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Dara Aisner



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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
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-87 - Acquired Resistance Mechanisms and Clinical Outcomes for Patients with Epidermal Growth Factor Receptor (EGFR) Positive Non-Small Cell Lung Cancer (NSCLC) Treated with Osimertinib (Now Available) (ID 2960)

      09:45 - 18:00  |  Author(s): Dara Aisner

      • Abstract
      • Slides

      Background

      Osimertinib is a 3rd generation TKI approved for stage IV EGFR+ NSCLC in the first line or post-progression with T790M. The spectrum of osimertinib resistance mutations and clinical outcomes post-osimertinib progression are not well described.

      Method

      Single-center retrospective review of patients with stage IV EGFR+ NSCLC treated with osimertinib was conducted. Resistance mutations were determined via tissue biopsy or circulating tumor DNA (Guardant) prior to and at time of progression on osimertinib. PFS was calculated using Kaplan-Meier method. PFS1 is start of osimertinib to radiographic progression. PFS2 is start of next therapy after osimertinib to next radiographic progression.

      Result

      We identified 95 patients with stage IV EGFR+ lung adenocarcinoma treated with osimertinib detected via NGS (56/95), real-time PCR (29/95), Sanger sequencing (8/95), and other techniques (2/95). Most patients were female (63/95) and never smokers (72/95). Osimertinib resistance and post-progression patterns are shown in Table 1. Potentially targetable mutations were found in 55% (26/47) samples and 14% (6/47) samples had oncogenes targetable with available TKIs. TP53 mutations prior to osimertinib did not significantly influence PFS (36 weeks vs 39 weeks; p = 0.13). MET amplification was only seen in the setting of undetectable T790M or in patients who received first line osimertinib. Median PFS1 for 1st line EGFR TKI (n=17), 2nd line EGFR TKI (n=41), 3rd or greater line EGFR TKI (n=29) was 36, 45 and 39 weeks respectively (p=0.268) with median follow up of 59, 81, and 64 weeks. 10 patients received locally ablative radiotherapy for oligoprogressive disease (defined as ≤ 3 progressive sites) and continued osimertinib post-progression with median PFS2 of 49 weeks.

      resistance table.png

      Conclusion

      There is utility to repeat biopsy after progression on osimertinib as targetable oncogenes can be found. Presence of TP53 prior to starting osimertinib did not influence PFS1. Continuing osimertinib and adding radiotherapy for oligoprogressive disease does increase post-progression PFS.

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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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      P1.14-09 - Unveiling Hidden MET-Mediated Primary Alectinib Resistance in ALK-Positive Non-Small Cell Lung Cancer (Now Available) (ID 1989)

      09:45 - 18:00  |  Author(s): Dara Aisner

      • Abstract
      • Slides

      Background

      Alectinib is an ALK inhibitor that is currently used for the treatment of ALK-positive NSCLC. This next generation ALK inhibitor was initially used as second-line therapy following resistance to crizotinib. More recently, alectinib has superseded crizotinib, an ALK/ROS1/MET inhibitor, as a first-line therapy due to its superiority in phase III trials. Although patients enjoy durable responses to alectinib, they eventually develop resistance. Here we describe four cases of primary resistance to alectinib in which the patients show little to no response to alectinib when administered as first or second-line therapy.

      Method

      In order to investigate primary resistance to alectinib, tissue was obtained during re-biopsy and subjected to routine clinical genetic analyses including gene fusion detection and genetic mutation analysis using the Archer FusionPlex and VariantPlex assays, respectively. Concurrently, at the time of biopsy, additional fresh tissue was procured for cell line derivation. The primary cell line was then used to assess ALK and other inhibitors’ potency by cell viability assays. Targeted analysis of signaling pathways was performed in the cell lines via western blot analysis and proximity ligation assays to determine resistance mechanisms.

      Result

      We present 4 cases of ALK patients with primary resistance to alectinib when used as either first (n=3) or second-line therapy (n=1). In 3 of the 4 cases, routine clinical resistance testing revealed no additional ALK or non-ALK related genetic abnormalities (e.g.; ALK kinase domain mutations, other oncogenic gain-of-function mutations, or gene amplification). However, examination of targeted gene expression data indicated elevated RNA transcripts of MET alone or combined MET and AXL. Analysis of the cell lines derived from these 4 patients further implicates MET in alectinib resistance alone or together with AXL or ERBB3. Signaling analysis shows that MET provides a prosurvival effect, signaling through the PI3K/AKT pathway. In the case where MET was the sole identified bypass mechanism of alectinib resistance, the patient also rapidly progressed through brigatinib, but a regimen of crizotinib plus brigatinib resulted in rapid tumor shrinkage.

      Conclusion

      Here, we document cases of primary resistance to alectinib therapy using human-derived cell lines to expose novel resistance mechanisms not identified by routine clinical testing. We show that MET is a critical component and serves as a bypass mechanism of alectinib resistance either alone or in combination with AXL or ERBB3. We also demonstrate that crizotinib could overcome MET-mediated ALK resistance in a patient.

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      P1.14-58 - A Phase II Study to Evaluate Neoadjuvant Osimertinib for Surgically Resectable, EGFR-Mutant Non-Small Cell Lung Cancer (ID 580)

      09:45 - 18:00  |  Author(s): Dara Aisner

      • Abstract
      • Slides

      Background

      The third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is well-tolerated and effective for first-line treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC). The efficacy of osimertinib in the treatment of early stage EGFR-mutant NSCLC, however, is unknown, and cytotoxic chemotherapy is considered the standard of care when systemic therapy is necessary for these patients. Neoadjuvant chemotherapy is an established therapeutic modality in locally-advanced NSCLC, in which a major pathologic response is associated with improved survival. Neoadjuvant use of targeted therapies in oncogene-driven NSCLC may offer the dual advantages of increased response rates and of more favorable toxicity profiles compared to cytotoxic chemotherapy, and also provides the opportunity to identify mechanisms underlying tumor cell persistence despite optimal oncogene-targeted therapy.

      Method

      This ongoing phase II, multi-institution study aims to enroll 27 patients with surgically resectable stage I-IIIA EGFR-mutant NSCLC. Patients are treated with one to two months of osimertinib 80 mg orally daily followed by surgical resection. The primary endpoint is major pathologic response (mPR) rate, defined as less than 10% residual viable tumor at surgical resection. Secondary endpoints include safety assessment, unanticipated delays to surgery, surgical complication rate, pathological complete response rate (pCR), unconfirmed objective response rate (ORR), rate of lymph node downstaging, disease-free survival, and overall survival. Tumor biopsies are obtained prior to osimertinib treatment in order to permit comparative correlative studies between pre- and post-osimertinib treated tumors. This includes genomic and transcriptomic analyses, evaluation of tumor immune cell infiltrates, and development of patient-derived model systems for functional validation studies.

      Result

      As of March 2019, five patients with EGFR-mutant NSCLC (2 stage IIIA, 1 stage IB, 2 Stage IA) have been enrolled and treated with osimertinib for an average of 56 days prior to surgical resection. Restaging imaging prior to surgical resection demonstrated an unconfirmed radiographic partial response in three patients (60% ORR) and stable disease in two patients (100% disease control rate). The mPR rate is 20% (1 of 5). No pCR’s were observed. One patient demonstrated lymph node downstaging from N2 to N0. Treatment was well-tolerated without SAEs and all patients proceeded to surgical resection without unscheduled delay or surgical complications. Genomic and immunophenotyping analyses are underway and will be reported.

      Conclusion

      Preliminary data from this phase II study indicates that neoadjuvant osimertinib treatment in surgically-resectable, EGFR-mutant NSCLC is well-tolerated and can induce pathological responses and downstaging of disease prior to surgery.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-06 - Detection of ctDNA and Correlation with Tumor Mutation Testing in Early Stage NSCLC (ID 2950)

      10:15 - 18:15  |  Author(s): Dara Aisner

      • Abstract

      Background

      In advanced disease, circulating tumor (ctDNA) has proven a viable alternative to tissue based molecular testing to identify patients with lung adenocarcinoma (LUAD) eligible for targeted therapies. ctDNA is under investigation for utility in early cancer detection and non-invasive companion diagnostics to allow for identification of targetable biomarkers in patients who may benefit from neoadjuvant targeted therapy. However, in the early stage cancer setting, ctDNA has been limited by reliance on interrogation of genomic alterations alone resulting in low detection rates (13% stage I, 22% stage II, 40% stage III, Abbosh et al, Nature 2017). Herein, we test the ability of the novel ctDNA-based assay to detect ctDNA in patients with early stage LUAD, and secondarily, to identify targetable oncogenes in these patients.

      Method

      Eligible patients had stage IA-IIIA LUAD deemed surgically resectable. Following consent, plasma samples were collected prior to surgery or neoadjuvant therapy. Circulating free DNA (cfDNA) was analyzed for ctDNA with the LUNAR assay (Guardant Health), which utilizes an integrated genomic and epigenomic ctDNA assessment at a tumor allelic fraction down to 0.01% to report “ctDNA detected” or “ctDNA not detected”. This single blood sample cfDNA assay utilizes a variant filter to distinguish tumor from non-tumor derived cfDNA alterations in the absence of other genomic DNA (e.g. tissue sequencing or peripheral blood mononuclear cells). Molecular analysis of paired FFPE primary tumor specimens was performed using the Illumina TruSight Tumor 26 or ArcherDx VariantPlex Solid Tumor library preparation kits followed by next-generation sequencing (NGS) on the Illumina platform in a CLIA-certified laboratory. Sensitivity for tumor driver mutation detection is evaluated by comparing tumor drivers identified in ctDNA with those identified in corresponding paired primary tumor specimens.

      Result

      We enrolled 31 patients with early stage LUAD who ultimately underwent surgical resection, 29 of whom completed LUNAR testing (19 with stage I, 4 with stage II and 6 with stage IIIA). Analysis of tumor tissue identified a driver mutation in 83% (24/29) of cases (KRAS=11, EGFR=10, MET=3, ALK=1). A genomic cancer-associated mutation was identified in 16%, 25% and 67% in stage I, II, and III, respectively. The LUNAR assay demonstrated 100% specificity for EGFR and KRAS mutations. The incorporation of the epigenomic classifier enhanced pre-operative ctDNA detection to 26% of Stage I, 50% of stage II, and 67% of stage III patients.

      Conclusion

      The majority of patients with early stage LUAD had an identifiable oncogene alteration, consistent with data from advanced disease. Utilizing a plasma only, integrated genomic and epigenomic ctDNA assay demonstrated improved performance over tumor informed approaches. The ctDNA detection rate increased with disease stage, consistent with increased tumor burden. With 100% tissue concordance of EGFR and KRAS alterations identified in ctDNA, ctDNA may prove an option for not only identification of early stage LUAD, but also identifying biomarker positive LUAD eligible for clinical trials utilizing targeted therapy in the neoadjuvant setting.