Early Metabolic Response by PET Predicts Sensitivity to Next-Line Targeted Therapy in -Mutated Lung Cancer with Unknown Mechanism of Acquired Resistance.

Targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has established the precision oncology paradigm in lung cancer. Most patients with -mutated lung cancer respond but eventually acquire resistance. Patients exhibiting the p.T790M resistance biomarker benefit from sequenced targeted therapy with osimertinib. We hypothesized that metabolic response as detected by F-FDG PET after short-course osimertinib identifies additional patients susceptible to sequenced therapy. Fourteen patients with -mutated lung cancer and resistance to first- or second-generation EGFR TKI testing negatively for p.T790M were enrolled in a phase II study. Five patients (36%) achieved a metabolic F-FDG PET response and continued osimertinib. In those, the median duration of treatment was not reached (95% CI, 24 mo to not estimable), median progression-free survival was 18.7 mo (95% CI, 14.6 mo to not estimable), and median overall survival was 41.5 mo. Connecting theranostic osimertinib treatment with early metabolic response assessment by PET enables early identification of patients with unknown mechanisms of TKI resistance who derive dramatic clinical benefit from sequenced osimertinib. This defines a novel paradigm for personalization of targeted therapies in patients with lung cancer dependent on a tractable driver oncogene.