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

Abstract

BackgroundIncreased 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 methodsWe 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.ResultsTwo 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.ConclusionPemetrexed-based platinum chemotherapy may be the most optimal therapy in acquired resistance to gefitinib. Further prospective randomized controlled study is needed urgently.

Combination TS‐1 plus EGFR‐tyrosine kinase inhibitors (TKIs) for the treatment of non‐small cell lung cancer after progression on first‐line or further EGFR‐TKIs: A phase II, single‐arm trial

“…Because the efficacy of continuous EGFR‐TKI monotherapy is relatively moderate, many studies have evaluated the efficacy of EGFR‐TKIs combined with other agents, such as chemotherapy, antiangiogenic drugs, or monoclonal antibodies. In the real world, many patients receive pemetrexed plus platinum chemotherapy and achieve PFS of 4.9–5.4 months and OS of 16.1–19.5 months after they develop symptomatic resistance to EGFR‐TKI treatment . The IMPRESS study showed that continuing gefitinib and chemotherapy (cisplatin plus pemetrexed) did not prolong the median PFS (5.4 months in both groups) and was also detrimental to the median OS (13.4 vs. 19.5 months, HR 1.44, 95% CI 1.07–1.94; P = 0.16) compared to the placebo plus chemotherapy.…”

“…In the real world, many patients receive pemetrexed plus platinum chemotherapy and achieve PFS of 4.9-5.4 months and OS of 16.1-19.5 months after they develop symptomatic resistance to EGFR-TKI treatment. 26,27 The IMPRESS study showed that continuing gefitinib and chemotherapy (cisplatin plus pemetrexed) did not prolong the median PFS (5.4 months in both groups) and was also detrimental to the median OS (13.4 vs. 19.5 months, HR 1.44, 95% CI 1.07-1.94; P = 0.16) compared to the placebo plus chemotherapy. Nearly 5% of patients in the IMPRESS study experienced grade 3 or worse AEs, including anemia and neutropenia.…”

Sequential treatment of tyrosine kinase inhibitor and platinum-based doublet chemotherapy on EGFR mutant non-small cell lung cancer: a meta-analysis of randomized controlled clinical trials

“…Meanwhile, pemetrexed has less side effects than other TKIs and a RCT has also proven it to be effective as maintenance therapy after first-line PCT in non-squamous NSCLC 23. Also, as a second-line, pemetrexed had significantly better clinical efficacy in patients with susceptible EGFR mutations after progression of first-line TKI 24. However, except for Sequist et al’s study, the other eight studies did not use pemetrexed in first-line treatment in order for us to compare TKIs in our analysis, due to the fact that pemetrexed was approved as first-line treatment by FDA in 2009 10…”

Disease flare after discontinuing gefitinib in a patient with lung adenocarcinoma and concomitant epithelial growth factor receptor mutation and anaplastic lymphoma kinase translocation

“…However, it was not available due to the financial problem. We selected the pemetrexed as a second-line therapy as pemetrexed has been known to be an effective option for patients with NSCLC harboring sensitive EGFR mutation after gefitinib failure in retrospective studies (16,17).…”