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) : '

Reviewer: Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 7, 2004

This presentation discusses off-label use of cetuximab in the treatment of NSCLC.

Presenter: R. Rosell
Presenter's Affiliation: Institut Catala d'Oncologia, Barcelona, Spain
Type of Session: Scientific

The advent of molecular therapeutics and anti-tumor targetted agents has at its center the much discussed and studied epidermal growth factor receptor (EGFR). EGFR is the protein product of the 28th exon on gene 7p11.2. The overexpression of EGFR is very commonly seen in patients with NSCLC. Cetuximab is a IgG1 monoclonal antibody with a very high affinity and specificity for the extracellular domain of EGFR. Upon binding, cetuximab blocks the transmission of downstream signals involved in various cellular functions including proliferation. The use of cetuximab in addition to standard chemotherapy has been shown to be safe and effective in EGFR-expressing tumors such as colorectal cancer and head and neck cancer. The authors of this study evaluated the tolerability and efficacy of cetuximab in combination with chemotherapy in EGFR-positive NSCLC patients.      

Materials and Methods

  • Eligible patients had histologically-confirmed stage III/IV NSCLC
  • All patients had immunohistochemistry-documented EGFR positivity
  • At least one measurable lesion was required for eligibility
  • 114 patients were screened, of whom 103 were EGFR-positive (90%)
  • A total of 86 patients were ultimately randomized to one of two arms:
  •     1) cetuximab 400 mg initially, then 250 mg weekly + cisplatin 80 mg/m2 on day 1 + vinorelbine            25 mg/m2 on day 1 and 8 (n=43)
  •     2) cisplatin 80 mg/m2 on day 1 + vinorelbine 25 mg/m2 on day 1 and 8 (n=43)
  • Both arms were well-balanced for age (median = 58 years old), gender (66% male), KPS (median KPS = 90), stage (40% stage IV), elevated LDH (33%) and histology (40% squamous cell, 20% adenocarcinoma) 
  • Primary study endpoint was objective response rate of cetuximab compared to chemotherapy alone
  • Secondary study endpoints included median survival, progression-free-survival (PFS), overall survival (OS), and toxicity.
  • Univariate analysis was done for age, histology, LDH level and grade of skin rash/reaction. 



  • The results presented here are for arm 1 (cetuximab + chemo) vs. arm 2 (chemo only).
  • Overall disease control (as measured by complete/ partial response or stable disease) was 84% vs. 67%, with confirmed complete or partial response rates of 35% vs. 28% and stable disease rates of 30% vs. 35%.
  • Median survival was 8.3 months vs. 7.0 months.
  • PFS was 4.8 months vs. 4.2 months
  • OS @ 12 months = 32% vs. 26%
  • OS @ 18 months = 14% vs. 0
  • OS @ 24 months = 14% vs. 0
  • No siginifcant difference was noted in toxicity (hematologic or non-hematologic) between the two arms.
  • On univariate analysis, age </= 60 years old and presence of skin toxicity were both associated with improved response rates.

Author's Conclusions

  • The addition of cetuximab increased the efficacy of cisplatin and vinorelbine as first line therapy in advanced NSCLC by demonstrating enhanced clinical response rates and survival rates.
  • The occurrence of a skin rash was predictive of response on subset analysis.
  • Cetuximab does not appear to aggravate the toxicity of cisplatin and vinorelbine, and it was well-tolerated overall.
  • The analysis of EGFR mutations in these patients is ongoing.


Clinical/Scientific Implications
This is very promising study demonstrating a benefit with the incorporation of cetuximab into standard cisplatin-based chemotherapy regimens for the managament of NSCLC patients. Although the patient sample size is relatively small, this is a well-selected, pre-screened group of EGFR-positive patients. The tolerability of cetuximab with chemotherapy further confirms the non-overlapping toxicities making its applicability in the clinic more feasible. The greater response rates in younger patients is interesting and may lead to further research in this subgroup. Additionally, the improved response rates in patients experiencing skin rash on cetuximab corroborates the findings of many prior studies. It will be interesting to evaluate the survival endpoints with longer follow-up. The pending EGFR mutation analyses from this study will be particularly important in better refining and optimizing which patients are most likely to derive clinical and meaningful benefit from cetuximab.