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Sukhmani Padda



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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA09.02 - In Vivo, Ex Vivo and Early Clinical Activity of EGFR Monoclonal Antibody and Osimertinib in EGFR Exon 20 Insertion NSCLC (Now Available) (ID 968)

      15:15 - 16:45  |  Author(s): Sukhmani Padda

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR Exon 20 insertions (Ex20Ins) are the 3rd most common class of EGFR activating mutation, but patients with NSCLC harboring EGFR Ex20Ins lack effective approved EGFR-TKIs. Newer-generation TKIs and combination strategies with EGFR-monoclonal antibodies (moAbs) may enhance activity against EGFR Ex20Ins.

      Method

      Xenografts derived from CRISPR-modified H2073 cells with Ex20Ins (A763_Y764InsFQEA, D770_N771InsSVD or V769_D770InsASV) and Ex20Ins patient-derived xenografts (PDXs) (D770_N771InsSVD, A797_V769dupASV, D770_N771_InsG, H773_V774_InsNPH) were treated with vehicle, osimertinib , cetuximab, and osimertinib+cetuximab. Ex20Ins spheroid models (D770_N771InsSVD and M766_A767InsASV) were treated with cetuximab at fixed dose and increasing concentrations of osimertinib. Ex20Ins PDX (A763_Y764InsFQEA) was also treated with afatinib and erlotinib; Ex20Ins PDX (D770_N771InsSVD) was treated with these combinations plus afatinib+cetuximab. Immunoblotting for pharmacodynamic studies of on-target and downstream proteins, phospho-proteins and apoptosis markers were performed at relevant timepoints for D770_N771InsSVD PDX and CRISPR model. A phase 1 clinical trial with a dose expansion cohort in Stage IV EGFR Ex20Ins NSCLC is currently open to accrual at osimertinib 80 mg qd and the EGFR-moAb necitumumab 800 mg IV D1 and D8 of 21D cycle with response assessment by RECIST 1.1 (NCT02496663).

      Result

      The combination of osimertinib and cetuximab achieved significant tumor growth inhibition compared to osimertinib alone across PDX and CRISPR cell line xenograft models (p=0.05), except for the A763_Y764InsFQEA PDX model where osimertinib alone and osimertinib+cetuximab were equivalently effective (both p<0.001 compared to control). Spheroid models for D770_N771InsSVD and M766_A767InsASV showed significantly increased cytotoxicity from the addition of cetuximab across multiple doses of osimertinib. Osimertinib+cetuximab was superior to erlotinib, cetuximab, afatinib and afatinib+cetuximab in a D770_N771InsSVD PDX model (p<0.001). In this model, inhibition of p-EGFR, p-ERK, p-HER2 and increased caspase 3 cleavage were noted, consistent with significant tumor growth inhibition. In the phase 1 EGFR Ex20Ins expansion cohort of necitumumab in combination with osimertinib, 6/18 patients enrolled with 4 patients evaluable for response; 2 patients achieved a partial response and median PFS was 5.3 months.

      Conclusion

      In vivo and ex vivo modeling in CRISPR cell line xenografts, PDXs and organoids demonstrated preclinical activity of dual EGFR blockade with osimertinib and EGFR monoclonal antibody in the 5 most common EGFR Ex20Ins representing a frequency of ~60% of detectable EGFR Ex20Ins in clinical practice. Osimertinib alone was as active as osimertinib plus cetuximab in A763_Y764InsFQEA, consistent with known sensitivity of this proximal insertion to single-agent EGFR-TKI. In a phase 1 study, osimertinib and the EGFR moAb necitumumab demonstrates preliminary clinically activity in EGFR Ex20Ins NSCLC.

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    MA16 - Prioritizing Use of Technology to Improve Survival of Lung Cancer Subgroups and Outcomes with Chemotherapy and Surgery (ID 142)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
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      MA16.04 - Discussant - MA16.01, MA16.02, MA16.03 (Now Available) (ID 3783)

      15:45 - 17:15  |  Presenting Author(s): Sukhmani Padda

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.15 - Thymoma/Other Thoracic Malignancies (ID 184)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.15-02 - Role of mTOR Inhibitor Everolimus in the Treatment of Metastatic Thymic Epithelial Tumors (ID 2763)

      09:45 - 18:00  |  Author(s): Sukhmani Padda

      • Abstract
      • Slides

      Background

      Optimal treatment for metastatic thymic epithelial tumors (TETs) after progression on platinum-based chemotherapy has yet to be determined. There is emerging evidence to support the use of mTOR inhibitor everolimus in this setting including the recent phase II study by Zucali et al. However, patient selection and identifying predictors of response remains a challenge. Here, we describe a single-center experience with everolimus in TETs and molecular markers associated with response to therapy using a computational biological model (CBM).

      Method

      Data on all patients with advanced TETs who were prescribed everolimus at our institution were retrospectively abstracted from the electronic medical record. Time to treatment failure (TTF) and overall survival (OS) were calculated. Solid Tumor Actionable Mutation Panel (STAMP), a targeted next generation sequencing (NGS) panel, was run on each TET and the results were computationally matched to a cohort of genomically similar TET patients from The Cancer Genome Atlas (TCGA). CBM was used to examine key genomic alterations of TETs correlated with response on everolimus. Responders were defined as having TTF > 6 months.

      Result

      Thirteen patients with TETs, including ten thymomas (T) and three thymic carcinomas (TC) treated with everolimus, were included. All patients had been heavily pre-treated with an average of three prior lines of therapy. Three patients discontinued treatment due to adverse events. The average TTF was 10.8 months in T and 2.6 months in TC with median OS of 205 months (T) and 67.8 months (TC). Molecular data was available for 11 of 13 patients and identified mutations in MAP2K, HRAS and NF1 as key molecular features associated with a response to everolimus. CBM accurately predicted response in 9 of 11 genomically similar TCGA tumors to our patient cohort.

      Conclusion

      Patients with previously treated metastatic TETs appear to benefit from everolimus. Molecular testing of these tumors using targeted NGS panel revealed an association with several key genes, which may help to guide patient selection in the future.

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