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Edurne Arriola



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    P1.09 - Pathology (Not CME Accredited Session) (ID 941)

    • 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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      P1.09-09 - Evaluation of a Novel ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in NSCLC Patients (ID 12744)

      16:45 - 18:00  |  Author(s): Edurne Arriola

      • Abstract

      Background

      After the approval of crizotinib in ROS1 rearranged NSCLCs, the importance of accurately identifying those patients has never been greater. Although the recently updated guideline for molecular testing supports the use of ROS1 IHC as a screening test, to the best of our knowledge, only one ROS1 clone is commercially available and most published comparison studies involve a relatively small numer of positive cases. This situation prompted us to investigate a novel ROS1 IHC antibody in a large series of ROS1 positive NSCLCs samples.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Thirty-nine ROS1 FISH-positive (i.e., gold standard) samples from patients with NSCLCs procured at 22 hospitals were used for this study. In addition, 20 consecutive ROS1 FISH-negative samples from NSCLCs diagnosed at the referral institution were included as negative controls. The material available for all tumors had been formalin-fixed and paraffin-embedded. The specifics of formalin fixation were unknown. All specimens were independently screened for ROS1 expression by two IHC antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 provided by Ventana Medical Systems, Inc.) according to previously published methodology or the manufacturer´s instructions. FISH-validated ROS1-positive external controls were included in all the slides. The slides were reviewed by two pathologists blinded to FISH results. The results of both ROS1 IHC assays were evaluated using a modified H-score: strong cytoplasmic staining (3+), clearly visible using a ×2 or ×4 objective; moderate staining (2+), requiring a ×10 or ×20 objective to be clearly seen; and weak staining (1+), cannot be seen until a ×40 objective is used. Both anti-ROS1 IHC staining results were finally interpreted using a binary scoring system: positive (3+ or 2+) or negative (1+ or 0).

      4c3880bb027f159e801041b1021e88e8 Result

      In ROS1 FISH-negative cases, positive immunoreactivity (3+ or 2+) was observed in 25% and 5% of samples by SP384 and D4D6, respectively. In ROS1 FISH-positive cases, positive expression above the threshold was always present with both antibodies except for one sample that was only stained with SP384. In 4 positive cases (10.3%) by SP384 and 22 positive tumors (56.4%) by D4D6, we noted significant intratumoral heterogeneity, ranging from weak to strong protein expression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We have studied a very large series of ROS1 FISH-positive NSCLCs with a novel IHC clone, which showed excellent sensitivity. The predominantly homogeneous and intense staining may support the use of a dichotomous scoring approach, before confirmation with FISH or a molecular method.

      Funding: I+D+I 2013-2016/Feder. ISCIII: PI14/01176

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-09 - Targetable Genomic Alterations in KRAS Mutant Lung Adenocarcinoma by Targeted Next Generation Sequencing (ID 13705)

      16:45 - 18:00  |  Presenting Author(s): Edurne Arriola

      • Abstract
      • Slides

      Background

      KRAS mutant (m) non-small cell lung cancer (NSCLC) represents 25% of cases. Despite the common mutation, biological and clinical behaviour of this disease is diverse. The aim of our study was to analyze co-occurring genomic alterations in advanced KRASm lung by next-generation sequencing (NGS) and compare them to a KRAS wild-type (WT) population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Advanced lung adenocarcinoma patients treated with a platinum doublet with KRAS mutation by Sanger were submitted to targeted NGS with the Oncomine Solid Tumor kit (DNA) and compared to a KRAS WT population of clinically similar patients. Association with outcome of the genomic alterations was evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      32 KRASm patients and 18 WT patients were analyzed. The most frequent KRAS mutation was p.Gly12Cys (45%), followed by p.Gly12Val (24%). TP53 mutation was observed in 55% of KRASm tumors and 60% of WT cases (Table 1). Mutations in STK11 were found in 10% of cases in the KRAS mutant cohort while none in the WT. 3 out of the 4 cases of STK11 mutations coexisted with TP53 mutations. FGFR3, SMAD4 and DDR2 mutations were more frequently found in cases with KRAS mutations, although at low frequencies. Neither KRAS nor TP53 mutations had an impact in OS. We then selected the KRAS mutant cohort and evaluated the impact of co-mutations. TP53 or STK11 did not significantly affect OS of KRAS mutant patients.

      Table 1. Co-ocurring alterations in KRAS mutant and WT tumors

      Mutations/CNG

      KRAS mutant % (N: 38)

      KRAS WT % (N: 15)

      TP53 mut

      55%*

      60%*

      STK11 mut

      10%**

      0%

      FGFR3 mut

      13%

      6%

      SMAD4 mut

      8%

      0%

      DDR2 mut

      5%

      0%

      MYC mut

      5%

      6%

      KRAS CNG

      8%

      6%

      8eea62084ca7e541d918e823422bd82e Conclusion

      KRASm lung adenocarcinoma is genomically diverse. NGS provides biologically relevant information and druggable targets in this subset of patients.

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-27 - Ph II Study of Oral Selective AXL Inhibitor Bemcentinib (BGB324) in Combination with Pembrolizumab in Patients with Advanced NSCLC (ID 14307)

      16:45 - 18:00  |  Author(s): Edurne Arriola

      • Abstract

      Background

      Bemcentinib (BGB324) is a first-in-class, highly selective oral inhibitor of the AXL tyrosine kinase currently in phase II clinical development across several cancer types. AXL overexpression has been observed in pts failing anti-PD-1 therapy in several cancers whereas AXL inhibition via bemcentinib has shown synergistic effect with checkpoint blockade in pre-clinical models of NSCLC.

      In pts with advanced, pre-treated NSCLC, bemcentinib monotherapy led to disease stabilisation in 2 out of 8 pts including evidence of tumour reduction. Combination therapy of bemcentinib with EGFR inhibition indicated the potential of AXL blockade to reverse resistance to targeted therapy in advanced EGFR therapy resistant NSCLC. Evidence of immune activation following bemcentinib monotherapy was observed in AML patients.

      This open label, single-arm, two-stage Phase 2 study was designed to test whether AXL inhibition may increase the efficacy of pembrolizumab in patients with advanced, previously treated adenocarcinoma of the lung.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with documented Stage IV adenocarcinoma of the lung who had progressed on previous platinum chemotherapy and – if applicable – at least one line of licensed EGFR or ALK targeted therapy, received 200 mg/d bemcentinib po and 200 mg/q3wk pembrolizumab iv. Patients were required to consent to a fresh pre-treatment biopsy. Tumour assessments were done 9-weekly. The primary endpoint was ORR. Tumour biopsies were analysed for PD-L1 and AXL as well as immune cell populations. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) in patients pre-dose and at C2D1.

      4c3880bb027f159e801041b1021e88e8 Result

      As of time of writing, the study had fully recruited its first stage. Of 24 patients enrolled, 14 were ongoing. 6 of 10 patients who had reached their first scan showed evidence of tumour shrinkage including 3 pts with partial responses in their target lesions. 2 patients had stable disease. There were no grade 4 treatment-related events. Dose reduction from 200 to 100 mg/d of bemcentinib as a consequence of adverse events was required in 12% of patients. Correlation of AXL and PD-L1 expression with response was evaluated. Soluble AXL plasma levels were increased following one cycle of treatment indicative of target engagement.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A preliminary analysis of response to combination treatment during the first stage of this study as well as biomarker correlation will be presented at the meeting. Clinical trial information: NCT03184571

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