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Manuel Domine



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    OA01 - Improving Outcomes in Locoregional NSCLC I (ID 892)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 107
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      OA01.05 - Phase II Study of Neo-Adjuvant Chemo/Immunotherapy for Resectable Stages IIIA Non-Small Cell Lung Cancer- Nadim Study-SLCG (ID 12907)

      11:15 - 11:25  |  Author(s): Manuel Domine

      • Abstract
      • Presentation
      • Slides

      Background

      The combination of chemotherapy and immunotherapy (CT-IO) has a high response rate and longer survival in unselected patients (pts) with metastatic non-small cell lung cancer (NSCLC). There are no data about this combination in the neoadjuvant setting.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A Phase II, single-arm, open-label multicenter study of local-advanced resectable stage IIIA N2-NSCLC adult patients with CT plus IO (nivolumab (NV)) followed by adjuvant treatment for 1 year. Neoadjuvant treatment: Three cycles of NV 360mg IV Q3W + paclitaxel 200mg/m2 + carboplatin AUC 6 IV Q3W. After completing neoadjuvant therapy, tumor assessment is performed in patients prior to surgery. Surgery is performed in the 3rd or 4th week after day 21 of the third cycle of neoadjuvant treatment. Adjuvant treatment: NV 240mg IV Q2W for 4 months and NV 480mg IV Q4W for 8 months (total one year) after surgical resection. The study aims to recruit 46 pts. The primary endpoint is Progression-Free Survival (PFS) at 24 months. Efficacy is explored using objective pathologic response criteria. We present preliminary data on patients that completed 3 cycles and underwent surgical resection.

      4c3880bb027f159e801041b1021e88e8 Result

      At the time of submission, 46 pts had been included and 20 underwent surgery. CT-IO was well-tolerated and surgery was not delayed in any patient. None of the pts was withdrawn from the study preoperatively due to progression or toxicity.

      Twenty surgeries had been performed and all tumors were deemed resectable. The overall clinical response rate was 5% complete (CR) and 65% PR. The pathological response evaluated after surgery: 13 cases (65.0%) achieved CR (CPR) (95% CI 40.8-84.6%), and 3 (15.0%) had a major pathologic response (MPR), defined as <10% viable tumor cells in the resection specimen. Considering both CPR and MPR, the overall response rate was 80.0% (95% CI 56.3-94.3%) and 60% of complete responses were unsuspected

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the first multicentric study testing CT-IO in the neoadjuvant setting with promising antitumor activity in locally advanced, potentially resectable NSCLC yields an unprecedented complete pathologic response rate. The data will be updated at the time of the congress. EudraCT Number: 2016-003732-20

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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): Manuel Domine

      • 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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    P2.04 - 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): Manuel Domine

      • 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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