The majority of patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) respond to first-line EGFR tyrosine kinase inhibitors (TKIs), but nearly all inevitably acquire resistance and develop disease progression. Conventional practice would be to switch treatments to second-line therapy. However, continuing TKIs beyond progression is becoming increasingly commonplace in patients with indolent, small volume asymptomatic growth, who may potentially continue to derive ongoing clinical benefit and to avoid a ‘withdrawal tumour flare’. Nevertheless, there are limitations to our current criteria for assessing disease response, which are based on radiological assessments without considering symptomatic benefit, or the complex molecular and clinical heterogeneity of tumour growth and drug response patterns. In this article, we review the rationale for continuing EGFR inhibitors in patients with EGFR mutant NSCLC beyond disease progression and discuss strategies that have been pursued in the context of molecularly and clinically heterogeneous populations of tumour growth depending on the different clinical scenarios encountered. We discuss the management of systemic disease progression, including continuing EGFR TKIs alone, introducing a drug holiday, or combining TKIs with chemotherapy or other molecularly targeted agents. We also focus on approaches in managing patients with indolent, small volume asymptomatic growth (non-CNS oligometastatic disease progression) and those with oligometastatic EGFR mutant NSCLC with involvement of the central nervous system. We envision future precision medicine strategies through the use of next generation sequencing strategies of serial tumour rebiopsies and circulating plasma DNA to individualise the management for such patients during disease progression.
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