Oxnard GR, et al. - Researchers sought to understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior in patients with EGFR T790M–positive lung cancer via conducting this cohort study of 143 patients who underwent tumor next-generation sequencing. Patients with osimertinib resistance commonly displayed loss of the EGFR T790M mutation that seemed associated with early treatment failure and development of a range of competing resistance mechanisms, some expected (MET amplification, small cell transformation) and some novel (acquired KRAS mutations, targetable gene fusions). Resistance in advanced non–small cell lung cancer (NSCLC) is thus evident to be heterogeneous. This highlights a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.