Osimertinib, platinum, and etoposide for patients with metastatic EGFR / TP53 / RB1 -mutant lung cancers at risk for histological transformation

Although EGFR inhibitors are highly effective for treating EGFR- mutant lung adenocarcinomas ( EGFR + LUADs), resistance inevitably emerges, with histologic transformation to small cell lung cancer (SCLC) representing a particularly aggressive mechanism. Our prospective trial enrolled patients with EGFR + LUAD at high risk of transformation ( TP53 / RB1 -deficient) and treated them with first-line osimertinib combined with platinum and etoposide. Despite the addition of SCLC-directed chemotherapy, nearly half of patients (5 of 11) underwent SCLC transformation, with median progression-free survival of 11 months and overall survival of 33 months. Genomic and single-cell transcriptomic profiling of patient samples revealed clinical and subclinical plasticity associated with TP53 / RB1 comutations, including histological transformation to SCLC, as well as mesenchymal and squamous histologies. These changes in plasticity were linked to progressive disruption of the RB pathway, leading to altered chromatin accessibility and induction of neuronal differentiation and epithelial-to-mesenchymal transition transcriptional programs, further intensified by osimertinib treatment. These findings provide insights into the role of plasticity in mediating drug tolerance.