Overcoming Resistance: How Targeted Approaches Are Changing Management of Advanced EGFR-Mutant Lung Cancer and Paving the Way for Precision Medicine

The introduction of third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) significantly improved outcomes for people with EGFR-mutant advanced non-small cell lung cancer (aNSCLC). Yet, unmet needs, most notably acquired TKI resistance and central nervous system metastasis, persist. Moreover, 25–30% of patients die before they reach a second-line treatment. Recent advances in the health community’s understanding of the mechanisms of resistance, however, have led to intensification strategies that are reshaping the treatment landscape. Recent clinical trials, such as FLAURA2 and MARIPOSA, demonstrated that combining osimertinib with chemotherapy, or using amivantamab plus lazertinib as first-line therapy, can improve outcomes. Emerging second-line strategies also look promising and, as the treatment landscape expands, matching the right patient to the right treatment will become ever more important. In this article, Raffaele Califano, Consultant Medical Oncologist at The Christie NHS Foundation Trust, and Honorary Professor at The Division of Cancer Sciences of The University of Manchester, UK, outlines the story so far. He explains current and potential future treatment options, and how monitoring tools are critical for detecting resistance early and tailoring treatment strategies. Califano also talks about patient education and minimising side effects. In addition, he explores the path to more tailored approaches, more refined treatment algorithms, and improved long-term outcomes in this patient population.