Importance: Patients with EGFR-mutant lung cancer benefit from treatment with EGFR inhibitors such as erlotinib, gefitinib, and afatinib, but outcomes are limited by the eventual development of resistance to these agents. Over half of patients acquire a secondary T790M mutation in EGFR at the time of progression and a substantial minority develops resistance through other mechanisms. Multiple treatment strategies are now available to patients whose disease has progressed on their initial EGFR inhibitor, including therapies targeting both T790M, and non-T790M-mediated resistance.
Observations: This review summarizes information about and current treatment strategies for patients with EGFR-mutant lung cancer whose disease progresses on their initial EGFR inhibitor, including those with T790M and other types of acquired resistance. Postprogression therapy should be tailored based on identified resistance mechanisms, sites, and pace of disease progression, and patient preference. Biopsy and genotyping of resistant tissue or plasma are essential to identifying resistance mechanisms and selecting the most appropriate treatment when patients' disease progresses during treatment with an initial EGFR inhibitor. Third-generation EGFR inhibitors are generally preferred for patients with T790M-positive resistance, whereas standard chemotherapy and clinical trials are preferred for those without T790M. For select patients, treatment can be continued beyond progression and local ablative therapies can be used to target sites of oligoprogression.
Conclusions and relevance: Treatment for patients who progress on their initial EGFR inhibitor should be tailored to identified resistance mechanisms and sites of progression. Emerging reports about resistance to third-generation EGFR inhibitors will lay the groundwork for overcoming the next generation of resistance, and further research is needed to develop more effective therapies.