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Darren Cross



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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 2
    • 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): Darren Cross

      • 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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      MA09.06 - Adaptive Mechanisms of Resistance to Targeted Therapy in EGFR Mutant Brain Metastasis (Now Available) (ID 1329)

      15:15 - 16:45  |  Author(s): Darren Cross

      • Abstract
      • Presentation
      • Slides

      Background

      A subset of non-small cell lung cancers (NSCLCs) can be effectively treated with EGFR tyrosine kinase inhibitors (TKIs). However, a significant proportion of patients with brain metastasis progress after front-line treatment, underscoring the central nervous system (CNS) as a unique sanctuary site for persistent disease. Herein, we performed an integrated examination of the cellular, pharmacological, and molecular causes of resistance to targeted therapies in brain metastases.

      Method

      The efficacy of osimertinib, a brain penetrant third generation TKI, was studied in mice using EGFR mutant NSCLC models derived from cell lines or patient biopsies. Animals with multi-organ metastases were treated continuously until disease progression was detected in the brain parenchyma. We also developed an in situ transcriptomic approach, referred to as Brain Metastasis Xenograft-RNA Sequencing (BMX-seq), to distinguish the transcriptome of tumor versus stroma in vivo. Molecular and biological responses were integrated with pharmacological analysis of loco-regional distribution of osimertinib in and around brain lesions.

      Result

      In EGFR mutant models with multi-organ metastases, extra-cranial tumors could be effectively controlled, while brain metastases eventually progress despite strong osimertinib penetrance into the normal and tumor bearing CNS. Importantly, tumor cells isolated from progressing brain metastases did not exhibit resistance in vitro. However, these cells exhibited an enhanced resistant capacity when transplanted into the brain, demonstrating that this resistant phenotype is selected for and that exposure to the brain is a requirement for drug resistance in vivo.

      BMX-seq reveals that the stroma of drug resistant brain metastasis is characterized by activation of innate pro-inflammatory pathways. Reciprocally, we identified stromal induced activation of cytoskeletal and interferon response genes in drug resistant tumor cells. Interestingly, several of these genes are induced in situ independently of drug treatment, suggesting that the brain metastatic niche can precondition tumor cells for ensuing drug resistance. Finally, we demonstrate that inhibiting mediators of interferon and cystoskeletal signaling increases the sensitivity of brain metastasis to osimertinib in vivo.

      Conclusion

      Although advances have been made in the brain penetrating abilities of targeted therapies, acquired resistance in this unique TME still develops. Our results suggest that adaptive molecular interactions within the brain TME preconditions metastatic cells for TKI resistance and that targeting such pathways in combination with osimertinib should be explored to treat NSCLC patients suffering from or at risk for brain relapse.

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