FLEX: A randomized,multicenter, phase III study of cetuximab in combination with cisplatin/ vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC)

Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 1, 2008

Presenter: R. Pirker
Presenter's Affiliation: Medical University of Vienna, Vienna, Austria
Type of Session: Plenary

  • Lung cancer represents the most common cause of cancer death in both men and women in the United States. Non-small cell lung cancer (NSCLC) occurs much more commonly than small cell lung cancer, accounting for approximately 80% of total lung cancer cases.
  • Approximately 40% of patients diagnosed with NSCLC present with advanced disease (stage IIIB with pleural effusion or stage IV).
  • Platinum-based chemotherapy doublets are generally delivered as first-line treatment to patients with advanced NSCLC, with the intent of improving overall survival as well as palliating symptoms.
  • Epidermal growth factor (EGFR) is expressed in over 80% of NSCLC tumors, and overexpression is associated with poor prognosis, tumor growth, and increased risk of metastasis.
  • Cetuximab (Erbitux) is an IgG1 monoclonal antibody that binds to EGFR, blocking signal transduction.
  • Overall survival benefit with addition of cetuximab to either conventional chemotherapy or radiotherapy in colorectal and head and neck cancers has been demonstrated in phase III trials (Hebbar 2007; Bonner 2006).
  • Several phase II trials have demonstrated potentially improved outcomes with addition of cetuximab to platinum-based chemotherapy in treatment of NSCLC (Rosell 2008; Butts 2007).
    • A previous randomized phase II FLEX (First-Line Treatment for Patients with EGFR-EXpressing Advanced NSCLC)trial compared cisplatin and vinorelbine to cisplatin, vinorelbine, and cetuximab in patients with advanced NSCLC. Forty-three patients were randomized to each arm. Improvement in outcomes were seen with the addition of cetuximab; tumor response was improved from 28% to 35% with addition of cetuximab, progression-free survival was improved from 4.6 months to 5 months, and overall survival was improved from 7.3 to 8.3 months (Rosell, 2008).
  • Data from the FLEX phase II trial prompted the design of the FLEX phase III trial, the results from which are presented here. This trial represents a phase III, randomized, controlled trial designed to determine overall survival benefit with addition of cetuximab to cisplatin/ vinorelbine.
Materials and Methods
  • Patients were randomized to one of two arms as part of this trial. The reference arm consisted of cisplatin (80 mg/ m2 on day 1) and vinorelbine (25 mg/l m2 on days 1 and 8) given every three weeks (CV). The experimental arm consisted of the same regimen, with the addition of cetuximab (400 mg/ m2 followed by 250 mg/ m2 weekly) (CV + C). Following a maximum of 6 cycles of chemotherapy, patients from either arm continued on maintenance cetuxiumab until progressive disease or drug intolerance developed.
    • Of note, vinorelbine dosing was originally planned to be 30 mg/m2. This dose was reduced to 25 mg/ m2 due to hematologic toxicity after enrollment began.
  • The primary endpoint evaluated was overall survival. Secondary endpoints were tumor response, progression free survival, disease control, quality of life, and safety.
  • The trial was designed to have 90% power to detect a significant difference in overall survival; the trial was intended to randomize 1100 patients.
  • Patient stratification was performed according to ECOG performance status and tumor stage.
  • Two interim safety analyses were planned.
  • Eligibility criteria included stage IIIB disease with pleural effusion ("wet" IIIB) or stage IV disease, NSCLC of any histology, ECOG performance status of 0-2, age of at least 18, and EGFR expression as measured by immunohistochemistry (IHC). Positive EGFR expression was defined as at least one cell staining positive on IHC.


· During the study period, 1688 patients were identified with newly diagnosed, untreated, advanced lung cancer. o Of these, 1442 (85%) had tumors expressing EGFR on IHC. o 1125 patients agreed to trial enrollment and randomization. 557 patients were randomized to CV + C and 568 to CV. · Baseline patient characteristics were well-balanced between the two arms. o Patients were 70% male, and median age was 59 years. o Tumor histology was adenocarcinoma in 47% of cases, and squamous cell carcinoma in 34%. o ECOG performance status was 2 in approximately 20% of patients treated on both arms. o The majority of patients randomized to both arms (94%) had stage IV disease. o Never smokers composed 22% of patients enrolled on both arms. · Treatment characteristics outside of the study randomization were also similar between study arms: o A median of 4 chemotherapy cycles were delivered to patients randomized to both arms, with median treatment duration of 14 weeks. o 80% of the total patients received maintenance cetuximab therapy, with a median course of 18 weeks of cetuximab. o Post-study treatments consisted of radiotherapy, chemotherapy, and other treatments, and were for the most part similar between arms. The single difference noted in post-study treatment between the two arms was greater use of EGFR-tyrosine kinase inhibitors (EGFR-TKI) in the CV arm. Patients randomized to CV received EGFR-TKI therapy in 27% of cases, versus 17% of patients randomized to CV + C (p < 0.05) · Median overall survival (OS) was 11.3 months in the CV + C arm, versus 10.1 months in the CV arm. One-year OS was 47% and 42% in the CV + C arm versus CV arm, respectively (p = 0.044) o Overall survival benefit with CV + C persisted across all subgroups, including those based on performance status, smoking status, tumor histology, gender, age, and tumor stage. · Outcomes were compared specifically between Caucasian (n = 946) and Asian (n = 121) patients enrolled on this study. o Overall survival was 19.5 months for Asians, versus 9.6 months for Caucasians. o Baseline characteristics differed between the two groups:

Caucasian (n = 946)

Asian (n = 121)

Adenocarcinoma histology



Female gender



Never-smoking status



Performance status 0/1



Post study tx with EGFR-TKI



  • The Asian subset of 121 patients was examined separately with regard to outcomes:
    • In the Asian subset of patients, OS was 17.6 months with CV + C versus 20.4 with CV (p = NS). Tumor response rate was 50% versus 44%, respectively (p = NS).
    • Of Asian patients randomized on this study, 65% of those randomized to CV + C had tumors with adenocarcinoma histology versus 80% of those randomized to CV.
    • Additionally, 50% of those randomized to CV + C received EGFR-TKI treatment post-study, versus 73% of those randomized to CV.
  • Examination of the Caucasian subset of 946 patients demonstrated an OS with CV + C, whereby patients randomized to receive CV + C had median OS of 10.5 months, versus 9.1 months for those receiving CV. One-year OS was 45% in the CV + C group versus 37% in the CV group (p = 0.003, hazard ratio 0.803).
    • On graphical representation, the survival curves were noted to separate early in the treatment course.
    • Survival benefit in Caucasian patients randomized to CV + C was valid across all subgroups.
    • Specifically, Caucasian patients with histologic diagnosis of adenocarcinoma randomized to CV + C had median OS of 12.0 months, versus 10.3 months for patients randomized to CV (p = 0.011, hazard ratio 0.815). Those with squamous cell carcinoma randomized to CV + C had median OS of 10.2 months, versus 8.9 months for those randomized to CV (p = 0.057, hazard ratio 0.794).
  • When secondary endpoints were examined, tumor response rate was found to be 36% in patients treated with CV + C versus 29% in those treated with CV (p = 0.012). Progression free survival was 4.8 months in both arms (p = NS). Time to treatment failure was prolonged from 3.7 months to 4.2 months in patients treated with CV + C (p = 0.015).
  • Safety analysis demonstrated the incidence of any even to be 91% in patients randomized to CV + C, and 86% in those randomized to CV.
    • Acneiform rash developed in 10% of patients receiving cetuximab, versus < 1 % of those receiving CV.
    • Neutropenic fever developed in 22% of patients receiving CV + C, versus 15% of those receiving CV.
    • Treatment-related death occurred in 3% of patients treated with CV + C, versus 2% of those treated with CV.
Author's Conclusions
  • The authors conclude that cetuximab added to first-line chemotherapy in treatment of patients with advanced NSCLC and EGFR expression provides a statistically significant increase in overall survival.
  • They note that side effect profiles were as expected between the two arms.
  • They specifically note that no definite conclusions could be drawn regarding the benefit of cetuximab in treatment of Asian patients, as the small sample size and variance in baseline and treatment characteristics between the two arms prevented a valid analysis.
  • They conclude that this trial sets a new standard for first line treatment of patients with advanced NSCLC, and opens new treatment opportunities for patients with earlier-stage disease.
Clinical/Scientific Implications
  • This trial represents a well-designed, well-executed, phase III randomized comparison of conventional chemotherapy plus cetuximab to conventional chemotherapy alone in advanced NSCLC.
  • As noted, close to half of patients with newly diagnosed NSCLC present with advanced disease, and treatment options are quite limited for these patients. The OS benefit demonstrated within this study is certainly a promising result, both for patients with advanced NSCLC, and potentially for patients with earlier stage disease.
  • The authors’ conclusions that this trial sets a new standard for first line treatment of patients with advanced NSCLC, however, should be considered carefully in light of several other factors:
    • First, the OS benefit provided from the addition of cetuximab to conventional chemotherapy was fairly modest, with cetuximab portending a median survival advantage of 1.2 months.
    • The economic ramifications of delivering this treatment to all patients with advanced NSCLC should not be underestimated. Although cetuximab is demonstrated in this study to provide a real survival benefit to patients with EGFR expression, the cost to other areas of healthcare from this economic investment must be considered carefully.
    • Additionally, the group of patients receiving CV + C in this trial had a 22% rate of febrile neutropenia, versus 15% of patients receiving CV. Although this increased rate of febrile neutropenia did not appear to increase sepsis rates, it is considerably higher than rates generally observed with first-line chemotherapy. No clear etiology for this increased risk exists, but will likely require further investigation should this result prove durable across other studies.
  • Having said this, a statistically significant OS benefit with addition of cetuximab was demonstrated within this study, and this benefit may be more important for certain patient subgroups.
    • Patients with histologic diagnosis of adenocarcinoma appeared to have improved prognosis at baseline, as well as improved response to cetuximab.
    • Additionally, patients were selected for inclusion in this trial based on IHC staining for EGFR. Recent data presented by the Southwest Oncology Group suggests that the number of EGFR copies as assessed by fluorescence in-situ hybridization (FISH) may be directly related to response to cetuximab (Hirsch, in press).
    • As further data with regard to molecular markers becomes available, further elucidation of subsets of patients with increased likelihood of response to cetuximab may become possible; this would certainly be helpful in terms of resource allocation and healthcare economics.
  • In the meantime, this trial demonstrates a modest but real survival advantage for patients with advanced NSCLC treated with cetuximab added to conventional chemotherapy versus chemotherapy alone. This data is interesting and supports findings in head and neck and colorectal cancer that cetuximab is effective and safe when utilized concurrently with conventional chemotherapy.
  • These findings are clinically important, and are an important contribution to the literature regarding treatment of patients with NSCLC.

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