Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR‐mutant non‐small‐cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole‐genome sequencing on samples from three patients who underwent histological transformation to small‐cell lung cancer. In 43 patients with known EGFR mutations from tumour, we identified them accurately in plasma of 41 patients (95%, 41/43). We also found additional mutations, including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%) and PTEN (4/50, 8%). Patients with both TP53 and EGFR mutations before treatment had worse overall survival than those with only EGFR. Patients who progressed without T790M had worse PFS during TKI continuation and developed alternative alterations, including small‐cell lung cancer‐associated copy number changes and TP53 mutations, that tracked subsequent treatment responses. Longitudinal plasma analysis can help identify dominant resistance mechanisms, including non‐druggable genetic information that may guide clinical management.

Patients with advanced stage non-small cell lung cancer with sensitizing epidermal growth factor receptor (EGFR) mutations using EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib and afatinib as first-line treatment had better progression-free survival, overall response rate and quality of life than those on chemotherapy. Although EGFR TKIs are commonly associated with skin-related (rash, xerosis and paronychia) and gastrointestinal-related (diarrhea and stomatitis) adverse events (AEs), these effects are usually mild. But severe cases can occur, significantly affecting patient's well-being, treatment compliance and quality of life. Therefore, patient education, early diagnosis, and prophylactic treatment are important strategies to optimally manage EGFR TKI-related adverse effects. In this review, we summarize the commonly encountered EGFR TKI-related AEs and provide a current overview of AE management in local practice with a focus on Asian patients. K E Y W O R D Sadverse drug events, gastrointestinal tract, mutations, non-small cell lung cancer, skin BACKGROUNDEighty percent of lung cancers are advanced-stage non-small cell lung cancer (NSCLC). (1) Epidermal growth factor receptor (EGFR) gene mutation, which is a major and potent oncogenic driver in NSCLC is a therapeutic target, with EGFR tyrosine kinase inhibitors (EGFR TKIs), altering the pattern of care in patients with advanced stage NSCLC.With EGFR TKIs (erlotinib, gefitinib and afatinib) as first-line treatment for patients with advanced stage NSCLC with sensitizing EGFR mutations, higher progression-free survival, overall response rate and quality of life than chemotherapy can be achieved. 1 These drugs are generally well tolerated as they have a predictable toxicity profile and less serious toxicities than traditional cytotoxic chemotherapy. 2 Nevertheless, EGFR TKIs can still produce severe adverse events (AEs) and impair quality of life.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. wileyonlinelibrary.com/journal/ajco 23

There was no improvement in efficacy with talactoferrin alfa in patients with advanced NSCLC whose disease had failed two or more previous regimens.

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