OBJECTIVES The inhibition of epidermal growth factor receptor (EGFR) signaling pathway by innovative therapeutics presents promising upshots in oncology. Our study aims to quantify first-line treatment with afatinib, an irreversible tyrosine kinase inhibitor, compared to pemetrexed+cisplatin (pem+cis), for patients with metastatic lung adenocarcinoma harboring common EGFR mutations (DEL19 or L858R) in the Netherlands. METHODS An area under the curve partitioned survival model, constructed to quantify lifetime consequences of therapy with afatinib versus pem+cis, was amended to the Netherlands. The updated (2014) LUX-Lung 3 trial results and data from public sources were used to populate the model. Study outcomes were expressed in quality-adjusted life years (QALY), incremental cost-utility ratios (ICUR) and net monetary benefits (NMB). The analyses were conducted from healthcare and societal perspectives. Uncertainty assessment was performed using one-way and probabilistic sensitivity analyses (PSA). RESULTS Metastatic lung adenocarcinoma patients with common EGFR mutations (89%) had higher overall survival when treated with afatinib compared to pem+cis (HR: 0.78, p=0.10). The corresponding base-case ICUR was <€20,000/QALY gained. For the subgroup of patients harboring DEL19 mutations (49%), treatment with afatinib resulted in cost-savings. Although NMB calculations were favorable for the genotype-directed therapy, inclusion of the entire patient population (all EGFR mutations) resulted in higher incremental costs. PSA results of lung adenocarcinoma patients with common EGFR mutations showed that afatinib is >95% cost-effective compared to pem+cis at a €80,000 threshold. CONCLUSIONS This study shows that genotype-directed therapy with afatinib improved survival in metastatic lung adenocarcinoma and translated itself as value-for-money, particularly for the DEL19 subgroup, in the Netherlands. Further research is encouraged to compare afatinib with reversible EGFR inhibitors in this setting.