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Kazuhiko Nakagawa



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    MA03 - Clinomics and Genomics (ID 119)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA03.11 - Chemotherapy After PD-1 Inhibitors Versus Chemotherapy Alone in Patients with Non–Small Cell Lung Cancer (WJOG10217L) (Now Available) (ID 409)

      10:30 - 12:00  |  Author(s): Kazuhiko Nakagawa

      • Abstract
      • Presentation
      • Slides

      Background

      Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response in patients with non–small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of subsequent chemotherapy after PD-1 inhibitors (CAP) compared with chemotherapy alone.

      Method

      We conducted a multicenter retrospective cohort study for patients with advanced or recurrent NSCLC who were treated at 47 institutions across Japan between 1 April 2014 and 31 July 2017 with chemotherapy (docetaxel with or without ramucirumab; S-1; or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort). The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors, including age, sex, smoking status, performance status, histology, EGFR or ALK genetic alterations, brain metastasis, and recurrence after curative radiotherapy.

      Result

      A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics—including age, histology, EGFR or ALK alterations, and brain metastasis—differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 10.8% for the control cohort (ORR ratio, 1.75; 95% confidence interval [CI], 1.25–2.45; P = .001). Median PFS was 3.5 and 2.6 months for the CAP and control cohorts, respectively (hazard ratio [HR], 0.862; 95% CI, 0.743–0.998; P = .048). The PFS rate at 3, 6, and 12 months was 53.3%, 28.5%, and 4.6%, respectively, for the CAP cohort, and 44.3%, 19.7%, and 6.1% for the control cohort. Median OS was 9.8 months for the CAP cohort and 10.3 months for the control cohort (HR, 0.979; 95% CI, 0.813–1.179; P = .822).

      Conclusion

      After adjustment for selection bias using propensity score–weighted analysis, CAP showed a significantly higher ORR and longer PFS compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into an OS advantage, and no PFS benefit was apparent at 12 months despite the improvement observed at 3 and 6 months. Our findings suggest that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.

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    MA13 - Going Back to the Roots! (ID 139)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA13.06 - Ph3 Study of Maintenance Therapy with S-1 vs BSC After Induction Therapy with Carboplatin + S-1 for Advanced Squamous Cell Lung Cancer (WJOG7512L) (Now Available) (ID 563)

      14:00 - 15:30  |  Author(s): Kazuhiko Nakagawa

      • Abstract
      • Presentation
      • Slides

      Background

      Our previous phase 3 study established carboplatin plus the oral fluorinated pyrimidine formulation S-1 as a standard option for first-line treatment of advanced non–small cell lung cancer (NSCLC) (J Clin Oncol 2010; 28:5240). The importance of maintenance therapy for patients with advanced squamous NSCLC has been unknown, however.

      Method

      WJOG7512L was designed as a randomized phase 3 study to evaluate whether maintenance therapy with S-1 improves clinical outcome after induction therapy with carboplatin plus S-1 in such patients. Before randomization, patients received carboplatin (AUC of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m2 twice per day on days 1 to 14 every 3 weeks) as induction therapy. Those who did not progress after four cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective was to confirm the superiority of S-1 plus BSC with regard to progression-free survival.

      Result

      Of the 365 patients enrolled, 347 participated in the induction phase and 131 of these individuals were randomized to receive S-1 plus BSC (n = 67) or BSC alone (n = 64). Baseline demographics and clinical characteristics of the subjects, including the response to induction therapy, were well balanced. Patients receiving S-1 plus BSC showed a significantly reduced risk of disease progression compared with those receiving BSC alone (hazard ratio [HR], 0.548; 95% confidence interval [CI], 0.374–0.802; P = 0.0019). Median overall survival from randomization did not differ significantly between the two arms: 17.8 months for BSC alone and 16.7 months for S-1 plus BSC (HR, 0.890; 95% CI, 0.583–1.357). Time to deterioration in quality of life also showed no significant difference (P = 0.8754 for FACT-TOI, P = 0.9016 for FACT-LCS). The incidence of adverse events during maintenance therapy was low, with neutropenia, anemia, and thrombocytopenia of grade 3 or 4 each occurring in ~1% to 4% of patients.

      Conclusion

      Maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC.

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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      OA02.06 - The Sequential Therapy of Crizotinib Followed by Alectinib: Real World Data of 840 Patients with NSCLC Harboring ALK-Rearrangement (WJOG9516L) (Now Available) (ID 2145)

      10:30 - 12:00  |  Author(s): Kazuhiko Nakagawa

      • Abstract
      • Presentation
      • Slides

      Background

      Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to-progression than crizotinib (CRZ) in 1st-line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of CRZ followed by other ALK-inhibitorcan provide extended OS. In Japan, ALEC was approved for a 1st-line setting earlier than in other countries.

      Method

      We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of CRZ followed by ALEC, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the TTF of CRZ plus the TTF of ALEC if patients were treated with ALEC followed by CRZ. In the ALEC group, the TTF of ALEC was calculated. The primary endpoint is the comparison between the combined TTF in the CRZ group with the TTF in the ALEC group.

      Result

      Of 864 patients enrolled from 61 institutions, 840 patients were analyzed. Median age was 61 (range, 20-94); 56% were female; and 95% had adenocarcinoma. There were 535/305 patients in the CRZ/ALEC group. In the CRZ group, 282 patients received ALEC after CRZ failure. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group; median, 34.4 vs 27.2 months (mo); hazard ratio (HR), 0.709 [95%CI;0.559- 0.899]; P=0.0044. However, there was no significant difference in OS between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group; median, 88.4 months vs. not reached; HR 1.048 [95%CI;0.758-1.451]; P=0.7770. In the whole population, the CRZ group had a significantly shorter OS than the ALEC group; median, 53.6 mo vs not reached HR, 1.821 [95%CI;1.372-2.415]; P<0.0001.

      Conclusion

      The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group, however, OS benefit of sequential therapy of CRZ followed by ALEC was not shown.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA14.08 - Discussant - OA14.06, OA14.07 (Now Available) (ID 3800)

      11:30 - 13:00  |  Presenting Author(s): Kazuhiko Nakagawa

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-01 - RELAY EU/US Subset: Ramucirumab Plus Erlotinib Improves Progression-Free Survival in First-Line EGFR Mutation-Positive NSCLC (Now Available) (ID 356)

      09:45 - 18:00  |  Author(s): Kazuhiko Nakagawa

      • Abstract
      • Slides

      Background

      Dual blockade of EGFR and VEGFR pathways in EGFR mutation-positive NSCLC augments anti-tumor efficacy versus EGFR inhibition alone. The RELAY (NCT02411448) phase 3 study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for erlotinib plus ramucirumab versus erlotinib plus placebo in patients with previously untreated EGFR mutation-positive metastatic NSCLC (median PFS 19.4 vs 12.4mo, HR 0.591 (95% CI 0.461–0.760), p<0.0001). Here we report efficacy and safety data of the EU/US subset.

      Method

      Eligible patients (untreated, metastatic NSCLC with an EGFR exon 19 deletion or exon 21 (L858R) substitution mutation and no CNS metastasis) were randomized (1:1) to receive 150 mg daily oral erlotinib plus 10 mg/kg intravenous ramucirumab (RAM+ERL) or placebo (PL+ERL) Q2W until progressive disease or unacceptable toxicity. Patients were stratified by geographic region (East Asia vs ‘other’, i.e. EU/US). Primary endpoint was investigator-assessed PFS. Other key objectives included safety, ORR, DoR, PFS2, and OS.

      Result

      In the EU/US, 113 (25.2%) of 449 total patients (58 RAM+ERL, 55 PL+ERL) were randomized between Feb 2016-Feb 2018. Baseline characteristics were balanced between treatment arms: ~60% female, ~52% never-smokers and ~66% Ex19del. RAM+ERL improved PFS and had a longer DoR (Table). PFS2 and OS data were immature. Grade≥3 TEAEs occurring in >5% of patients included (RAM+ERL vs PL+ERL): hypertension (29.8% vs 7.3%), diarrhea (12.3% vs 1.8%), AST increased (7.0% vs 3.6%), ALT increased (7.0% vs 1.8%), dermatitis acneiform (5.3% vs 9.1%), fatigue (5.3% vs 0%), and rash (0% vs 5.5%).

      Abbreviations: CI=confidence interval; DoR=duration of response; ERL=erlotinib; HR=hazard ratio; N=total population; n=total responders; NR=no response; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PL=placebo; RAM=ramucirumab
      RAM + ERL (N=58) PL + ERL (N=55) Unstratified HR (95% CI) p-value
      PFS
      Median, months (95% CI) 20.6 (14.7-26.0)
      10.9 (8.3-19.4)
      0.605 (0.362-1.010) 0.0523

      Censoring rate

      52% 38%

      ORR, % (95% CI)

      74.1 (62.9-85.4) 76.4 (65.1-87.6) NA 0.8319
      DoR, for responders only n=43 n=42
      Median, months (95% CI) 18.0 (12.7-22.0) 10.0 (7.1-17.7) 0.527 (0.296-0.939) 0.0274

      Censoring rate

      54% 33%
      PFS2
      Median, months (95% CI) NR NR 0.632 (0.304-1.313) 0.2143
      Censoring rate 79% 67%
      OS
      Median, months (95% CI) NR NR 1.096 (0.465-2.582) 0.8344
      Censoring rate 81% 82%

      Conclusion

      The EU/US subset analysis was consistent with the full ITT population where RAM+ERL demonstrated a statistically significant improvement in PFS over PL+ERL. Efficacy and tolerability were similar to that of the overall RELAY study population. Ramucirumab is an effective and safe addition to standard-of-care EGFR-TKI for treating EGFR mutation-positive metastatic NSCLC.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-15 - Impact of Coexisting Gene Mutations in EGFR-Mutated Non–Small Cell Lung Cancer Before Treatment on EGFR T790M Mutation Status After EGFR-TKIs (ID 1347)

      10:15 - 18:15  |  Author(s): Kazuhiko Nakagawa

      • Abstract

      Background

      The T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation–positive non–small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after treatment.

      Method

      A total of 57 EGFR mutation–positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software.

      Result

      Progression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P = 0.024).

      Conclusion

      Coexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.