a combined patient-level analysis of the BR. 21 and SATURN trials [abstract]. J Clin Oncol. 2013;31(suppl 15):8080.