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Noboru Yamamoto



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    EP1.01 - Advanced NSCLC (ID 150)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.01-51 - Efficacy Impact of Serum VEGF for Elderly or Poor PS Patients Receiving Anti-PD-1 Antibody with Advanced Non-Small Cell Lung Cancer (ID 1691)

      08:00 - 18:00  |  Author(s): Noboru Yamamoto

      • Abstract
      • Slides

      Background

      Anti-programmed cell death (PD)-1 antibody therapies have shown durable clinical efficacy and manageable toxicity profiles, and have become a standard therapy in advanced non-small cell lung cancer (NSCLC). Because of manageable toxicity profiles, extensive interest in the potential benefits of anti-PD-1 antibody has expanded to high-risk patients such as the elderly or poor performance status (PS) patients. Here, we aimed to investigate predictive markers for the efficacy of anti-PD-1 antibody in elderly patients and poor PS patients.

      Method

      The medical records of 75≥ years old or PS2 NSCLC patients treated with anti-PD-1 antibody (e.g., nivolumab and pembrolizumab) at the National Cancer Center Japan between December 1, 2015, and May 31, 2018, were reviewed retrospectively. We evaluated the association between efficacy for anti-PD-1 antibody and gender, smoking status, histology, PD-ligand 1(PD-L1) expression on tumor cells, white blood cell counts, lymphocyte counts, albumin, lactate dehydrogenase, c-reactive protein, and serum vascular endothelial growth factor (VEGF). We divided patients into two groups with the median values.

      Result

      A total of 235 patients with advanced NSCLC treated with anti-PD-1 antibody were reviewed. Of these patients, 31 patients were ≥ 75 years old, and 22 patients were PS2. The median PFS was 6.9 months in patients aged ≥ 75 years and 2.1 months in PS2 patients. Cox proportional hazard regression analysis showed that only the low-VEGF was significantly associated with longer PFS in patients aged ≥ 75 years (HR, 0.35; 95% CI, 0.13-0.88; P = 0.025) and in PS2 patients (HR, 0.31; 95% CI, 0.10-0.85; P = 0.023). The overall response rate of patients with low-VEGF was tend to be higher than that with high-VEGF among patients aged ≥ 75 years (43% vs. 20%; P = 0.18) and PS2 patients (20% vs. 0%; P = 0.084).

      Conclusion

      Low-VEGF in patients aged ≥ 75 years and PS2 patients was associated with longer PFS. Serum VEGF may thus be a biomarker for the efficacy of anti-PD-1 antibody therapy.

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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA11.07 - Efficacy of Immune-Checkpoint Inhibitors and EGFR-TKIs in NSCLC Patients with High PD-L1 Expression (Now Available) (ID 667)

      14:00 - 15:30  |  Author(s): Noboru Yamamoto

      • Abstract
      • Presentation
      • Slides

      Background

      Recently, several studies have demonstrated that patients with non-small cell lung carcinoma (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations show poor clinical outcomes in response to treatment with anti-programmed cell death-1 (PD-1) inhibitors. Conversely, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are not effective in NSCLC showing high programmed death ligand 1 (PD-L1) expression levels. In this study, we retrospectively investigated the relationship between high PD-L1 expression and the efficacy of PD-1 inhibitors and EGFR-TKIs in patients with NSCLC.

      Method

      The subjects of this study were patients with NSCLC who had received treatment with PD-1 inhibitors at the National Cancer Center Hospital between March 2017 and December 2018. The PD-L1 expression in the tumor cells was divided into two groups based on the tumor proportion score (TPS): <50% (low) and ≥50% (high).

      Result

      Of the 414 patients treated with PD-1 inhibitors, the 263 patients in whom the PD-L1 expression levels could be evaluated were considered as being eligible for inclusion in this study. Among the 153 patients with high PD-L1 expression, we assessed the efficacy of PD-1 inhibitors according to the EGFR mutation status. The objective response rate (ORR) was 29.4% (95% confidence interval [CI], 1.3 to 53.1) in the EGFR-mutated patients and 43.4% (95% CI, 35.4 to 51.8) in the EGFR wild-type patients. The median progression-free survival (PFS) was 5.3 months (95% CI, 1.3 to 12.4) in the EGFR-mutated patients and 8.3 months (95% CI, 6.0 to 11.7) in the EGFR wild-type patients (hazard Ratio [HR] = 0.62; 95% CI, 0.62 to 1.14). A total of 33 patients received EGFR-TKI therapy. We assessed the efficacy of EGFR-TKIs according to the PD-L1 expression level. The ORR was 50.0% (95% CI, 28.0 to 72.0) in the high PD-L1 expression group and 52.9% (95% CI, 31.0 to 73.8) in the low PD-L1 expression group. The median PFS was 18.8 months (95% CI, 2.8 to 35.7) in the high PD-L1 expression group and 12.7 months (95% CI, 7.2 to 20.9) in the low PD-L1 expression group (HR = 0.83; 95% CI, 0.38 to 1.81).

      PD-L1 High

      EGFR+

      PD-L1 High

      EGFR−

      PD-L1 Low

      EGFR+

      PD-L1 Low

      EGFR−

      Total N

      17

      136

      18

      92

      Median age, years (range)

      62 (47–85)

      62 (33–87)

      64.5 (37–83)

      62 (33–83)

      Sex (n)

      Female

      Male

      7

      10

      36

      100

      15

      3

      25

      67

      ECOG PS (n)

      0, 1

      2

      14

      3

      125

      11

      16

      2

      81

      11

      Smoking history (n)

      Never-smoker

      Smoker

      7

      10

      21

      115

      12

      6

      13

      79

      EGFR mutation status (n)

      Ex 19 del

      L858R

      Others

      7

      6

      4

      13

      2

      3

      ICI agent used (n)

      Pembrolizumab

      Nivolumab

      11

      6

      105

      31

      4

      14

      21

      71

      Line of ICI therapy (n)

      First-line

      Second-line

      Third-line or more

      2

      3

      12

      85

      42

      9

      5

      64

      23

      0

      2

      16

      Efficasy

      ORR (%)

      PD-1 inhibitors

      EGFR-TKIs

      PFS (months)

      PD-1 inhibitors

      EGFR-TKIs

      29.4

      50.0

      5.3

      18.8

      43.4

      8.3

      0

      52.9

      1.6

      12.7

      16.3

      3.8

      Conclusion

      Even in a population of NSCLC patients showing high PD-L1 expression, the efficacy of PD-1 inhibitors tended to be lower in the EGFR-mutated patients as compared to the EGFR wild-type patients. In regard to EGFR-mutated patients with a PD-L1 TPS of ≥50%, our findings suggested that high PD-L1 expression might not predict a poor efficacy of EGFR-TKIs.

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    MA25 - Precision Medicine in Advanced NSCLC (ID 352)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA25.10 - First-In-Human Phase 1 Study of DS-1062a (TROP2 Antibody-Drug Conjugate) in Patients with Advanced Non-Small Cell Lung Cancer (Now Available) (ID 3854)

      14:30 - 16:00  |  Author(s): Noboru Yamamoto

      • Abstract
      • Presentation
      • Slides

      Background

      DS-1062a is a trophoblast cell-surface antigen 2 (TROP2)-targeting antibody-drug conjugate with Daiichi-Sankyo exatecan derivative (DXd) technology. TROP2 is highly expressed in epithelial cancers, including non-small cell lung cancer (NSCLC), and is associated with poor survival. In preclinical studies DS-1062a showed promising antitumor activity in xenograft mouse models. Updated results from the dose escalation part of a phase 1 study of DS-1062a in patients with advanced NSCLC are reported.

      Method

      This is an ongoing US and Japan dose-escalation/dose-expansion phase 1 study of DS-1062a in patients with unselected NSCLC (NCT03401385). Adult (age ≥20 years [Japan] or ≥18 years [US]) patients with measurable disease per RECIST v1.1 and available tumor for TROP2 measurement were eligible. The primary objectives are to identify the maximum tolerated dose (MTD) and recommended dose for expansion, assess safety and tolerability. Endpoints include safety, efficacy, pharmacokinetics, and molecular and genomic analyses.

      Result

      At most recent data cutoff (April 12, 2019) 39 patients with advanced NSCLC were treated with DS-1062a at doses of 0.27 (n=4), 0.5 (n=5), 1.0 (n=7), 2.0 (n=6), 4.0 (n=6), 6.0 (n=8) and 8.0 (n=3) mg/kg. Overall, patients were exposed to a median (range) of 3.0 (1–10) treatment cycles over a duration of 8.86 (3.0–31.1) weeks. Patient disposition included dose interruption (n=2), reduction (n=1) and discontinuation (n=23; primary reason was progressive disease (PD) per RECIST in 13/23 patients). The majority (87.2%; 34/39) of patients reported ≥1 treatment-emergent adverse event (TEAE), regardless of severity or causality; the most common (in ≥30% of patients) were fatigue (33.3%) and nausea (30.8%). Grade ≥3 TEAEs were reported in 41.0% (16/39) of patients, of which 12.5% (2/16) were considered drug related. Drug-related TEAEs occurred in 59.0% (23/39 [21/23 grade 1 or 2], and serious TEAEs in 25.6% (10/39 [n=8 grade 3 (n=1 grade 5/sepsis/6.0-mg/kg dose; n=1 grade 3/drug-related/maculopapular rash/6.0-mg/kg dose; n=1 grade 2/drug-related/pyrexia/4.0-mg/kg dose) of patients. One DLT (maculopapular rash, grade 3; resolved) occurred with the 6.0-mg/kg dose; the MTD has not been reached. Of tumor-evaluable patients, as of May 23, 2019, 10 partial responses (PR) were observed (7 PRs were observed at the April 12, 2019 datacut), with a clear dose response and good durability: n=1 in the 2mg/kg, n=2 in the 4-mg/kg, n=3 in the 6 mg/kg, and n=4/5 evaluable in the 8.0-mg/kg groups (4 of the PRs remain to be confirmed). Across all dose groups (April 12, 2019 datacut), 16 stable disease (SD), and 11 PD were observed. Systemic DS-1062a exposure increased in an approximate dose-proportional manner; plasma DS-1062a levels and total anti-TROP2 antibody were similar, suggesting DS-1062a stability in circulation. Updated tumor response profile and durability, biomarker analyses and correlation with clinical outcome will be presented, including immunohistochemistry and circulating tumor DNA analysis of baseline and sequential on-treatment samples, and other related markers.

      Conclusion

      DS-1062a was well tolerated and 10 PRs were observed during dose selection in unselected NSCLC patients having progressed on standard of care, including immune checkpoint inhibition in 8 of 10 patients. Updated data will be presented.

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    OA12 - Profiling the Multidisciplinary Management of Stage III NSCLC (ID 144)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      OA12.02 - Randomized Phase II Study of CDDP+S-1 vs CDDP+PEM Combined with Thoracic RT for Locally Advanced Non-Sq NSCLC: SPECTRA Study (Now Available) (ID 428)

      15:45 - 17:15  |  Author(s): Noboru Yamamoto

      • Abstract
      • Presentation
      • Slides

      Background

      SPECTRA, a multicenter, randomized phase II study of CDDP+S-1 versus CDDP+pemetrexed (PEM) combined with thoracic radiotherapy (TRT) for locally advanced non-squamous non-small cell lung cancer (NSCLC), previously reported that toxicities were tolerable and manageable in both arms; however, febrile neutropenia was more frequently observed in the CDDP+S-1 arm (9.6%/2%). Completion rate of TRT (60Gy) and chemotherapy (4 cycles) was 92%/98% and 73%/86%, respectively. Response rate was 60%/64% (WCLC 2017, MA17.06). Here, we present primary analysis of 2-year survival data.

      Method

      Patients were randomly assigned to receive CDDP+S-1 (CDDP 60mg/m2, d1, and S-1 80mg/m2, d1-14, q4w, up to 4 cycles) or CDDP+PEM (CDDP 75mg/m2, d1, and PEM 500mg/m2, d1, q3w, up to 4 cycles) combined with TRT 60Gy in 30 fractions. The primary endpoint was 2-year progression-free survival (PFS) rate. The sample size was set at 100 patients.

      Result

      Between Jan 2013 and Oct 2016, 102 patients were enrolled in this study from 9 institutions in Japan. All 102 patients were eligible and assessable, of whom 52 were assigned to CDDP+S-1 and 50 to CDDP+PEM. Baseline characteristics were similar (CDDP+S-1/CDDP+PEM): median age (range) 64.5 (39-73)/63.5 (32-74) years; women, n=17 (33%)/n=17 (34%); stage IIIB, n=21 (40%)/n=20 (40%); ECOG PS of 1, n=14 (27%)/n=14 (28%); never smoker, n=12 (23%)/n=12 (24%); and adenocarcinoma, n=47(90%)/n=45(90%); activating EGFR mutation, n=9 (17%)/n=4 (8%); ALK fusion, n=2 (4%)/n=3 (6%). A total of 72 PFS events were observed at the data cut-off (28 November 2018). After a median follow-up of 32.1 months, median PFS was 12.7/13.8 months (HR=1.16, 95% CI, 0.73-1.84, p=0.538), and 2-year PFS rate was 36.5% (95% CI, 23.5-49.6)/32.1% (95%CI, 18.9-45.4). Disease progression was observed in 33 and 36 patients. Distant metastases were the first site of failure in 24 and 31 patients. Local relapse as the first site of failure was observed in 14 and 13 patients. After a median follow-up of 34.6 months, 44 OS events were observed. Median OS was 48.3/59.1 months (HR=1.05, 95%CI, 0.58-1.90, p=0.883), and 2-year OS rate was 69.2% (95%CI, 56.7-81.8)/66.4% (95%CI, 53.0-79.9). 27 patients in each arm received post-study chemotherapy including EGFR-TKIs (n=7/n=5), ALK-TKIs (n=0/n=3), and immune checkpoint inhibitors (n=6/n=10).

      Conclusion

      2-year PFS rate in the CDDP+S-1 arm was better than that in the CDDP+PEM arm. We will select the CDDP+S-1 arm as the investigational arm in a future phase III study. UMIN000009914 (release date: 31/Jan/2013)

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-102 - Actionable Gene Aberration and the Response of Matched Therapy Among Patients with Non-Small-Cell Lung Carcinoma (Now Available) (ID 1177)

      09:45 - 18:00  |  Author(s): Noboru Yamamoto

      • Abstract
      • Slides

      Background

      Tumor genotyping using multiplex gene panel is now standard for precision medicine in non-small-cell lung carcinoma (NSCLC). We sought to assess the prevalence of actionable genomic alterations among NSCLC patients using our next-generation sequencing panel (NCC Oncopanel) and the response of matched therapy.

      Method

      This is a post-hoc analysis of prospective study in which patients with advanced solid cancer were prospectively enrolled to undergo the comprehensive genomic profiling panel (NCC Oncopanel) conducted between July 2013 and March 2018 in National Cancer Center Hospital. The NCC Oncopanel assay, a multiplexed next-generation sequencing (NGS) assay of 114 cancer-associated genes, was performed in a CLIA-compliant laboratory in National Cancer Center. Subjects were primarily patients without any known actionable alteration such as EGFR or ALK. Patients with NSCLC were extracted into this analysis. Clinical data and treatment outcomes were retrospectively collected.

      Result

      In total, 100 patients were extracted. Sufficient tumor tissue for NGS analysis were available in 91 patients; median age was 57 (range 30‒77); 74 (81.3%) adenocarcinoma; 44 (48.4%) female; 42 (46.2%) never smoker. According to the OncoKB and CIViC database, and the Clinical Practice Guidelines for NGS in Cancer Diagnosis and Treatment issued by three major Japanese cancer-related societies, 85 patients (93.4%) had at least one potential pathogenic alteration. Actionable gene aberrations were identified in 49 (53.9%). Evidence levels were ranked as follows: 24 (26%) harbored level 1 aberrations (ALK, EGFR, ROS1, BRAF); 15 (16%) harbored level 2 (RET, DDR2, MET, ATM, BRCA2, CDK4, CTNNB1, EZH2, JAK2, NRAS, TSC1); 10 (11%) harbored level 3A (CDKN2A, ERBB2, HRAS, PTEN, SMARCA4, STK11). Matched therapy was administered into 29 (31.9%) leading to the objective response rate of 58.6% and the disease control rate of 79.3% with the median progression-free survival of 10.5 months (95%CI; 5.1‒15.8).

      Conclusion

      Multiplex gene panel is feasible and useful in screening candidates for matched therapy among NSCLC patients. NSCLC patients without any known actionable mutations should be considered to undergo comprehensive genomic profiling.

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