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Anastasios Dimou



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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)

      14:00 - 15:30  |  Author(s): Anastasios Dimou

      • Abstract
      • Presentation
      • Slides

      Background

      Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.

      Method

      620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.

      Result

      Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.

      Conclusion

      In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

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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): Anastasios Dimou

      • 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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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-03 - HLA Affinity for Mutant EGFR Derived Peptides Identifies a Group of Patients with EGFR Driven NSCLC and Favorable Prognosis (ID 965)

      09:45 - 18:00  |  Presenting Author(s): Anastasios Dimou

      • Abstract

      Background

      Tumor mutations generate neopeptides with the potential to elicit T cell responses. Most commonly, passenger mutations are involved in this process, whereas driver mutations are restricted by the HLA genotype. Here, we hypothesized that peptides derived from mutant EGFR with ability to be presented by the host HLA molecules might elicit T cell responses against EGFR mutation positive tumors.

      Method

      We used the NETMHCpan platform to predict HLA A, B and C alleles that bind to peptides derived from EGFR p.L858R and EGFR p.E746_A750del but not to the closest wild type peptides. We termed the identified alleles as “protective alleles” based on their potential to elicit T cell responses against mutant EGFR. Further, we classified patients with EGFR mutation positive lung adenocarcinoma in the TCGA database with known HLA genotype into having at least one protective allele (“protected” group) or having none of these alleles (“non-protected” group).

      Result

      We identified HLA alleles A*31:01, A*33:01, A*68:01 and B*08:01 as protective for EGFR p.L858R and alleles A*03:01 and A*11:01 as protective for EGFR p.E746_A750del. These alleles with the exception of A*11:01 are found more common in European compared to Asian populations. In the TCGA population, we identified 20 patients with EGFR p.L858R and 14 patients with EGFR p.E746_A750del positive lung adenocarcinoma and complete follow up and HLA data. Among them, 11 classified in the “protected” and 23 in the “non-protected” group. There were no significant differences in the two groups with respect to gender, age or stage at diagnosis. Patients in the “protected” group had longer overall survival (p value=0.0011) and disease-free survival (p value=0.0047) compared to the “non-protected” group. Presence of the same alleles did not affect prognosis in patients from the TCGA with KRAS mutation positive adenocarcinoma. Difference in overall survival remained significant after controlling for stage, gender and age at diagnosis in a Cox proportional hazards model (risk ratio 0.01, 95% CI 0.001-0.34).

      Conclusion

      Here, we present a methodology to identify HLA alleles with the potential to elicit EGFR directed T cell responses against mutant EGFR. Interestingly, the identified alleles are more common in European populations, known to carry less risk for EGFR mutations compared to Asian populations. Presence of such alleles predicts better prognosis in an early stage EGFR mutation positive lung cancer population, consistent with our hypothesis that they might drive adaptive immunity against mutant EGFR.

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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  |  Presenting Author(s): Anastasios Dimou

      • 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.