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Maria E. Arcila



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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-122 - A Clinical Utility Study of Plasma DNA Next Generation Sequencing Guided Treatment of Uncommon Drivers in Advanced Non-Small-Cell Lung Cancers (ID 2997)

      09:45 - 18:00  |  Author(s): Maria E. Arcila

      • Abstract
      • Slides

      Background

      Although EGFR and ALK testing in non-small-cell lung cancers (NSCLC) is now considered standard practice, next generation sequencing (NGS) for extended molecular testing of uncommon drivers is often difficult to perform in the community due to factors surrounding tissue adequacy, availability and turnaround time. We set out to prospectively determine the clinical utility of plasma ctDNA NGS in detecting uncommon actionable drivers and their plasma guided treatment response.

      Method

      Patients with advanced NSCLC who were driver unknown after routine EGFR and ALK testing were eligible. Patients were enrolled prospectively at Memorial Sloan Kettering Cancer Center (NY, USA) and Northern Cancer Institute (Sydney, Australia). Peripheral blood (10-20mL) was collected and sent to Resolution Bioscience (Kirkland, WA) for targeted ctDNA NGS using a bias-corrected hybrid-capture 21 gene assay in a CLIA laboratory achieving a mean unique read of at least 3000x and sensitivity above 0.1%. Clinical endpoints included detection of uncommon oncogenic drivers defined as actionable alterations in ROS1, RET, BRAF, MET, HER2, turnaround time, concordance with tissue NGS when available, and plasma guided treatment outcome.

      Result

      614 patients were prospectively accrued. Plasma NGS detected an uncommon oncogenic driver in 7% (45/614) of patients including ROS1, RET fusions, BRAF, MET exon 14 and HER2 exon 20 mutations, of whom 3% (20/614) were matched to targeted therapy producing 12 partial responses. Mean turnaround time for plasma NGS was significantly shorter than tissue NGS (10 vs 25 days, P <0.0001). 399 patients had concurrent tissue NGS results available for concordance analysis; Overall concordance, defined as the proportion of patients for whom an uncommon driver was uniformly detected or absent in both plasma and tissue NGS, was 94.7% (378/399, 95% confidence interval [CI] 92.1 – 96.7%). Among patients who tested plasma NGS positive for uncommon drivers, 87.5% (28/32, 95% CI 71.0-96.5%) were concordant on tissue NGS, and among patients tested tissue NGS positive for uncommon driver, 62.2% (28/45, 95% CI 46.5-76.2%) were concordant on plasma NGS.

      Conclusion

      Plasma NGS uncovered uncommon oncogenic drivers with faster turnaround time than tissue NGS, directly matched patients to targeted therapy and produced clinical responses independent of tissue results. A positive finding of an oncogenic driver in plasma is highly specific and can immediately guide treatment, but a negative finding may still require tissue biopsy. Our findings provide prospective evidence to support a “blood first” approach in molecular diagnostics for the care of patients with NSCLC.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-06 - Tissue-Based Molecular and Histologic Landscape of Acquired Resistance to Osimertinib in Patients with EGFR-Mutant Lung Cancers (ID 1392)

      09:45 - 18:00  |  Author(s): Maria E. Arcila

      • Abstract
      • Slides

      Background

      Even though osimertinib (osi) is now the initial treatment for patients with EGFR-mutant lung cancers, our knowledge about mechanisms of resistance (MOR) is largely derived from patients who received osi after acquiring EGFR T790M on treatment with another EGFR inhibitor. Other studies of osi resistance have mainly reported genotyping of plasma which suboptimally detects lineage plasticity, copy number changes, and chromosomal rearrangements.

      Method

      To identify MOR to osi and characterize clinical, molecular and histologic factors associated with duration of response, we identified patients with EGFR-mutant lung cancers who had targeted next-generation sequencing (MSK-IMPACT) performed on tumor tissue obtained before treatment and after developing resistance to osi received as either first-line or later line EGFR-TKI.

      Result

      From January 2016 to March 2019, we collected paired pre-treatment and resistance specimens from 53 patients (1st line osi: 21. Osi after prior TKI: 32). MOR are summarized in the table. Histologic transformation was identified in 18% of 1st line cases and 17% of all cases. When osi was given as initial treatment, with median follow up of 18 months, early emerging MOR rarely included on-target resistance mechanisms (acquired EGFR G724S in 1/21). Other acquired alterations representing potential resistance mechanisms not listed in the table included CCNE1 and MYC amplifications, and mutations in MTOR A1098S and MET H1094Y.

      First line (n = 21)

      Osi after prior TKI

      (n = 32)

      All

      (n = 53)

      Squamous transformation

      3

      3

      6

      Neuroendocrine transformation

      1

      2

      3

      On target mutation (EGFR C797X or other)

      1

      9

      10

      Loss of EGFR T790M only

      -

      8

      8

      Fusions (ALK, RET, BRAF)

      0

      3

      3

      Amplifications (HER2, MET, EGFR)

      2

      3

      4

      Off target mutations (KRAS, BRAF, HER2)

      1

      2

      3

      Conclusion

      In this analysis of MOR identified on NGS from tumor tissue, we found a spectrum of resistance mechanisms to osi. By evaluating tissue rather than plasma we provide data on histologic transformation (including squamous cell transformation). Subsequent studies are needed to assess patients with a longer time on initial osi as early progressors may have different MOR, with off-target MOR emerging earlier and on-target resistance mutations later.

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      P1.14-50 - A Phase 2 Trial of Cabozantinib in ROS1-Rearranged Lung Adenocarcinoma (Now Available) (ID 2753)

      09:45 - 18:00  |  Author(s): Maria E. Arcila

      • Abstract
      • Slides

      Background

      To date, no ROS1 inhibitor is approved for the treatment of ROS1-rearranged lung cancers after progression on crizotinib. Progression on crizotinib can be mediated by the acquisition of ROS1 kinase domain mutations (e.g. ROS1G2032R or ROS1D2033N). Cabozantinib is a highly potent ROS1 tyrosine kinase inhibitor that has superior activity over lorlatinib against these mutations. We evaluated the activity of cabozantinib in patients with ROS1-rearranged lung cancers on a phase 2 trial.

      Method

      In this single-center, open-label, Simon two-stage, phase 2 study, eligible patients had ROS1-rearranged unresectable/metastatic non-small cell lung cancer, a Karnofsky performance status >70%, and measurable disease. ROS1 fusion was identified by local testing in a CLIA-compliant environment. Cabozantinib was dosed at 60 mg once daily. The primary endpoint was objective response (RECIST v1.1). In the first stage of this trial, 1 response was required to move to the second stage. Secondary endpoints included safety.

      Result

      Six patients received cabozantinib in the ongoing first stage of this study. All patients had >1 prior ROS1 inhibitor. The median age was 59 years; all were never smokers. The best response to therapy was: 1 partial response (-92%, confirmed), 1 unconfirmed partial response (-31%), and 4 stable disease. All patients had disease regression (-7 % to -92%); no patients had primary progressive disease. The only patient with a confirmed partial response was a patient whose cancer acquired a ROS1D2033N solvent front mutation after crizotinib. None of the other five ROS1 inhibitor pre-treated patients (who did not have a confirmed response) had a known on-target acquired resistance mutation in their cancer. After progression on cabozantinib (9.1 months after therapy initiation), the patient whose cancer harbored the ROS1D2033N mutation acquired a METD1228N kinase domain mutation on paired sequencing of pre-cabozantinib and post-progression tumor. The most common grade 3 treatment-related adverse events were hypertension (50%), and mucositis, palmar-plantar erythrodysesthesia, and hypophosphatemia (each in 17%). Most patients (83%) required a dose reduction.

      Conclusion

      Cabozantinib can re-establish disease control in ROS1-rearranged lung cancers after progression on a prior ROS1 inhibitor. The first stage of this ongoing trial met its prespecified endpoint for efficacy to move into the second stage. Response was only observed in the setting of a known ROS1 kinase domain resistance mutation.

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