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Toshiaki Takahashi



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    OA08 - Mesothelioma: Immunotherapy and microRNA for Diagnosis and Treatment (ID 907)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 201 BD
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      OA08.01 - Long-Term Efficacy and Safety of Nivolumab in Second- or Third-Line Japanese Malignant Pleural Mesothelioma Patients (Phase II: MERIT Study) (ID 11833)

      15:15 - 15:25  |  Author(s): Toshiaki Takahashi

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is a rare and highly aggressive malignancy with poor prognosis and no treatment is approved for patients (pts) progressing after 1st line pemetrexed-platinum doublet. Here, we report latest analysis of MERIT study in previously treated Japanese MPM pts to update the previous report (WCLC 2017, Goto Y, et al).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This open-label study enrolled advanced or metastatic MPM pts previously treated with up to two regimens of chemotherapy including pemetrexed-platinum doublet. Enrollment criteria also included histologically-confirmed, unresectable MPM without prior surgery, measurable lesion and ECOG performance status 0-1. There was no restriction of PD-L1 status. Pts received Nivolumab 240 mg flat dose Q2W until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) (modified RECIST by independent review committee, expected response rate was 19.2%); secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety.

      4c3880bb027f159e801041b1021e88e8 Result

      Thirty-four pts received Nivolumab in this study. Males: 85.2%, median age: 68.0 years (range 43-78), PS 1: 61.8%, epithelial/sarcomatoid/biphasic: 79.4%/8.8%/11.8%, 1 prior regimen: 70.6% and PD-L1 (≧1%)/PD-L1 (<1%)/not evaluable: 58.8%/35.3%/5.9%. At a median follow-up of 16.8 months (range: 1.8-20.2), ORR was 29.4 % (n=10, 95%CI: 16.8-46.2). DCR was 67.6% (n=23, 95%CI: 50.8-80.9). Median DOR was 11.1 months (95%CI: 3.5-16.2). Median PFS was 6.1 months (95%CI: 2.9-9.9) in all pts, 7.2 months (2.8-15.0) in PD-L1 (≧1%) and 2.9 months (1.4-9.3) in PD-L1 (<1%). Median OS was 17.3 months (95%CI: 11.5-NR) in all pts, 17.3 months (8.2-NR) in PD-L1 (≧1%), 11.6 months (5.8-NR) in PD-L1 (<1%), across tissue types, 15.7 months (95%CI: 8.0-NR) in epithelioid and not reached in sarcomatoid/biphasic pts. Six- and 12-month survival rates were 85.3% (95%CI: 68.2-93.6) and 58.8% (95%CI: 40.6-73.2). Twenty-six (76.5%) pts experienced treatment-related adverse event (TRAE), and 11 (32.4%) experienced grade 3/4 TRAEs. Most commonly reported TRAEs were skin disorder (n=6, 17.6%), elevated lipase (n=5, 14.7%), elevated amylase and diarrhea (n=4, 11.8%). Four pts required dose discontinuation because of interstitial pneumonia (n=2, grade2 and 3) and pneumonitis (n=2, grade3).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab shows durable long term efficacy and manageable safety profile in Japanese 2nd/3rd line MPM pts.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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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
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-34 - Docetaxel Plus Ramucirumab with Prophylactic PEG-G-CSF Support for Chemo-NaïVe Elderly NSCLC Patients: A Phase II Study (WJOG9416L) (ID 12400)

      16:45 - 18:00  |  Author(s): Toshiaki Takahashi

      • Abstract

      Background

      Docetaxel monotherapy is the standard of care for chemo-naïve Japanese elderly patients with advanced non-small cell lung cancer (NSCLC), according to our results of phase III trial comparing docetaxel and vinorelbine monotherapies (WJTOG9904). In a pivotal phase III study (REVEL), docetaxel plus ramucirumab demonstrated superior response rate (RR) and progression-free survival (PFS) over docetaxel monotherapy in second-line setting for advanced NSCLC. These differences in RR and PFS were translated into overall survival (OS) benefit. This evidence prompted us to investigate docetaxel plus ramucirumab for chemo-naïve elderly patients. However, in a similarly designed Japanese randomized phase II trial (JVCG trial), febrile neutropenia (FN) was observed in 34.2% of docetaxel plus ramucirumab arm. This high incidence of FN is a clinical concern when using docetaxel plus ramucirumab for elderly patients. The ASCO practice guideline recommends primary prophylactic granulocyte-colony stimulating factor (G-CSF) when the risk of FN is 20% or higher. PEGylated-G-CSF (pegfilgrastim) administered once a cycle demonstrated reduction of FN incidence in many types of cancers. Based on the above background, we considered that primary prophylactic PEG-G-CSF would be beneficial for elderly NSCLC patients who received docetaxel plus ramucirumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a prospective multicenter, single-arm, phase II study conducted by West Japan Oncology Group (WJOG). Main inclusion criteria includes: chemo-naïve; aged ≥75; histologically or cytologically confirmed NSCLC; ECOG PS 0/1; adequate organ functions; with measurable disease; without contraindication of ramucirumab; written informed consent; and estimated life expectancy of at least 3 months. Intravenous docetaxel (60 mg/m2, day 1) plus ramucirumab (10 mg/kg, day 1) with subcutaneous PEG-G-CSF (3.6 mg, day 2) every 3 weeks is administered until progression. Continuous docetaxel or ramucirumab monotherapy is permitted when intolerable toxicities occur but clinical benefit is obtained by each drug. The primary endpoint is objective response rate (ORR). Secondary endpoints are PFS, OS, disease control rate, and safety. We assumed that the threshold and expected ORR were 20% and 35%, respectively. Based on this, the number of patients was calculated to be 59 to provide a power of 80% with probability of one-sided type I error being 0.05. Taking ineligible patients into account, the sample size was set at 65. When the study results are promising, we plan to conduct a phase III trial to compare docetaxel plus ramucirumab with PEG-G-CSF support vs. docetaxel monotherapy for chemo-naïve elderly NSCLC patients. Clinical trial information: UMIN000030598.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion


      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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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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      P1.13-06 - First-Line Lorlatinib Versus Crizotinib for Advanced Anaplastic Lymphoma Kinase-Positive (ALK<sup>+</sup>) Non-Small Cell Lung Cancer (ID 12773)

      16:45 - 18:00  |  Author(s): Toshiaki Takahashi

      • Abstract
      • Slides

      Background

      Lorlatinib and crizotinib are oral tyrosine kinase inhibitors with activity against ALK and ROS1 fusion proteins. Crizotinib is well tolerated and has superior efficacy compared to chemotherapy for treatment of patients with advanced ALK+ non-small-cell lung cancer (NSCLC). However, resistance to crizotinib can develop, and the central nervous system (CNS) is often a site of disease relapse. Second-generation ALK inhibitors, ceritinib and alectinib, have demonstrated activity in crizotinib-naive or resistant treatment settings, and alectinib has been shown to have superior progression-free survival (PFS) compared to crizotinib as first-line therapy. Lorlatinib is a selective, CNS-penetrant ALK inhibitor that has potent activity against ALK and kinase domain resistance mutations, including the difficult-to-treat G1202R mutation.Lorlatinib has shown clinical activity in patients previously treated with crizotinib and other ALK inhibitors, including patients with progressive CNS metastases. This study aims to determine if lorlatinib is superior to crizotinib in prolonging PFS in treatment-naïve patients and to identify candidate biomarkers predictive of clinical efficacy or treatment resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Trial Design

      This global, multicenter, open-label phase 3 study will enroll ~280 treatment-naïve patients. Eligible patients must be aged ≥18 years, have Eastern Cooperative Oncology Group performance status of 0–2 and ≥1 measurable extracranial target lesion not previously treated with radiotherapy. Patients with asymptomatic brain metastases are eligible. Patients will be randomized (1:1) to lorlatinib 100 mg once daily or crizotinib 250 mg twice daily and stratified by presence of brain metastases (yes/no) and ethnicity (Asian/non-Asian). Treatment will continue until disease progression, patient refusal, or unacceptable toxicity. Crossover between treatment arms will not be permitted. The primary endpoint is PFS based on blinded independent central review (BICR) using RECIST v1.1. Secondary endpoints include PFS based on investigator assessment, overall survival, objective response (OR) by BICR and investigator assessment; intracranial (IC) OR (periodic magnetic resonance imaging will be performed for central nervous system evaluation), IC time to progression, duration of response and time to response all by BICR; tumor tissue and peripheral blood circulating free DNA biomarker assessment, adverse events and patient-reported health-related outcomes as assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 EORTC (QLQ-C30) and EORTC Lung Cancer Module (QLQ-LC13), and the 5-level EuroQol 5-dimension questionnaire (EQ-5D-5L). The first patient was screened on April 14, 2017. This study is registered with ClinicalTrials.gov as NCT03052608.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.01-54 - A Historical Comparison of Patients with Advanced NSCLC Harboring Uncommon EGFR Mutations Before and After the Approval of Afatinib in Japan (ID 12711)

      12:00 - 13:30  |  Author(s): Toshiaki Takahashi

      • Abstract
      • Slides

      Background

      Afatinib demonstrated durable responses in patients with metastatic non-small cell lung cancer (NSCLC) harboring uncommon non-resistant epidermal growth factor receptor (EGFR) mutations (G719X, L861Q, and/or S768I) in a pooled analysis of three clinical trials. However, the clinical impact of afatinib therapy in patients with these uncommon EGFR mutations remains unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively evaluated patients with advanced NSCLC whose tumors have uncommon EGFR mutations, and who had received first-line systemic therapy at the Shizuoka Cancer Center between January 2010 and December 2017. Patients with resistant EGFR mutations (T790M, exon 20 insertions) and patients who had received investigational EGFR-TKIs were excluded from this study. Characteristics, therapy regimens and survival outcomes were compared between patients who had received a systemic therapy before (Group A) and after (Group B) the approval of afatinib in Japan. Overall survival (OS) was measured from the first day of first-line systemic therapy until death or the final day of the follow-up period.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 23 patients (11 in Group A, and 12 in Group B) were included in this study. The characteristics of the 23 patients were: median age 69 years (range: 41 to 82); 39% male; 26% performance status (PS) 0, 57% PS 1, 13% PS 2 and 4% PS3; 48% with brain metastasis; and 57% current or former smokers. With regard to EGFR mutation type, 30% had G719X, 30% had L861Q, 5% had S768I, 22% had a complex of uncommon mutations, and 13% had both uncommon and common mutations. Patient characteristics were similar in the two groups except for PS. First-line systemic therapy regimens were: gefitinib 73%, erlotinib 9% and platinum-doublet chemotherapy 18% in Group A; gefitinib 8%, erlotinib 25% and afatinib 67% in Group B. Median OS was 10 months for Group A and 25 months for Group B. A significant difference in OS was observed between the two groups (P = 0.018). In a subgroup analysis of patients with PS 0 or 1, there was also a significant difference in OS between the two groups (median, 10 months for Group A vs. 25 months for Group B; P = 0.033).

      8eea62084ca7e541d918e823422bd82e Conclusion

      After the approval of afatinib in Japan, a majority of patients with advanced NSCLC harboring uncommon EGFR mutations received afatinib therapy as first-line systemic therapy, and it may be related to OS improvement.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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