Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M–Positive Lung Cancer and Acquired Resistance to Osimertinib

Abstract

<div class="section"> <a class="named-anchor" id="ab-coi180060-1"> <!-- named anchor --> </a> <h5 class="section-title" id="d6952717e502">Question</h5> <p id="d6952717e504">What molecular and clinical biomarkers can be used to better understand osimertinib mesylate resistance and develop treatment strategies? </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180060-2"> <!-- named anchor --> </a> <h5 class="section-title" id="d6952717e507">Findings</h5> <p id="d6952717e509">In this cohort study of 143 patients who underwent tumor next-generation sequencing, loss of the <i>EGFR</i> T790M mutation was common on resistance to osimertinib and was associated with early treatment failure and development of a range of competing resistance mechanisms, some expected ( <i>MET</i> amplification, small cell transformation) and some novel (acquired <i>KRAS</i> mutations, targetable gene fusions). Early changes in plasma <i>EGFR</i> mutation levels may indicate probable resistance patterns. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180060-3"> <!-- named anchor --> </a> <h5 class="section-title" id="d6952717e524">Meaning</h5> <p id="d6952717e526">Strategies to detect and target multiple coexistent resistance mechanisms will be needed to achieve more durable control of drug resistance in <i>EGFR</i>-mutant lung cancer. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180060-4"> <!-- named anchor --> </a> <h5 class="section-title" id="d6952717e533">Importance</h5> <p id="d6952717e535">Osimertinib mesylate is used globally to treat <i>EGFR</i>-mutant non–small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the <i>EGFR</i> T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180060-5"> <!-- named anchor --> </a> <h5 class="section-title" id="d6952717e544">Objective</h5> <p id="d6952717e546">To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180060-6"> <!-- named anchor --> </a> <h5 class="section-title" id="d6952717e549">Design, Setting, and Participants</h5> <p id="d6952717e551">Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort ( <a data-untrusted="" href="https://clinicaltrials.gov/ct2/show/NCT01802632" id="d6952717e553" target="xrefwindow">NCT01802632</a>) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180060-7"> <!-- named anchor --> </a> <h5 class="section-title" id="d6952717e557">Main Outcomes and Measures</h5> <p id="d6952717e559">Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180060-8"> <!-- named anchor --> </a> <h5 class="section-title" id="d6952717e562">Results</h5> <p id="d6952717e564">Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, <i>EGFR</i> C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired <i>KRAS</i> mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant <i>EGFR</i>, loss of T790M at resistance was associated with a smaller decrease in levels of the <i>EGFR</i> driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; <i>P</i> = .01). </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180060-9"> <!-- named anchor --> </a> <h5 class="section-title" id="d6952717e582">Conclusions and Relevance</h5> <p id="d6952717e584">Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance. </p> </div><p class="first" id="d6952717e587">This cohort study examines mechanisms of acquired resistance to osimertinib in patients with non–small cell lung cancer and the associated clinical implications. </p>