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Tomohiro Sakamoto



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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-04 - Clinical Validation of Large NGS Gene Panel Using Residual Specimen (Now Available) (ID 391)

      10:15 - 18:15  |  Presenting Author(s): Tomohiro Sakamoto

      • Abstract
      • Slides

      Background

      Precision medicine based on driver oncogenes is now developed for non-small cell lung cancer (NSCLC). A large number of next-generation sequencing (NGS) gene panels with various characteristics have been developed, and it is important to use properly according to the purpose. TruSight Oncology (TSO) 500 is an NGS tumor profiling assay that targets over 500 genes to analyze cancer-related biomarkers including SNVs, indels, fusions, splice variants, tumor mutation burden (TMB) and microsatellite instability (MSI).

      Method

      Of the cases diagnosed with advanced NSCLC at Tottori University Hospital, 30 cases with consent to this observational study were enrolled. TSO500 was performed at the CLIA-certified laboratory (RIKEN GENESIS CO., LTD.) using DNA and RNA extracted from archived formalin-fixed paraffin-embedded (FFPE) lung cancer specimens. These were compared with gene alterations measured in the clinical practice.

      Result

      Specimens were collected by bronchoscopy in 21 cases (70%), percutaneous biopsy in 3 cases (10%), surgery in 3 cases (10%), cell block of pleural effusion in 2 cases (7%) and thoracoscopy in 1 case (3%). The success rates of DNA analyses, including TMB and MSI analysis, and RNA analyses were 83% (25/30 cases) and 97% (29/30 cases), respectively. In the 30 cases analyzed, a total of 25 actionable gene alterations (13 EGFR mut, 4 ALK fus, 2 KRAS mut, 2 BRAF mut, 2 MET ex14 skipping, 1 RET fus, 1 PIK3CA mut) were detected in 24 cases (80%). Of the 21 cases that actionable gene alterations were identified in the clinical practice, TSO500 detected similar gene alterations in 20 cases (95%) except for one case that RNA analysis was failed. In addition, TSO500 detected BRAF V600E mutation in one case that had not been tested for BRAF mutation. TMB analysis succeeded in 26/30 cases (87%) and 9/26 cases (35%) were TMB-high when 10 mutations per mega base was set as the threshold.

      Conclusion

      Despite analyzing small biopsy specimens with a large NSG panel, TSO500 could detect not only gene alterations for clinical use but also exploratory gene alterations.

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      P2.14-44 - Tumor Mutation Burden and Efficacy of Molecular Targeted Therapy in Lung Cancer (ID 1584)

      10:15 - 18:15  |  Author(s): Tomohiro Sakamoto

      • Abstract

      Background

      Precision medicine based on driver oncogenes is now developed for non-small cell lung cancer (NSCLC). Recently, next-generation sequencing (NGS) has made it possible to analyze Tumor mutation burden (TMB), and it was revealed that TMB is an effective biomarker of immune checkpoint inhibitors. However, the impact of TMB on the effects of targeted therapy for driver alterations is still unclear.

      Method

      Of the cases diagnosed with advanced NSCLC at Tottori University Hospital, 30 cases with consent to this observational study were enrolled. TruSight Oncology (TSO) 500 was performed at the CLIA-certified laboratory (RIKEN GENESIS CO., LTD.) using DNA and RNA extracted from archived formalin-fixed paraffin-embedded (FFPE) lung cancer specimens.

      Result

      Specimens were collected by bronchoscopy in 21 cases (70%), percutaneous biopsy in 3 cases (10%), surgery in 3 cases (10%), cell block of pleural effusion in 2 cases (7%) and thoracoscopy in 1 case (3%). The success rate of TMB analysis was 83% (25/30 cases). In the 25 cases, a total of 23 actionable gene alterations (11 EGFR mut, 4 ALK fus, 2 KRAS mut, 2 BRAF mut, 2 MET ex14 skipping, 1 RET fus, 1 PIK3CA mut) were detected in 22 cases (88%). The median TMB was 7.84 (1.56-21.11) mutations/Mb. 7 of 25 (28%) patients showed high TMB, and the others showed low TMB when 10 mutations per mega base was set as the threshold. 5 of 7 (71%) patients with high TMB had one of the common driver mutations (2 EGFR mut, 2 BRAF mut and 1 PIC3CA mut) and 17 of 18 (94%) patients with low TMB had one of the driver mutations (9 EGFR mut, 4 ALK fus, 2 KRAS, 2 MET ex14 skipping and 1 RET fus). Additionally, no ALK fusion was identified in patients with high TMB. 12 of 15 patients (80%) received targeted therapy with low TMB achieved clinical response, while no patient (0/2 pts, 0%) received targeted therapy with high TMB achieved clinical response.

      Conclusion

      TMB might have the impact for the presence of driver alterations and the effects of targeted therapies.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)

      08:00 - 10:15  |  Author(s): Tomohiro Sakamoto

      • Abstract
      • Presentation
      • Slides

      Background

      No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.

      Method

      This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.

      Result

      As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.

      Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.

      The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

      Conclusion

      LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

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