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Keywords:

  • nonsmall cell lung cancer;
  • cetuximab;
  • epidermal growth factor receptor;
  • carboplatin;
  • docetaxel

Abstract

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

BACKGROUND.

Cetuximab, an immunoglobulin (Ig) G1 chimeric monoclonal antibody against the epidermal growth factor receptor, has demonstrated evidence of activity in nonsmall cell lung cancer (NSCLC). When administered in combination with carboplatin and docetaxel, a commonly used regimen for advanced NSCLC, cetuximab has exhibited synergistic interaction in preclinical studies. Therefore, a phase 2 study was conducted to evaluate the efficacy of the combination of cetuximab, carboplatin, and docetaxel for the treatment of advanced NSCLC.

METHODS.

Chemotherapy-naïve patients aged ≥18 years with stage IIIB (with effusion) or stage IV NSCLC received cetuximab (at a dose of 400 mg/m2 on Day 1 and 250 mg/m2 on Days 8 and 15) plus docetaxel (at a dose of 75 mg/m2 on Day 1) and carboplatin (area under the concentration vs time curve [AUC] = 6 on Day 1) every 21 days for up to 6 cycles (graded according to the American Joint Committee on Cancer Staging System). Thereafter, patients without evidence of disease progression were continued on single-agent cetuximab for a maximum of 1 year or until disease progression. The primary endpoint was response rate.

RESULTS.

Eighty patients were enrolled. The median number of cycles administered was 4 (range, 1-6 cycles). The objective response rate was 15.2%, with a median progression-free survival of 4.6 months and a median overall survival of 10.3 months. The salient grades 3 of 4 adverse events were neutropenia (30%), hypotension (3%), hypokalemia (4%), and hypomagnesemia (3%). Twenty-five patients received single-agent cetuximab (median duration, 12 weeks) and this was well tolerated.

CONCLUSIONS.

The results of this large, multicenter, phase 3 study indicate that the novel combination of cetuximab with docetaxel and carboplatin demonstrate modest anticancer activity for patients with advanced and metastatic NSCLC and has an acceptable toxicity profile. Cancer 2008. © 2008 American Cancer Society.

Nonsmall cell lung cancer (NSCLC) is diagnosed at an advanced stage in approximately 40% of the patients.1 Systemic chemotherapy is the primary treatment modality for advanced-stage NSCLC.2 The platinum-based combination regimens are considered the ‘standard of care’ for patients with advanced NSCLC. Both quantitative and qualitative benefits have been noted with combination chemotherapy for advanced NSCLC patients with a good performance status.3, 4 Several 2-drug regimens are in routine use because comparisons of various 2-drug regimens have yielded similar efficacy in this setting.3, 5, 6 The efforts in recent years to improve upon the efficacy of 2-drug combinations have primarily focused on the addition of a targeted agent to standard chemotherapy.

Cetuximab is an immunoglobulin (Ig) G1 chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR).7 The activation of the EGFR pathway leads to proliferation, metastasis, and angiogenesis, thus facilitating the progression of cancer.8 In addition, in vitro studies suggest the importance of IgG1-mediated antibody dependent cell-mediated cytotoxicity (ADCC) activity as an immunologic mechanism of cetuximab in lung cancer patients.9 The EGFR pathway is aberrant in a majority of patients with NSCLC, secondary to receptor overexpression, mutation, or gene amplification. Therefore, inhibition of the EGFR pathway has emerged as an important strategy to treat NSCLC. Cetuximab, as a single agent, has demonstrated activity in patients with recurrent and advanced NSCLC. In a phase 2 study of patients with refractory NSCLC, cetuximab monotherapy resulted in a response rate of 4.5% and disease stabilization in approximately 30% of patients.10 Cetuximab potentiates the anticancer effects of the platinum compounds and docetaxel in the preclinical setting.11–14 Combination cisplatin with cetuximab blocks activation of receptor tyrosine kinase and induces EGFR down-regulation.13

The combination of carboplatin and docetaxel is a commonly used regimen for the treatment of patients with advanced-stage NSCLC. The efficacy of this combination was established by a phase 3 study that compared it with a standard regimen of cisplatin and vinorelbine.15 There was comparable survival reported between the 2 regimens and the overall quality of life was found to be favorable with the use of the combination of carboplatin and docetaxel. Based on these factors, we conducted a phase 2 study to evaluate the efficacy and safety of cetuximab in combination with carboplatin and docetaxel for patients with previously untreated advanced or metastatic NSCLC.

MATERIALS AND METHODS

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

The primary objective of the current study was to determine the objective response rate associated with the combination of cetuximab, carboplatin, and docetaxel in patients with previously untreated advanced/metastatic NSCLC. The secondary endpoints included the determination of overall and progression-free survival and the assessment of toxicity associated with the regimen. The study protocol was reviewed and approved by the Institutional Review Board of each participating institution. All patients provided written informed consent to participate in the study.

The eligibility criteria were histologic/cytologic confirmation of NSCLC; stage IIIB with pleural/pericardial effusion or stage IV disease; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; age ≥18 years; presence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria; and willingness to provide informed consent (graded according to the American Joint Committee on Cancer Staging System). The qualifying laboratory criteria were hemoglobin >9 g/dL, an absolute neutrophil count ≥1500/μL, platelet count ≥100,000/μL, serum total bilirubin ≤institutional upper limit of normal (ULN), serum transaminases ≤2.5 × ULN, and serum creatinine ≤ULN. Patients with serum creatinine levels ≥ULN were eligible if their estimated creatinine clearance was ≥60 mL/minute/1.73 m2. The patients with prior chemotherapy, untreated or unstable brain metastasis, prior therapy with a known EGFR inhibitor, the presence of severe comorbid illness, peripheral neuropathy >grade 1, and known hypersensitivity to docetaxel or other drugs formulated with polysorbate 80 were excluded. At least 2 weeks should have elapsed since any prior radiotherapy before study entry.

Treatment Plan

Cetuximab was administered weekly at a dose of 250 mg/m2 (1-hour infusion) after an initial loading dose of 400 mg/m2 (2-hours infusion) on Week 1. After the cetuximab infusion, docetaxel and carboplatin were administered intravenously on Day 1 of each treatment cycle. Docetaxel was administered at a dose of 75 mg/m2 (1-hour infusion). Carboplatin was dosed to achieve an area under the concentration versus time curve (AUC) of 6 mg/mL and was infused over 30 minutes. The dose was calculated using the Calvert formula and the creatinine clearance was estimated by the Cockroft-Gault formula.16 The premedication regimen included dexamethasone (administered orally at a dose of 8 mg twice daily for 3 days), 5-HT3 antagonist, and diphenhydramine. During the maintenance phase, premedication for cetuximab consisted of diphenhydramine (50 mg intravenously) or a therapeutically equivalent histamine receptor inhibitor before each dose. The treatment cycles were repeated every 3 weeks. Chemotherapy was administered for a maximum of 6 cycles. The patients who achieved an objective response or disease stabilization after 6 cycles of therapy were treated with cetuximab monotherapy for up to 1 year. During the maintenance phase, 4 weeks of therapy with cetuximab constituted 1 treatment cycle. The treatment cycles were discontinued earlier in the event of disease progression, unacceptable toxicity, or withdrawal of informed consent. Granulocyte-colony–stimulating factor was not allowed during the first cycle of therapy, but was allowed during subsequent cycles according to institutional guidelines.

Patient Evaluation and Response Assessment

The pretreatment evaluations consisted of history and physical examination, assessment of PS, complete blood count (CBC), and hepatic and renal function tests. A baseline electrocardiogram was obtained if clinically indicated. Women of reproductive age underwent a serum pregnancy test. During the combination therapy phase, patients underwent weekly toxicity and PS assessment and determination of CBC. The serum chemistry panel was obtained during the initiation of each new cycle. For the maintenance phase, toxicity evaluation was performed every week and PS, CBC, and serum chemistry were assessed every 6 weeks. The radiologic studies were performed after every 2 cycles of therapy during the combination therapy phase. History and physical examination and assessment of PS were performed before the initiation of each new cycle. The responses were assessed with RECIST criteria.17

Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria (version 3.0). Mild to moderate infusion reactions with cetuximab were managed by slowing the infusion rate and with antihistamine therapy. Grade 3 or 4 infusion reactions led to permanent discontinuation of cetuximab infusion. The skin reactions were managed with supportive care measures such as topical corticosteroids and antibiotics for mild to moderate reactions. Dose reductions by 50 mg/m2 decrements were done for grade 3/4 skin rashes. Docetaxel was reduced to 60 mg/m2 (dose level −1) and then to 50 mg/m2 (dose level −2) for each instance of dose reduction. The dose of carboplatin was reduced by decrement of AUC = 1 mg/mL for each level of dose reduction. No more than 2 dose reductions were allowed for each patient. The dose of carboplatin was reduced by 1 dose level for grade 3/4 thrombocytopenia and docetaxel was reduced for grade 3/4 neutropenia. For other grade 3 or 4 toxicities, the dose of the drug attributable to the event was reduced by 1 dose level.

Statistical Analysis

The response rate was the primary endpoint of the study. An exact 2-sided 95% Clopper-Pearson confidence interval was computed for the response rate. The estimates of the median progression-free survival and the median survival, along with corresponding 95% confidence intervals, were calculated using the Kaplan-Meier product-limit method. Toxicity was summarized and reported as worst grade per subject.

RESULTS

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

A total of 80 patients were enrolled to the study over a period of 18 months. The patient baseline characteristics are outlined in Table 1. The median age was 63 years and 36 patients (45%) were aged ≥65 years. Women accounted for 47% of the study population. The majority of the patients had stage IV disease. White patients represented 80% of the study population, whereas African Americans accounted for 16%. Five patients had received prior radiotherapy and 2 had prior surgical intervention. Seventy-four patients had no prior therapeutic intervention for NSCLC.

Table 1. Patient Baseline Characteristics (N = 80 Patients)
CharacteristicNo.
  1. ECOG indicates Eastern Cooperative Oncology Group.

Sex 
 Male42 (53%)
 Female38 (47%)
Median age (range), y63 (42–83)
 ≥6536 (45%)
ECOG performance status 
 031 (39%)
 149 (61%)
Stage 
 IIIB5 (6%)
 IV75 (94%)
Histology 
 Adenocarcinoma42 (42%)
 Squamous cell carcinoma12 (15%)
 Other26 (33%)

A median of 4 cycles of combination therapy was administered (range, 1-6 cycles). The median dose of carboplatin and docetaxel was 5.6 (AUC) and 74.7 mg/m2, respectively. Twenty-five patients received maintenance therapy with cetuximab for a median of 2 cycles (range, 1-7 cycles). The treatment was discontinued in 50 patients because of disease progression and in 16 patients because of adverse events. The majority of the adverse events noted in the 16 patients were primarily related to the disease rather than therapy. In 6 patients, the physician discontinued therapy because of symptomatic progression of disease without radiologic confirmation. Six patients withdrew informed consent and 2 patients were lost to follow-up.

Toxicity

The adverse events were assessed from the date of first dose until 30 days after the end of therapy. During the combination therapy phase, hematologic toxicities were the most commonly reported events. Grade 3/4 neutropenia was noted in 24 (30%) patients, although it was associated with fever in only 4 (5%) patients. One patient experienced grade 4 hypersensitivity reaction during cetuximab infusion. Acneiform rash was noted in 29 (36%) patients during the combination therapy phase, although only 3 patients had grade 3 severity. Grades 1 and 2 fatigue was noted in 14 and 17 patients, respectively, during the combination therapy phase. The maintenance therapy was well tolerated. The majority of the toxicities were of grade 1 or 2 severity with the exception of skin rash. Four patients had grade 3 skin toxicity with cetuximab monotherapy. The toxicity data are summarized in Table 2.

Table 2. Toxicity*
ToxicityCombination Therapy (N=80)Maintenance Cetuximab (N=25)
Grade 3Grade 4Grade 3Grade 4
  • *

    Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria (version 3.0).

  • By highest grade during treatment, based on patients receiving at least 1 cycle of therapy.

Anemia2000
Neutropenia111300
Fever with neutropenia4000
Thrombocytopenia0100
Dehydration3010
Nausea2100
Vomiting1100
Hypotension2000
Hypertension1000
Skin rash3030
Motor neuropathy0100
Sensory neuropathy1010
Hypomagnesemia1100
Hypokalemia3000

Efficacy

Seventy-nine patients were evaluable for assessment of response to therapy (Table 3). One patient achieved a complete response and 11 achieved partial responses; the overall response rate was 15%. Disease stabilization was achieved in 18 (23%) patients. In 5 (28%) patients, disease stabilization lasted for ≥6 months. Response assessments were incomplete in 6 patients and the available information was inadequate to make a determination in 8 patients. Thirty-five patients (44%) had progressive disease. The median progression-free survival was 4.6 months and 4 patients (14%) remained free of disease progression at 12 months (Fig. 1A). The median survival and 1-year survival rate were 10.3 months and 36%, respectively. The 2-year survival rate was 16% (Fig. 1B).

thumbnail image

Figure 1. (A) Kaplan-Meier curve for progression-free survival. (B) Kaplan-Meier curve for overall survival. PD indicates progressive disease.

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Table 3. Efficacy
Best Objective ResponseEvaluable Patients (N=79)
  1. PFS indicates progression-free survival; 95% CI, 95% confidence interval.

Complete response1
Partial response11
Overall response rate15.2%
Stable disease18 (23%)
Median PFS, mo4.6 (95% CI, 3.2–6.2)
Median survival, mo10.3 (95% CI, 7.5–11.5)

DISCUSSION

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

An efficacy plateau has been noted with various platinum-based regimens for the treatment of advanced NSCLC. Therefore, combinations of molecularly targeted agents with standard chemotherapy are undergoing rigorous evaluation in this disease. The results of the current study demonstrate the feasibility and safety of combining cetuximab with the regimen of carboplatin and docetaxel for patients with advanced or metastatic NSCLC. Although the response rate was low, the median progression-free survival and overall survival are promising in this patient population. In addition, the current study also documented the ability to administer single-agent cetuximab as maintenance therapy after 6 cycles of chemotherapy in combination with cetuximab. The study was conducted in multicenter community-based practices and therefore provides the opportunity to interpret these results as being valid in the ‘real world’ setting. To our knowledge, this is the largest phase 2, single-arm study to date that has evaluated cetuximab in combination with platinum-based, 2-drug chemotherapy regimens in the first-line treatment of patients with advanced NSCLC.18–20 In contrast to EGFR tyrosine kinase inhibitors, the monoclonal antibodies against EGFR appear to be more suited for combinations with chemotherapy, based on data from recent randomized studies.21, 22 A randomized phase 2 study of cisplatin and vinorelbine with or without cetuximab demonstrated higher response rates and overall survival in favor of cetuximab-based therapy.18 Another randomized study that compared treatment with platinum/gemcitabine with or without cetuximab also demonstrated a higher response rate and progression-free survival with the addition of cetuximab.23

The results of the current phase 2 studies have now been verified by 2 phase 3 studies that have been reported since the completion of our phase 2 study. Lynch et al24 randomized patients with advanced NSCLC to treatment with a combination of carboplatin and taxane alone or in combination with cetuximab. Although the response rate was higher with the addition of cetuximab, no superiority was noted in progression-free survival. However, a subset analysis demonstrated improved progression-free survival for patients who received the combination of carboplatin, docetaxel, and cetuximab over the same chemotherapy alone. We are currently awaiting the survival data from this study. Similar to the phase 2 study reported herein, the study by Lynch et al did not use any molecular markers for patient selection for their trial. In contrast, a study by Pirker et al25 treated EGFR-expressing NSCLC patients (by immunohistochemistry) with the combination of cisplatin and vinorelbine alone or in combination with cetuximab. That phase 3 study demonstrated an improvement in overall survival (11.3 months vs 10.1 months; P = .044) and response rate with the addition of cetuximab to chemotherapy, although the progression-free survival was found to be similar between the 2 arms. It is premature to conclude that molecular selection alone played a role in the positive results of the FLEX study,25 but the use of these novel agents in enriched patient populations is highly desirable.

Other molecular markers for patient selection for cetuximab-based therapy are also being evaluated by ongoing studies. In a recent study conducted by the Southwest Oncology Group,26 patients with advanced NSCLC were treated with carboplatin and paclitaxel in combination with either the concurrent or sequential administration of cetuximab. The median survival was 11 months for both the concurrent and sequential approaches. However, patients whose tumor tissues had a higher EGFR gene copy number had a median survival of 16 months, compared with 8 months in patients with low EGFR gene copy numbers. This demonstrates the feasibility of using molecular markers to select patients for therapy with the novel cetuximab-based combination therapy and may provide evidence supporting a difference between monoclonal antibodies and small-molecule tyrosine kinase inhibitors in this disease. The lack of information regarding the relevant molecular markers on patient tumor specimens is a limitation of the current study. In addition to gene amplification, certain mutations in the EGFR gene have also been linked with sensitivity to EGFR tyrosine kinase inhibitors.27 To our knowledge, the clinical impact of the presence of EGFR mutation on the efficacy of therapy with cetuximab-based combinations or monotherapy has not been adequately studied and represents another important area of future investigation.

In summary, the combination of cetuximab with chemotherapy represents a novel strategy for the treatment of patients with advanced NSCLC. The regimen of carboplatin and docetaxel is a well-tolerated platform for the addition of cetuximab for patients with previously untreated advanced/metastatic NSCLC.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Jemal A,Siegel R,Ward E,Murray T,Xu J,Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007; 57: 4366.
  • 2
    Ramalingam S,Belani CP. State-of-the-art chemotherapy for advanced non-small cell lung cancer. Semin Oncol. 2004; 31: 6874.
  • 3
    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.
  • 4
    Kelly K,Crowley J,Bunn PAJr, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. JClin Oncol. 2001; 19: 3210328.
  • 5
    Treat J,Belani CP,Edelman M,Socinski MA,Ansari R. A randomized phase III trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in advanced non-small cell lung cancer: update of the Alpha Oncology Trial [abstract]. J Clin Oncol. 2005; 23: 1096. Abstract 7025.
  • 6
    Smit EF,van Meerbeeck JP,Lianes P, et al. Three-arm randomized study of 2 cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group—EORTC 08975. J Clin Oncol. 2003; 21: 39093917.
  • 7
    Baselga J. The EGFR as a target for anticancer therapy—focus on cetuximab. Eur J Cancer. 2001; 37( suppl 4): S1622.
  • 8
    Baselga J,Albanell J. Targeting epidermal growth factor receptor in lung cancer. Curr Oncol Rep. 2002; 4: 317324.
  • 9
    Kurai J,Chikumi H,Hashimoto K, et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res. 2007; 13: 15521561.
  • 10
    Hanna N,Lilenbaum R,Ansari R, et al. Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer. J Clin Oncol. 2006; 24: 5253528.
  • 11
    Nakata E,Hunter N,Mason K,Fan Z,Ang KK,Milas L. C225 antiepidermal growth factor receptor antibody enhances the efficacy of docetaxel chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2004; 59: 11631173.
  • 12
    Morelli MP,Cascone T,Troiani T, et al. Sequence-dependent antiproliferative effects of cytotoxic drugs and epidermal growth factor receptor inhibitors. Ann Oncol. 2005; 16( suppl 4): iv61iv8.
  • 13
    Baselga J,Norton L,Masui H, et al. Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J Natl Cancer Inst. 1993; 85: 13271333.
  • 14
    Baselga J,Pfister D,Cooper MR, et al. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol. 2000; 18: 904914.
  • 15
    Fossella F,Pereira JR,von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003; 21: 30163024.
  • 16
    Calvert AH,Newell DR,Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989; 7: 17481756.
  • 17
    Therasse P,Arbuck SG,Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000; 92: 205216.
  • 18
    Rosell R,Daniel C,Ramlau R,Szczesna A,Constenla M,Mennecier B. Randomized phase II study of cetuximab in combination with cisplatin (C) and vinorelbine (V) vs. CV alone in the first-line treatment of patients (pts) with epidermal growth factor receptor (EGFR)-expressing advanced non-small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004; 23: 618.
  • 19
    Thienelt CD,Bunn PAJr,Hanna N, et al. Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer. J Clin Oncol. 2005; 23: 87868793.
  • 20
    Robert F,Blumenschein G,Herbst RS, et al. Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naive advanced non-small-cell lung cancer. J Clin Oncol. 2005; 23: 90899096.
  • 21
    Giaccone G,Herbst RS,Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. JClin Oncol. 2004; 22: 777784.
  • 22
    Herbst RS,Giaccone G,Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol. 2004; 22: 785794.
  • 23
    Butts C,Bodkin D,Middleman E, et al. Gemcitabine/platinum alone or in combination with cetuximab as first-line treatment for advanced non-small cell lung cancer [abstract]. J Clin Oncol. 2007; 25: 394s. Abstract 7539.
  • 24
    Lynch T,Patel T,Dreisbach L, et al. A randomized phase III study of cetuximab in combination with taxane/carboplatin verus taxane/carboplatin alone as first-line treatment for patients with advanced/metastatic non-small cell lung cancer [abstract]. J Thorac Oncol. 2007; 2: S340. Abstract B3-03.
  • 25
    Pirker R,Szczesna A,Von Pawel J, et al. FLEX: a randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine verus cisplatin/vinorelbine alone in the first-line treatment of patients with advanced non-small cell lung cancer [abstract]. J Clin Oncol. 2008; 26: 6s. Abstract 3.
  • 26
    Herbst RS,Chansky K,Kelly K, et al. A phase II randomized selection trial evaluating concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in patients with advanced non-small cell lung cancer (NSCLC): final report of SWOG 0342 [abstract]. J Clin Oncol. 2007; 25: 395s. Abstract 7545.
  • 27
    Paez JG,Janne PA,Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304: 14971500.