Resistance Mechanisms in EGFR-Mutated Lung Cancer Post-Treatment
In patients with EGFR‑mutated NSCLC who progressed after first‑line osimertinib therapy, genetic alterations related to resistance were identified in 87% of samples, revealing a spectrum of mechanisms that support the development of multi‑targeted second‑line therapies.
A Phase II ORCHARD study evaluated 400 tissue and 191 plasma samples from EGFR‑mutated NSCLC patients who progressed on first‑line osimertinib. Next‑generation sequencing identified resistance‑related genetic alterations in 87% of cases, with 46% exhibiting multiple mechanisms. Frequent alterations involved TP53, MDM2/4, PI3K pathway components, SOX2, and MYC, and distinct co‑occurring EGFR mutations correlated with the primary EGFR subtype. These findings highlight the heterogeneous resistance landscape and underscore the need for combination strategies targeting multiple pathways.
Osimertinib is the standard treatment for NSCLC patients with mutations in the epidermal growth factor receptor (EGFR) gene, which helps cancer cells grow. However, many patients eventually experience disease progression due to tumor resistance. Understanding the genetic changes responsible for resistance can help clinicians select better second‑line treatments, potentially improving outcomes for patients and advancing precision medicine in cancer care.
Evidence level: Korai humán adat. Kis vagy feltáró emberi adat.
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