Gefitinib

Lung cancer

Cancer research

T790M

Epidermal growth factor receptor

Overall survival

Progression-free survival

Internal medicine

Confidence interval

Hazard ratio

Oncology

Medicine

Osimertinib

Cancer

Pathology

Erlotinib

Journal of Thoracic Oncology

<h2>Abstract</h2><h3>Introduction</h3> Preferred first-line treatment for patients with metastatic <i>EGFR</i>-mutant lung cancer is osimertinib, yet it is not known whether patient outcomes may be improved by identifying and intervening on molecular markers associated with therapeutic resistance. <h3>Methods</h3> All patients with metastatic <i>EGFR</i>-mutant lung cancer treated with first-line osimertinib at the Memorial Sloan Kettering Cancer Center (n = 327) were identified. Available pretreatment and postprogression tumor samples underwent targeted gene panel sequencing and mutational signature analysis using SigMA algorithm. Progression-free survival (PFS) and overall survival were estimated using the Kaplan-Meier method. <h3>Results</h3> Using multivariate analysis, baseline atypical <i>EGFR</i> (median PFS = 5.8 mo, <i>p</i> < 0.001) and concurrent <i>TP53/RB1</i> alterations (median PFS = 10.5 mo, <i>p</i> = 0.015) were associated with shorter PFS on first-line osimertinib. Of 95 patients with postprogression biopsies, acquired resistance mechanisms were identified in 52% (off-target, n = 24; histologic transformation, n = 14; on-target, n = 12), with <i>MET</i> amplification (n = 9), small cell lung transformation (n = 7), and acquired <i>EGFR</i> amplification (n = 7), the most frequently identified mechanisms. Although there was no difference in postprogression survival on the basis of identified resistance (<i>p</i> = 0.07), patients with subsequent second-line therapy tailored to postprogression biopsy results had improved postprogression survival (hazard ratio = 0.09, <i>p</i> = 0.006). The paired postprogression tumors had higher tumor mutational burden (<i>p</i> = 0.008) and further dominant APOBEC mutational signatures (<i>p</i> = 0.07) compared with the pretreatment samples. <h3>Conclusions</h3> Patients with <i>EGFR-</i>mutant lung cancer treated with first-line osimertinib have improved survival with treatment adaptation on the basis of identified mechanisms of resistance at time of progression using tissue-based genomic analysis. Further survival gains may be achieved using risk-based treatment adaptation of pretreatment genomic alterations.

Molecular Biomarkers of Disease Outcomes and Mechanisms of Acquired Resistance to First-Line Osimertinib in Advanced EGFR-Mutant Lung Cancers