Pemetrexed had significantly better clinical efficacy in patients with stage IV lung adenocarcinoma with susceptible EGFR mutations receiving platinum-based chemotherapy after developing resistance to the first-line gefitinib treatment

Chih-Jen Yang, Ming-Ju Tsai, Jen-Yu Hung, Ta-Chih Liu, Shah-Hwa Chou, Jui-Ying Lee, Jui-Sheng Hsu, Ying-Ming Tsai, Ming-Shyan Huang, Inn-Wen Chong, Chih-Jen Yang, Ming-Ju Tsai, Jen-Yu Hung, Ta-Chih Liu, Shah-Hwa Chou, Jui-Ying Lee, Jui-Sheng Hsu, Ying-Ming Tsai, Ming-Shyan Huang, Inn-Wen Chong

Abstract

Background: Increased evidences show that epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors such as gefitinib could prolong progression-free survival (PFS) compared with cytotoxic chemotherapy for metastatic lung nonsquamous cell carcinoma harboring susceptible EGFR mutation, and gefitinib was served as the first-line therapy. However, acquired resistance is inevitable, but the salvage therapies are still unclear.

Patients and methods: We designed a retrospective study of the salvage therapy and enrolled patients with stage IV lung adenocarcinoma who had mutated EGFR and developed an acquired resistance to the first-line gefitinib in two university-affiliated hospitals in Taiwan during June 2011 to December 2014. Age, sex, smoking history, EGFR gene mutation, performance statuses, response rate, PFS2 (the PFS in salvage therapy), and overall survival (OS2, the OS in salvage therapy) were recorded.

Results: Two hundred and nine patients with mutated EGFR and who took gefitinib as first-line therapy were identified in the period, and a total of 98 patients who had been treated with salvage therapy with cytotoxic chemotherapy or erlotinib were eligible for this study. The overall response rate of second salvage therapy is 13%, and none of them received erlotinib. Patients who received chemotherapy had a trend for better PFS2 than those who received erlotinib (4.3 months vs 3.0 months, P=0.1417) but not in OS. Furthermore, patients who received platinum-based doublet had a trend for better PFS2 and a significantly better OS2 than those who received chemotherapy without platinum (PFS2: 4.9 months vs 2.6 months, P=0.0584; OS2: 16.1 months vs 6.7 months, P=0.0007). Analyses of the patients receiving platinum-based doublet showed that patients receiving pemetrexed had a significantly better PFS2 (6.4 months vs 4.1 months, P=0.0083) and a trend for better OS2 than those without pemetrexed treatment.

Conclusion: Pemetrexed-based platinum chemotherapy may be the most optimal therapy in acquired resistance to gefitinib. Further prospective randomized controlled study is needed urgently.

Keywords: acquired resistance; chemotherapy; epidermal growth factor receptor; gefitinib; pemetrexed.

Figures

Figure 1
Figure 1
Kaplan–Meier curves of progression-free survival (PFS2; A, C, and E) and overall survival (OS2; B, D, and F) with the second-line treatment. Notes: (A and B) Analyses of the whole study population showed that patients receiving chemotherapy had a trend for better PFS2 than those receiving erlotinib (MST of PFS2: 4.3 months vs 3.0 months, log-rank P=0.1417), whereas no significant difference in OS2 was noted (MST of OS2: 14.6 months vs 12.3 months, log-rank P=0.4909). (C and D) Analyses of the patients receiving chemotherapy showed that patients receiving platinum-based doublet had a trend for better PFS2 and a significantly better OS2 than those receiving chemotherapy without platinum (MST of PFS2: 4.9 months vs 2.6 months, log-rank P=0.0584; MST of OS2: 16.1 months vs 6.7 months, log-rank P=0.0007). (E and F) Analyses of the patients receiving platinum-based doublet showed that patients receiving pemetrexed had a significantly better PFS2 and a trend for better OS2 than those without pemetrexed treatment (MST of PFS2: 6.4 months vs 4.1 months, log-rank P=0.0083; MST of OS2: 19.2 months vs 14.1 months, log-rank P=0.1639). Abbreviations: PFS, progression-free survival; PFS2, the PFS in salvage therapy; OS, overall survival; OS2, the OS in salvage therapy; MST, median survival time.

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