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A. John Iafrate



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    MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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      MA26.03 - Activity of Osimertinib and the Selective RET Inhibitor BLU-667 in an EGFR-Mutant Patient with Acquired RET Rearrangement (ID 14731)

      13:40 - 13:45  |  Author(s): A. John Iafrate

      • Abstract
      • Presentation
      • Slides

      Background
      The spectrum of acquired resistance (AR) to osimertinib is not yet fully characterized. We present a single-center cohort of osimertinib AR biopsies and results of a patient with RET-mediated AR treated with the investigational RET-specific TKI BLU-667 and osimertinib.
      a9ded1e5ce5d75814730bb4caaf49419 Method
      We assayed tissue via SNaPshot or Foundation One next-generation sequencing (NGS) and plasma via Guardant360 NGS under an IRB-approved protocol. In vitro studies assessed implications of RET fusions in EGFR-mutant cancers. We treated one patient with osimertinib/BLU-667 using an IRB and FDA-approved compassionate use protocol.
      4c3880bb027f159e801041b1021e88e8 Result
      41 EGFR-mutant patients with AR to osimertinib were assessed histologically and queried by tissue NGS (n=22), plasma NGS (n=9) or both (n=10). Key AR findings: SCLC transformation (2/32 tissue); EGFR C797S (5/32 tissue, 5/19 plasma, all cis with T790M); MET amplification (7/32 tissue, 3/19 plasma); BRAF rearrangement (2/32 tissue) and CCDC6-RET rearrangement (1/32 tissue, 1/19 plasma [distinct case]).
      CCDC6-RET was expressed in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells, which maintained MAPK signaling and conferred resistance to osimertinib and afatinib. Inhibition of RET by BLU-667 or cabozantinib resensitized cells expressing CCDC6-RET to EGFR inhibition.
      A 60-year-old woman with EGFR del19 progressed on afatinib (T790M+), then osimertinib. Tissue biopsy at osimertinib AR showed acquired CCDC6-RET (T790-wt). She began osimertinib 80mg/BLU-667 200mg daily x2 weeks, then BLU-667 was increased to 300mg daily. Her dyspnea improved within days of initiation. Scans after 8 weeks revealed a marked response with RECIST tumor shrinkage of 78% (Figure). She experienced only grade 1 toxicities of fatigue, leukopenia, hypertension, dry mouth, and elevated transaminases.
      8eea62084ca7e541d918e823422bd82e Conclusion
      RET rearrangements are rare but recurrent in EGFR-mutant patients with AR to osimertinib. In vivo models suggest they mediate AR and this patient provides proof-of-concept that combination EGFR+RET inhibition with osimertinib/BLU-667 is a well-tolerated and effective regimen for RET-mediated AR. Further study is ongoing.

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    P3.13 - Targeted Therapy (Not CME Accredited Session) (ID 979)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.13-03 - Real-World Anaplastic Lymphoma Kinase Testing Practices: Results from a Survey in the United States (ID 12603)

      12:00 - 13:30  |  Presenting Author(s): A. John Iafrate

      • Abstract

      Background

      Anaplastic lymphoma kinase (ALK) translocation is a clinically validated predictive biomarker in multiple cancer types including non-small cell lung cancer, and widespread adoption of diagnostic assays permits a review of test performance. This analysis presents ALK and epidermal growth factor receptor (EGFR) testing rates, expediency, and results from 4 large national laboratories.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Deidentified data from January 2013 to December 2015 were compiled from 40 states and Washington DC and included in the final analysis. ALK status was evaluated with the Vysis ALK Break Apart FISH Probe Kit; EGFR status was evaluated by therascreen EGFR RGQ PCR Kit, cobas EGFR Mutation Test, or Sanger sequencing. Results from the most recent conclusive test were used. Collection to order (time from date of biopsy to date of biomarker test order), order to results (time from date of biomarker test order to date of available results), and overall turnaround times (collection to order + order to results) were evaluated. Results were analyzed by laboratories and US regions (Northeast, Midwest, South, and West). Data were summarized with descriptive statistics.

      4c3880bb027f159e801041b1021e88e8 Result

      Results of 59,058 ALK and 50,992 EGFR tests were collected; 50,023 patients were tested for both ALK and EGFR, 9035 had results for ALK only, and 969 for EGFR only. Mean patient ages at ALK-positive (ALK+) and EGFR-positive (EGFR+) diagnoses were 62.5 and 69.0 years, respectively. Overall ALK+ and inconclusive rates were 2.8% and 6.5%, respectively, vs 10.4% and 6.2% for EGFR testing. ALK+ (2.3–5.1%) and inconclusive (1.1–17.4%) rates varied between test centers. In the western US, the ALK+ rate (3.3%) was comparably greater than in other regions (2.4–2.7%). The median turnaround time was 15 days, with a median of 10 days for collection to order and 4 days for order to results; some regional variation was seen in turnaround time (14–18 days). No correlation was seen between age and turnaround time.

      8eea62084ca7e541d918e823422bd82e Conclusion

      EGFR+ and ALK+ rates and age distributions were consistent with prior reports. An interesting geographic difference in ALK rates was seen that warrants further investigation. The average turnaround time was longer than current guidelines recommend, suggesting an opportunity to improve current testing practices.

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