Clinical surrogate markers of survival in advanced non-small cell lung cancer (NSCLC) patients treated with second–third line erlotinib
Introduction
Non-small cell lung cancer (NSCLC) is the leading cause of death cancer in the western world [1]. In metastatic disease chemotherapy (CT) prolongs survival and an overall median survival of 9–12 months can be reached. The epidermal growth factor receptor (EGFR) is a transmembrane receptor expressed at a high level in a variety of solid tumors, including NSCLC, and has been implicated in the control of cell survival, proliferation, metastases and angiogenesis [2]. Erlotinib is a potent reversible inhibitor of EGFR tyrosine-kinase domain that has been proven to prolong survival in NSCLC patients after failure of at least one prior CT regimen [3].
Knowing predictive markers of clinical benefit using EGFR tyrosine-kinase inhibitors is of great clinical relevance. Molecular markers, such as EGFR mutations and amplification or polisomy, have been correlated with higher response levels when EGFR tyrosine-kinase inhibitors are used [4], [5], [6], [7]. In retrospective studies using tyrosine-kinase inhibitors, clinical characteristics (adenocarcinomas, females, non-smokers and Asian ethnicity) have been associated with higher response rates [3], [4], [8], [9]. However, the role of clinical factors as predictors of a differential survival is in discussion. Furthermore in the recently published INTEREST study comparing gefitinib with docetaxel, these factors were associated with longer survival in both group of treatment [10]. Rash is the most frequent adverse event of patients treated with anti-EGFR agents and some retrospective studies have found a correlation between rash and survival [3], [9], [11], [12], [13]. Thus, the aim of this study is to evaluate potential clinical predictor factors of time to tumor progression (TTP) and overall survival (OS) in advanced NSCLC patients treated with erlotinib.
Section snippets
Study design
We analyzed data from 62 patients included in a phase II pharmacodynamic study which evaluated the effect of erlotinib on patients with NSCLC after CT failure [14]. Eligibility criteria were histologically/cytologically confirmed advanced NSCLC, disease progression after ≥1 platinum-based chemotherapy regimen; tumor biopsy; age >18 years; performance status (PS) 0–1; life expectancy of ≥12 weeks; ≥14 days (radiotherapy) or 28 days (chemotherapy) since last treatment; adequate bone marrow,
Results
Characteristics of the patient population included in this study are outlined in Table 1. All 62 patients were evaluable for response and survival. Partial responses were noted in 6 patients (9.6%) and stable disease in 16 patients (26%). Median follow-up for all patients was 123.5 days (range, 15–610 days). The median TTP was 43 days (95% CI 19–326 days) and OS was123.5 days (95% CI 15–610 days).
Most of the patients (65%) presented some degree of rash. The distribution of skin rash was: grade
Discussion
Clinical and molecular parameters have been identified as possible predictors of clinical benefit to tyrosine-kinase inhibitors in patients with advanced NSCLC [11], [15].
Women, adenocarcinoma, Asian ethnicity and never smokers presented better outcomes in some reports, but most recent studies suggests these factors as prognostic but not all as predictors of response [3], [10], [13].
In our study only never smokers and patients with skin rash were associated with higher TTP and OS. Gender was
Conflict of interest statement
Author's have no conflict of interest.
References (24)
- et al.
Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small cell lung cancer. Results from a randomized, placebo, controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer)
Lancet
(2005) - et al.
Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomized phase III trial
Lancet
(2008) - et al.
the EGF receptor provides an essential survival signal for SOS-dependent skin tumour development
Cell
(2000) - et al.
Global cancer statics, 2002
CA Cancer J Clin
(2005) - et al.
In vitro and in vivo expressions of transforming growth factor alpha and tyrosine kinase receptors in human non-small cell lung carcinomas
Am J Pathol
(1993) - et al.
Erlotinib in previously treated non-small cell lung cancer
N Engl J Med
(2005) - et al.
Erlotinib in lung cancer-molecular and clinical predictors of outcome
N Engl J Med
(2005) - et al.
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib
N Engl J Med
(2004) - et al.
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy
Science
(2004) - et al.
Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small cell lung cancer
J Natl Cancer Inst
(2005)
Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126
J Clin Oncol
phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor
J Clin Oncol
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Treatment monitoring program for implementation of adherence to second-line erlotinib for advanced non-small-cell lung cancer
2013, Clinical Lung CancerCitation Excerpt :Currently available second-line treatment options for patients with A-NSCLC include the oral EGFR TKI erlotinib, as well as the intravenous cytotoxic agents docetaxel and pemetrexed.26 Several patient- and disease-related factors may play a role in selecting the most appropriate drug for each clinical case.2,27,28 Among these factors, adherence to orally administrable agents may be crucial because nonadherent behavior may decrease activity or increase toxicity of AODs (such as erlotinib), as has been observed in other diseases.2,17,18
Relationship between skin rash and outcome in non-small-cell lung cancer patients treated with anti-EGFR tyrosine kinase inhibitors: A literature-based meta-analysis of 24 trials
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Clinical predictive factors for advanced non-small cell lung cancer (NSCLC) patients receiving third-line therapy: Selecting the unselectable?
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