The safety and efficacy of EGFR TKIs monotherapy versus single-agent chemotherapy using third-generation cytotoxics as the first-line treatment for patients with advanced non-small cell lung cancer and poor performance status

Summary

Purpose

To assess the risk/benefit profiles of EGFR TKIs monotherapy using erlotinib or gefitinib in comparison with single-agent chemotherapy using third-generation cytotoxics (gemcitabine, vinorelbine, taxanes) as the first-line treatment for chemonaÏve patients with advanced non-small cell lung cancer (ANSCLC) and poor performance status (PS).

Methods

A pooled analysis and systematic review was performed using trials identified through MEDLINE, EMBASE, Cochrane Library, and the Clinical-Trials.gov. Data were collected from randomized and non-randomized phase II or III clinical trials of EGFR TKIs monotherapy or single-agent chemotherapy using third-generation cytotoxics published before 3/1/2010, and the pooled estimates for efficacy and safety outcomes of interest were calculated.

Results

Fifteen eligible trials (1425 patients) were selected from 323 studies that initially were identified. In 5 of the selected single-agent chemotherapy studies, the elderly were included together with poor PS patients. Outcomes from these studies still were employed for a thorough analysis. Targeting poor PS patients, we found that the pooled response rate (95% confidence interval) to EGFR TKIs for unselected population was 6% (3–8%), not substantially different from 9% (6–13%) reported by single-agent chemotherapy trials using third-generation cytotoxics. However, EGFR TKIs had better disease control rates with a pooled estimate of 40% (33–47%), significantly higher than 30% (20–41%) of the cytotoxics. Single-agent chemotherapy trials enrolling both elderly and poor PS patients had better results with the pooled response rate and the pooled disease control rate was 13% (11–16%) and 41% (36–46%) respectively. For safety information, despite both treatments were well-tolerated, the toxicity profile of EGFR TKIs was clearly more favorable than that reported by chemotherapy. The severe hematological adverse events related to EGFR TKIs treatment were rare. EGFR TKIs also tended to be more effective in improvement of symptoms or quality-of-life (QOL).

Conclusion

Although, both of the treatments had low response rates, EGFR TKIs tended to be more effective in control of tumor progression, reduction of therapy-related toxicities, improvement of symptoms or quality-of-life in the first-line treatments of ANSCLC patients with poor PS. Moreover, our data also suggest that the elderly patients without selection carefully according their PS should be separated from this population. Further investigations with valid comparison groups are necessary.

Introduction

Lung cancer is the leading cause of cancer death worldwide, and approximately 80% of cases are non-small cell lung cancer (NSCLC) [1], [2]. The majority of NSCLC patients present with advanced disease [3]. Performance status (PS) is the strongest predictor of survival in patients with advanced NSCLC (ANSCLC) [4]. It measures the impact of tumor related symptoms and comorbidities on patients’ functioning in daily life and the capability of self care. The PS is classified as a six-point scale worsening from 0 to 5 by the Eastern Cooperative Oncology Group, and PS ≥ 2 is characterized as poor PS [5].

ANSCLC patients with poor PS tend to have worse clinical outcomes and higher risk of toxicities than those with good PS following chemotherapy treatment [6], [7]. For this reason, such patients have traditionally been excluded from receiving standard platinum-based chemotherapy [8], [9]. Although, there is no consensus on standard treatment for these patients, single-agent chemotherapy appears to be a reasonable choice for them. This conclusion arises from the efficacy and tolerability observed with third-generation cytotoxics (gemcitabine, vinorelbine, taxanes) as single-agent therapy in both phase II and III trials [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. However, this treatment appears only justified for patients with a PS of 2, there is no recommended treatment for PS 3 or 4 ANSCLC patients [20], [21], [22], [23].

Recently, targeting the epidermal growth factor receptor (EGFR) pathway represents a novel approach to treat NSCLC patients. Two EGFR TKIs, erlotinib (Tarceva; Genentech, San Francisco, CA) and gefitinib (Iressa; Astra-Zeneca, Wilmington, DE), have received approval for the treatment of ANSCLC in the second- or third-line setting worldwide [24], [25]. Because the toxicity of EGFR TKIs is less than that of cytotoxics, its utility as first-line treatment for ANSCLC patients with poor PS has been studied [26], [27]. While individual studies of EGFR TKIs demonstrated promising efficacy and favorable toxicity have been reported [28], [29], [30], [31], [32], there has been no systematic evaluation of risk/benefit profiles of EGFR TKIs in comparison with single-agent chemotherapy as a first-line treatment among chemonaÏve ANSCLC patients with poor PS. This study was conducted to combine efficacy and safety information from all published trials to obtain pooled efficacy results and absolute risk estimates associated with these treatment regimens.