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Original Investigation
November 2018

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

Author Affiliations
  • 1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 2Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 3Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina
  • 4Moores Cancer Center, University of California San Diego, La Jolla
  • 5Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 6Medical student, Tufts University School of Medicine, Boston, Massachusetts
  • 7Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 8Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 9Translational Sciences, Oncology IMED Biotech Unit, AstraZeneca, Boston, Massachusetts
JAMA Oncol. 2018;4(11):1527-1534. doi:10.1001/jamaoncol.2018.2969
Key Points

Question  What molecular and clinical biomarkers can be used to better understand osimertinib mesylate resistance and develop treatment strategies?

Findings  In this cohort study of 143 patients who underwent tumor next-generation sequencing, loss of the EGFR 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 (MET amplification, small cell transformation) and some novel (acquired KRAS mutations, targetable gene fusions). Early changes in plasma EGFR mutation levels may indicate probable resistance patterns.

Meaning  Strategies to detect and target multiple coexistent resistance mechanisms will be needed to achieve more durable control of drug resistance in EGFR-mutant lung cancer.

Abstract

Importance  Osimertinib mesylate is used globally to treat EGFR-mutant non–small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood.

Objective  To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior.

Design, Setting, and Participants  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 (NCT01802632) (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.

Main Outcomes and Measures  Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib.

Results  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, EGFR 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 KRAS 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 EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01).

Conclusions and Relevance  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.

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