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Adam J Schoenfeld



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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 3
    • 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  |  Presenting Author(s): Adam J Schoenfeld

      • 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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      P1.14-12 - A Novel Activating MAP2K1 In-Frame Deletion Mediates Acquired Resistance to ROS1 TKIs in a Patient with ROS1 Fusion-Positive NSCLC (ID 2450)

      09:45 - 18:00  |  Author(s): Adam J Schoenfeld

      • Abstract

      Background

      ROS1 tyrosine kinase inhibitors (TKIs) such as crizotinib, entrectinib and lorlatinib provide significant benefit in non-small cell lung cancer (NSCLC) patients with ROS1 fusions. As observed with all targeted therapies however, resistance arises. With the widespread adoption of large panel next generation sequencing (NGS) at the time of acquired resistance (AR), our appreciation of novel off-target mechanisms continues to grow. Detecting additional mechanisms of acquired resistance (AR) is crucial to find novel therapies and improve patient outcomes.

      Method

      We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) of paired pre-treatment and post-progression samples from patients treated with ROS1 TKIs. Genetic alterations hypothesized to confer AR were modeled in a patient-derived cell line (LUAD-0003, expressing EZR/ROS1) as well as isogenic human (HBEC) and murine (NIH-3T3) cell lines. ROS1 fusions were expressed in these cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). Using these cell line models, alterations in drug sensitivity and downstream signal pathways were examined. We also explored possible therapeutic strategies to overcome the drug resistance caused by the novel AR mechanisms examined in this study.

      Result

      We identified a patient with NSCLC harboring a MAP2K1 (MEK1) variant encoding an in-frame deletion of amino acids E41-L54 (MEK1del) in a sample taken at the time of resistance to lorlatinib (after 9 months’ treatment). This mutation was not detected in the pre-TKI sample. Induction of ROS1 fusions in HBEC and NIH-3T3 cells increased the sensitivity of these cells to ROS1 TKIs and stimulated activation of MEK/ERK signaling in comparison with AKT signaling, suggesting the importance of the RAS-MAPK pathway in driving ROS1 fusion-positive cancers. Underscoring the importance of the RAS-MAPK pathway in ROS1-mediated tumorigenesis, we identified three patients (pancreatic, salivary, and breast cancer) with a ROS1 fusion and NF1 loss-of-function mutation concurrently, in TKI-naïve samples. Expression of MEK1del in HBEC and NIH-3T3 cells harboring ROS1 fusions, and knockdown of NF1 in LUAD-0003, activated ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 (crizotinib, lorlatinib) and MEK (selumetinib, trametinib) inhibited growth of cells expressing both ROS1 fusion and MEK1del.

      Conclusion

      Our results suggest that the activation of the RAS-MAPK pathway plays a critical role in tumorigenesis mediated by ROS1 fusions, and that activating mutations in this pathway can drive AR to ROS1 TKIs. Combined inhibition of ROS1 and MEK is a potential therapeutic strategy that should be explored clinically.

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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): Adam J Schoenfeld

      • 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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