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Brittany Beach



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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-12 - Tyrosine Kinase Inhibitor Resistance Mechanisms in EGFR T790M-Positive Lung Cancer: The University of Chicago Experience (ID 2709)

      10:15 - 18:15  |  Author(s): Brittany Beach

      • Abstract
      • Slides

      Background

      Acquired resistance to osimertinib in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is a poorly understood phenomenon and presents an ongoing challenge. Previously described mechanisms include emergence of mutations at EGFR C797S, MET amplification, transformation to small cell lung cancer, and BRAF mutation. Next-generation sequencing (NGS) of tumors at progression through osimertinib may help to illuminate novel mechanisms of resistance to osimertinib.

      Method

      We surveyed University of Chicago Medicine case records for osimertinib-treated NSCLC patients treated who progressed through therapy. Panels utilized for NGS included, among others, the University of Chicago’s validated panel (the UCM-OncoPlus, surveying greater than 1,100 genes) and Guardant (Guardant Health; Redwood City, CA). Patients were stratified according to presence of EGFR T790M mutation at the initiation of osimertinib therapy.

      Result

      28 patients were identified to have progressed through osimertinib. 23 patients (82.1%) had next-generation performed at the time of progression. Among osimertinib-resistant patients who had NGS, 17 (73.9%) demonstrated at least one resistance mechanism, of which 8 (34.8% of tested patients) were subsequently treated with tyrosine kinase inhibitor-containing regimens or clinical trial of targeted therapy. Mutational profile at progression through osimertinib included: 2 patients (11.8%) with EGFR C797 mutation, 2 patients (11.8%) with MET amplification, 2 patients (11.8%) with RET fusion protein, 2 patients (11.8%) with MET point mutation, 1 patient (5.9%) with EGFR amplification, and 1 patient (5.9%) with small cell transformation. Newly identified resistance mechanisms (n = 1 for each) included mutation to EGFR G724 and L718 residues, ROS1 fusion protein, and in the same patient CBLB Q371* and SMAD4 loss. Of the 23 patients undergoing NGS at progression, 11 (47.8%) harbored EGFR T790M mutations prior to treatment, 3 (27.3%) of whom demonstrated resistance mutations susceptible to additional tyrosine kinase inhibitor therapy.

      Conclusion

      On the basis of these data, we confirm many previously described mechanisms of osimertinib resistance, including EGFR amplification, MET amplification, fusions involving RET, and transformation to small cell lung cancer, as well as novel resistance mechanisms including ROS1 fusion protein. We demonstrate the utility of NGS at the time of progression through osimertinib in our practice, regardless of the patient’s EGFR T790M status. We conclude that re-biopsy and utilization of NGS identifies a significant subset of osimertinib-resistant patients in whom well-tolerated tyrosine kinase inhibitor therapies remain an option and, in the interests of both patient well-being and clinical trial enrollment, should be considered standard practice at progression.

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