Current and Future Approaches in the Management of Non–Small-Cell Lung Cancer Patients With Resistance to EGFR TKIs

Metastatic non–small-cell lung cancer carries a dismal prognosis. However, the recognition of the predictive value of activating epidermal growth factor receptor (EGFR) mutations and the availability of tyrosine kinase inhibitors has markedly improved the prognosis of these patients, because treatment with these inhibitors induces rapid and robust responses. Unfortunately, the responses are not durable and resistance inevitably occurrs after a median of 9 to 14 months. Although the management of resistant patients who harbor EGFR mutations is rapidly evolving, there are no conclusive guidelines regarding this issue. However, palliative cytotoxic chemotherapy is considered the standard of care for these patients. The elucidation of the mechanisms of acquired resistance has led to efforts to personalize the treatment approach. Promising results from early clinical trials using the third-generation inhibitors that specifically target the most common mechanism of resistance, the gatekeeper T790M mutation, provide the basis to look to the future with cautious optimism. Moreover, it has been shown that in some cases of oligoprogressive disease, aggressively treating all metastatic sites while continuing the targeted treatment could improve outcomes. Herein, we review the treatment strategies being evaluated that will shape the future management of these patients.