Treatment Options of First-Line Tyrosine Kinase Inhibitors and Subsequent Systemic Chemotherapy Agents for Advanced EGFR Mutant Lung Adenocarcinoma Patients: Implications From Taiwan Cancer Registry Cohort

Abstract

ObjectivesLarge-scale, population-based real-world studies on the treatment outcomes of first-line tyrosine kinase inhibitors (TKIs) and subsequent systemic chemotherapy agents for lung adenocarcinoma (with activating epidermal growth factor receptor [EGFR] mutations) remain limited.Materials and MethodsFrom March 2014 to December 2016, patients with advanced lung adenocarcinoma, identified from the Taiwan Cancer Registry were included in this study if they received any of the three TKIs as first-line treatment. The primary outcome was overall survival (OS). The secondary outcome was time-to-treatment discontinuation (TTD).ResultsA total of 4,889 patients (median age: 67 years and two-thirds with distant metastasis) were recruited (1,778 gefitinib, 1,599 erlotinib, and 1,512 afatinib users). A 1:1 propensity score (PS)-matched cohorts of 1,228 afatinib/erlotinib and 1054 afatinib/gefitinib was created. After PS matching, it was found that afatinib was not associated with better OS (afatinib vs. erlotinib, HR: 0.96, 95% CI: 0.86–1.07; afatinib vs. gefitinib, HR: 0.91, 95% CI: 0.81–1.02). In the subgroup analysis, afatinib demonstrated a survival benefit in patients with active smoking (afatinib vs. erlotinib, HR: 0.69, 95% CI: 0.51–0.93; afatinib vs. gefitinib, HR: 0.67, 95% CI: 0.48–0.94) and ECOG > 1 (afatinib vs. erlotinib, HR: 0.79, 95% CI: 0.63–0.99; afatinib vs. gefitinib, HR: 0.78, 95% CI: 0.62–0.98). A total of 41.1% (n = 1992) of first-line TKI users received subsequent chemotherapy. Among the three TKI groups, pemetrexed usage was associated with better OS compared with other chemotherapy agents, with the exception of gemcitabine in the afatinib and gefitinib groups. Pemetrexed and gemcitabine had the longest TTD of 3–4 months.ConclusionsAmong patients with EGFR mutant lung adenocarcinoma, afatinib use may not provide longer OS compared with first-generation TKIs. Afatinib may be preferably considered among patients with active smoking and should not be withheld among those with worse performance status. With 40% of patients receiving subsequent chemotherapy, pemetrexed may be the preferred agent, while gemcitabine can be a reasonable alternative.

Oral uracil–tegafur compared with intravenous chemotherapy as adjuvant therapy for resected early‐stage non‐small cell lung cancer patients

“…The enrolled population was identified, and their basic profile, underlying diseases, and use of chemotherapy or oral UFT were determined from the National Health Insurance Research Database (NHIRD) in Taiwan 25,26,28,29 . Meanwhile, the information of mortality was obtained from the Department of Statistics, Taiwan.…”

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

“…Pemetrexed is an anti-folic acid drug that can interfere with folic acid metabolism, resulting in aberrant DNA synthesis in tumor cells ( 144 ). A cancer registration cohort analysis from Taiwan showed that pemetrexed may be suitable as a first choice for chemotherapy in patients undergoing chemotherapy after progression with EGFR-TKI treatment ( 145 ). A 2018 meta-analysis showed that second-line drugs combined pemetrexed chemotherapy resulted in a longer PFS and OS duration than therapy with pemetrexed ( 146 ).…”

Comparative effects of oral uracil–tegafur versus intravenous chemotherapy as adjuvant therapy for resected early-stage NSCLC patients: Taiwan cancer registry cohort study

“…The dataset we used is a population-based registry system, Taiwan Cancer Registry (TCR), which includes over 90% of all cancer patients in Taiwan [23][24][25]. We retrieved patients with early-stage NSCLC identi ed by pathological con rmation, including those in stages IB and IIA (without any lymph node involvement) from the TCR during January 2011 and December 2017.…”

“…The enrolled population was identi ed, and their basic pro le, underlying diseases, and use of chemotherapy or oral UFT were ascertained from the Taiwan NHI database [24,25,27,28]. Meanwhile, the information of mortality was obtained from the Department of Statistics, Taiwan.…”

“…The Eastern Cooperative Oncology Group (ECOG) scoring system was applied for evaluating patients' performance status [29]. Additionally, our patients' comorbidities were assessed by the Charlson comorbidity index (CCI) from the NHI claims data [30], but malignancy-related score should be excluded (cancer-free CCI) as it was previously reported [23,25]. Hospital levels were classi ed hierarchically into medical centers, regional hospitals, and local hospitals [31].…”