Pemetrexed for Previously Treated Patients with Non-Small Cell Lung Cancer and Differences in Efficacy according to Thymidylate Synthase Expression

Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan.
Chemotherapy (Impact Factor: 1.55). 11/2012; 58(4):313-320. DOI: 10.1159/000343048
Source: PubMed

ABSTRACT The purpose of this study was to evaluate the efficacy of pemetrexed monotherapy in previously treated patients with advanced non-small cell lung cancer (NSCLC) including salvage treatment, and to evaluate whether thymidylate synthase (TS) expression is a predictor for pemetrexed efficacy. Hundred and four previously treated patients with advanced NSCLC who received pemetrexed monotherapy were retrospectively evaluated for clinical efficacy and toxicity. If available, tissue specimens of patients were also analyzed immunohistochemically for TS expression. The patients' median age was 65 years (range: 43-82). An overall response rate of 9.6% and a median progression-free survival (PFS) time of 3.4 months were achieved. The response rates for the second-line, third-line, fourth-line or further treatments were 9.1, 9.3 and 10.2% (p = 0.33); the median PFS were 3.3, 3.2 and 3.8 months (p = 0.21). The median follow-up duration was 14.9 months; the median overall survival (OS) was 11.9 months. The median PFS and OS were significantly longer in the TS-negative group than in the TS-positive group (5.8 months vs. 1.6 months; p = 0.03, and 14.7 months vs. 8.6 months; p = 0.04, respectively). Pemetrexed monotherapy could be considered as an option in the fourth or later lines of treatment of previously treated patients with advanced NSCLC as well as a second- or third-line treatment, and TS expression may be a potentially predictive factor for pemetrexed efficacy in NSCLC patients.

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    ABSTRACT: Introduction Folate receptor alpha (FRA) regulates cellular uptake of folates and antifolates (e.g. pemetrexed) and is frequently expressed in pulmonary adenocarcinoma. Epidermal Growth Factor Receptor (EGFR) is an established therapeutic target in Non-Small Cell Lung Cancer (NSCLC). Therapies targeting FRA or EGFR are available. The association between FRA and EGFR expression in advanced NSCLC has not been explored. Combining therapeutic FRA-antibodies with an EGFR inhibitor might be beneficial, if both of the targets are significantly co-expressed. Patients and Methods Specimens from 160 advanced NSCLC patients receiving pemetrexed-based chemotherapy were assessed for membranous FRA and EGFR protein expression by immunohistochemistry using the H-score. EGFR (exons 18-21) and K-Ras (exon 2) mutations were determined. Results were correlated to patients’ clinicopathological data, progression-free survival (PFS) and overall survival (OS). Results 47 patients (29%) had tumors with strong FRA and EGFR expression, but no statistically significant correlation was seen between protein levels of FRA and EGFR. High membranous FRA expression (H-score ≥20) was associated with prolonged PFS (5.5 vs. 3.4 months, HR=0.6060, P=0.0254) and improved OS (12.1 vs. 6.4 months, HR=0.5726, P=0.0076). Conclusion Survival times are improved in NSCLC patients whose tumors show strong membranous FRA expression. No statistical correlation between membranous FRA and EGFR expression was demonstrated in advanced NSCLC, but 29% of patients had higher expression of both the receptors and could be suitable for combined targeted therapies.
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May 15, 2014