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Aaron S. Mansfield



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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-17 - Immune-Related Adverse Events in Patients with Metastatic Non-Small Cell Lung Cancer: Sex Differences and Response to Therapy. (Now Available) (ID 12642)

      16:45 - 18:00  |  Author(s): Aaron S. Mansfield

      • Abstract
      • Slides

      Background

      Sex differences in non-small cell lung cancer (NSCLC) outcomes have been described. Immune-related adverse events (IRAEs) have emerged as a serious clinical problem in the use of immune checkpoint inhibitors (ICI). Risk factors for IRAEs and their association with response to therapy remain controversial. Therefore, we studied sex differences in IRAEs and their association with response to therapy.

      Method

      All patients with metastatic NSCLC treated with anti-PD1 and anti-PDL1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Patients receiving treatment at an outside facility or with history autoimmune disorders were excluded. Kaplan-Meier method was used for time-to-event analysis.

      Result

      231 patients were identified, 120 (52%) were women and 111 (48%) were men. Baseline characteristics and ICI distribution were similar among groups (Table 1). Women were more likely to experience IRAEs compared to men (48% vs. 31%, p<0.008). Among patients with IRAEs, women were more likely to be prescribed systemic steroids (63% vs. 41%, p<0.02). Women were more likely to develop pneumonitis (23% vs. 12%, p<0.03) and arthralgia (17% vs. 3%, p<0.04). However, dermatologic toxicities (35% vs. 9%, p<0.002) were more commonly seen in men. In 17% of women the ICI was discontinued due to toxicity (men 7%). Besides sex, no other clinical characteristic was associated with increased IRAEs. Women with IRAEs were more likely to have a radiographic response compared with women without IRAEs (78% vs. 23%, p<0.0001), although this was not observed in men (37% vs. 26%, p>0.22). Better PFS was observed in women with IRAEs (10 months vs. 3.3 months, p<0.0006) compared to women without IRAEs.

      Women % (n)

      Men % (n)

      p value

      PD-L1 expression ≥1%

      30 (36)

      34 (38)

      0.29

      Adenocarcinoma

      77 (92)

      66 (73)

      0.02

      Bone metastasis

      34 (41)

      47 (52)

      0.05

      Brain metastasis

      20 (24)

      22 (24)

      0.76

      Liver metastasis

      13 (15)

      10 (11)

      0.53

      Prior chemotherapy

      74 (89)

      85 (94)

      0.06

      Prior palliative radiation

      53 (63)

      57 (63)

      0.52

      IRAEs

      48 (57)

      31 (34)

      0.006

      ≥3 grade IRAEs

      42 (24)

      29 (10)

      0.22

      Received systemic steroids

      63 (36)

      41 (14)

      0.02

      Required intravenous steroids

      30 (17)

      24 (8)

      0.47

      Conclusion

      Women with metastatic NSCLC are more likely to experience IRAEs compared to men. In women, an association between IRAEs and response to therapy was observed. Larger studies are needed to investigate the mechanisms underlying these associations.

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-12 - EGFR Therapy in ASCL1 Positive Lung Adenocarcinoma (ID 14211)

      16:45 - 18:00  |  Author(s): Aaron S. Mansfield

      • Abstract

      Background

      Greater than 40% of lung adenocarcinomas (LUAD) contain no known driver mutations from point mutation or structural variance analysis. Recently, we discovered that 15-20% of LUAD have abnormally high levels of ASCL1, a key regulator of neuroendocrine differentiation in the lung. ASCL1 in these tumors orchestrates the expression of a network of genes that affect the behavior of tumors and their microenvironments and provide opportunities for treatment that has largely been understudied. The goal of this study was to explore potential therapeutic options in these tumors.

      Method

      Bioinformatics analyses used public and internally generated expression data from LUAD. In vitro co-immunoprecipitation and cytotoxicity assays were used to determine the interaction between proteins and the sensitivity to EGFR blockers gefitinib and lapatinib. These drugs were also tested in patient derived xenograft (PDX) models from cisplatin resistant brain met LUAD with (A+AD) and without (A-AD) ASCL1 expression.

      Result

      Our data demonstrated that ASCL1 acts upstream of RET and promotes chronic over-expression of the oncogene in A+AD. In vitro experiments revealed a strong interactions between wild type EGFR and RET in A+AD which rendered these tumors vulnerable to treatment by EGFR blockers. Furthermore, while EGFR inhibitors blocked tumor growth in the A+AD PDX model, they were completely ineffective in the A-AD PDX model. EGFR therapy also markedly changed key regulators of the tumor microenvironment in favor of anti-tumor immunity. Analysis of TCGA data identified some overlap between A+AD and other LUAD subtypes, such as KRAS or EGFR mutant tumors. Further meta-analysis in a compendium of microarray data in stage-1 LUAD from multiple institutions demonstrated that high expression of wild type RET was significantly associated with a poor overall survival. Furthermore, high expression of EGFR (or its ligand TGFA) and RET imparted an aggressive phenotype in A+AD with overall survival similar to small cell lung cancer. Notably, EGFR, TGFA, and RET did not have any prognostic value in A-AD.

      Conclusion

      Our data provide strong evidence that patients with A+AD may benefit from a multipronged treatment strategy that include EGFR therapy even in the absence of mutations in EGFR.

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    PL02 - Presidential Symposium - Top 5 Abstracts (ID 850)

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 08:15 - 09:45, Plenary Hall
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      PL02.07 - IMpower 133: Primary PFS, OS and Safety in a PH1/3 Study of 1L Atezolizumab + Carboplatin + Etoposide in Extensive-Stage SCLC (Now Available) (ID 12892)

      09:00 - 09:10  |  Author(s): Aaron S. Mansfield

      • Abstract
      • Presentation
      • Slides

      Background

      First-line (1L) standard-of-care treatment for extensive-stage small cell lung cancer (ES-SCLC) is platinum (carboplatin or cisplatin) with etoposide. Despite high initial response rates, there has been limited progress in the last two decades and outcomes remain poor with a median overall survival (OS) of ~10 months. IMpower133 (NCT02763579), a global Phase 1/3, double-blind, randomized, placebo-controlled trial evaluated efficacy and safety of adding atezolizumab, a humanized monoclonal anti–PD-L1 antibody, or placebo to 1L carboplatin and etoposide in ES-SCLC.

      Patients with measurable (RECIST v1.1) ES-SCLC, ECOG performance status 0 or 1, who had not received prior systemic treatment for ES-SCLC were enrolled. PD-L1 immunohistochemical testing was not required. Patients were randomized 1:1 to receive four 21-day cycles of carboplatin (AUC 5 mg/mL/min IV, Day 1) plus etoposide (100 mg/m2 IV, Days 1-3) with either atezolizumab (1200 mg IV, Day 1) or placebo, followed by maintenance therapy with atezolizumab or placebo until intolerable toxicity or progressive disease per RECIST v1.1. Patients meeting predefined criteria could receive treatment beyond progression. Co-primary endpoints were OS and investigator-assessed progression-free survival (PFS). Adverse events (AEs) were graded per NCI-CTCAE v4.0. Blood-based tumor mutation burden (bTMB) was assessed using prespecified cutoffs of ≥16 vs. <16 and ≥10 vs. <10 mutations/Mb.

      In total, 201 patients were randomized to the atezolizumab group, and 202 to the placebo group. Median follow-up was 13.9 months. Median OS was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio [HR] 0.70 [95% confidence interval (CI): 0.54, 0.91; P=0.0069]). Median PFS was 5.2 months and 4.3 months, respectively (HR 0.77 [95% CI: 0.62, 0.96; P=0.017]). OS and PFS benefits were consistent across key patient subgroups. Investigator-assessed confirmed objective response rates were 60.2% and 64.4% in the atezolizumab and placebo groups, respectively; median duration of response, 4.2 and 3.9 months. Exploratory analyses showed OS survival benefits in subgroups above and below prespecified bTMB cutoffs. Grade 3-4 treatment-related AEs were reported in 56.6% vs. 56.1% patients in atezolizumab vs. placebo groups, respectively; serious treatment-related AEs occurred in 22.7% and 18.9% patients, respectively.

      Addition of atezolizumab to carboplatin and etoposide provided a significant improvement in OS and PFS in 1L ES-SCLC in an all-comer patient population. No unexpected safety signals were identified. Atezolizumab plus carboplatin and etoposide may represent a new standard regimen for patients with untreated ES-SCLC.

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    WS02 - Mesothelioma Workshop (ID 996)

    • Event: WCLC 2018
    • Type: Workshop
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/23/2018, 08:00 - 11:15, Room 205 AC
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      WS02.10 - An Overview of Present and Future Immunotherapy Trials in Mesothelioma: Progress and Problems (Now Available) (ID 14753)

      09:35 - 09:50  |  Presenting Author(s): Aaron S. Mansfield

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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