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Masahiro Tsuboi



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    IS02 - Industry Symposium Sponsored by AstraZeneca: Evolving the Role of Immunotherapy in Lung Cancer: ES-SCLC and Unresectable Stage III NSCLC (ID 278)

    • Event: WCLC 2020
    • Type: Industry Symposium
    • Track:
    • Presentations: 1
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      IS02.01 - Opening Remarks (ID 4309)

      10:30 - 11:30  |  Presenting Author(s): Masahiro Tsuboi

      • Abstract

      Abstract not provided

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    OA06 - Updates on EGFR Targeted Perioperative Therapy and Precision Adjuvant Chemotherapy (ID 118)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Early Stage/Localized Disease
    • Presentations: 2
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      OA06.03 - Patient-Reported Outcomes from ADAURA: Osimertinib as Adjuvant Therapy in Patients with Resected EGFR Mutated (EGFRm) NSCLC (ID 3505)

      16:45 - 17:45  |  Author(s): Masahiro Tsuboi

      • Abstract
      • Slides

      Introduction

      Osimertinib is a third-generation, irreversible, central-nervous system-active, EGFR-tyrosine kinase inhibitor. The Phase III, double‑blind, randomized ADAURA study (NCT02511106) of completely resected stage IB–IIIA EGFRm non-small cell lung cancer (NSCLC), with/without adjuvant chemotherapy, reported a highly statistically significant and clinically meaningful disease-free survival (DFS) benefit with adjuvant osimertinib vs placebo (HR: 0.20 [99.12% CI: 0.14, 0.30]; p<0.0001). The effect of adjuvant treatment on health-related quality of life (HRQoL) is an important clinical consideration for patients who, following surgery with curative intent, are disease-free and require long-term treatment to reduce the risk of disease recurrence. We report patient-reported outcomes from ADAURA.

      Methods

      Adult patients with completely resected stage IB/II/IIIA (AJCC 7th edition; pathologic stage) EGFRm NSCLC (postoperative chemotherapy allowed, per physician and patient choice) were randomized 1:1 to osimertinib 80 mg once daily or placebo for three years (treatment completion)/until discontinuation. Per protocol, HRQoL was measured by the Short Form-36 (SF-36) health survey. Patients completed the SF‑36 health survey (eight domains and two aggregated summary scores: physical [PCS] and mental [MCS] component summary) at baseline, 12 and 24 weeks, then every 24 weeks until treatment completion/discontinuation. SF-36 was scored using norm-based scoring relative to the 2009 US general population (mean ± standard deviation, 50±10), resulting in T‑scores (higher T‑scores indicate better health). Here we report an exploratory post-hoc analysis of HRQoL in the overall patient population (N=682; stage IB–IIIA). A mixed model of repeated measures (MMRM) was used to analyze changes in SF-36 scores from baseline until Week 96 (to ensure balanced comparison between arms, due to earlier disease recurrence with placebo). Time to deterioration (TTD) was defined as time from randomization to first confirmed clinically important worsening/death. Clinically meaningful changes at the individual (PCS ±3.8 points, MCS ±4.6 points; TTD analyses) and group (PCS ±2 points, MCS ±3 points; MMRM analyses) level were assigned based on pre‑specified definitions from the SF-36 manual, 3rd edition. Data cut‑off: 17/01/2020.

      Results

      Compliance rates for completion of the SF-36 health survey were high (≥85%) across all visits in both arms. Baseline PCS and MCS scores were comparable in the osimertinib and placebo arms (range 46–47); scores in both arms were only slightly lower than the mean scores in the general population (0.3–0.4 SD below the normative mean [50]). PCS/MCS scores increased from baseline to Week 96 by 1.13/1.34 for osimertinib and 2.31/2.68 for placebo, with no clinically meaningful differences between arms (PCS -1.18 [95% CI: -2.02, -0.34]; MCS -1.34 [95% CI: ‑2.40, ‑0.28]. There were no differences in TTD of PCS (HR: 1.17 [95% CI: 0.82, 1.67]) or MCS (HR: 0.98 [95% CI: 0.70, 1.39]) between osimertinib and placebo.

      Conclusion

      In ADAURA, adjuvant osimertinib demonstrated a highly statistically significant improvement in DFS vs placebo in patients with resected stage IB–IIIA EGFRm NSCLC. HRQoL was maintained during osimertinib treatment with no clinically meaningful differences observed between arms. Collectively, these data further support adjuvant osimertinib as a new treatment strategy in this setting, with significant DFS benefit and maintained HRQoL.

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      OA06.04 - Postoperative Chemotherapy Use and Outcomes from ADAURA: Osimertinib as Adjuvant Therapy for Resected EGFR Mutated NSCLC (ID 3464)

      16:45 - 17:45  |  Author(s): Masahiro Tsuboi

      • Abstract
      • Slides

      Introduction

      Approximately 30% of patients with non-small cell lung cancer (NSCLC) present with resectable disease. Adjuvant chemotherapy is recommended in patients with resected stage IIꟷIIIA NSCLC, and selected stage IB patients; however, recurrence rates are high. In the Phase III, double-blind, randomized ADAURA study (NCT02511106), osimertinib (a third-generation, irreversible, CNS-active EGFR-tyrosine kinase inhibitor) demonstrated a highly statistically significant and clinically meaningful improvement in disease-free survival (DFS; hazard ratio [HR]: 0.20 [99.12% CI 0.14, 0.30]; p<0.001) in patients with completely resected stage IBꟷIIIA EGFR mutation-positive (EGFRm) NSCLC following adjuvant chemotherapy, when indicated. We report an exploratory analysis of adjuvant chemotherapy use and outcomes in ADAURA.

      Methods

      Patients with resected stage IB–IIIA (AJCC 7th edition; pathologic stage) EGFRm NSCLC were randomized 1:1 to receive osimertinib 80 mg once daily or placebo for three years (study completion) or until disease recurrence. Disease staging was based on electronic case report forms for baseline characteristics data, and interactive voice response system (IVRS) for efficacy data (per statistical analysis plan). Delivery of standard postoperative adjuvant chemotherapy prior to randomization was allowed, per physician and patient choice, but not mandatory. Assessment of adjuvant chemotherapy use was exploratory. DFS analysis in the overall population of patients (stage IB–IIIA disease) with/without adjuvant chemotherapy was a predefined subgroup analysis, performed using a Cox proportional hazards model. Data cutoff: 17/01/20.

      Results

      In ADAURA, 60% (410/682) of all patients randomized received adjuvant chemotherapy for a median duration of 4.0 (Q1: 4.0, Q3: 4.0) cycles, balanced across treatment arms. Overall, 409 patients received platinum-based chemotherapy, most with stage IIꟷIIIA (II: 71% [165/231]; IIIA: 80% [187/235]), and fewer with stage IB (26% [57/216]), disease. Across disease stages, the overall proportion of patients who received chemotherapy was 66% in patients aged <70 years (338/509), compared with 42% (72/173) in patients aged ≥70 years, reducing to 27% (21/78) in patients aged ≥75 years. WHO performance status (PS) did not impact chemotherapy use. The table reports DFS analysis with/without chemotherapy in the overall population and by disease stage, according to IVRS.

      Stage IB

      Stage II

      Stage IIIA

      Overall population
      (stage IB–IIIA)

      With chemotherapy

      OSI
      n=28

      PBO
      n=30

      OSI
      n=81

      PBO
      n=85

      OSI
      n=94

      PBO
      n=92

      OSI
      n=203

      PBO
      n=207

      DFS events, patients (%)

      4 (14)

      11 (37)

      6 (7)

      36 (42)

      12 (13)

      56 (61)

      22 (11)

      103 (50)

      DFS HR
      (95% CI)

      NC (NC, NC)

      0.15 (0.06, 0.32)

      0.13 (0.06, 0.23)

      0.16 (0.10, 0.26)

      Without chemotherapy

      OSI
      n=78

      PBO
      n=76

      OSI
      n=37

      PBO
      n=33

      OSI
      n=21

      PBO
      n=27

      OSI
      n=136

      PBO
      n=136

      DFS events, patients (%)

      7 (9)

      18 (24)

      5 (14)

      16 (48)

      3 (14)

      22 (81)

      15 (11)

      56 (41)

      DFS HR
      (95% CI)

      0.38 (0.15, 0.88)

      0.20 (0.07, 0.52)

      0.10 (0.02, 0.29)

      0.23 (0.13, 0.40)

      CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; NC, not calculable; OSI, osimertinib; PBO, placebo

      Disease stage recorded by interactive voice response system.
      Subgroup categories with less than 20 events were excluded from the analysis. A hazard ratio of less than 1 favors osimertinib.

      Conclusion

      Adjuvant chemotherapy use in ADAURA was in line with uptake observed in previous studies and clinical practice. As expected, younger age and higher disease stage were associated with increased chemotherapy use, whereas use did not vary according to PS. DFS benefit with osimertinib vs placebo in patients who received prior chemotherapy was similar to that in patients who had not received prior chemotherapy, regardless of disease stage.

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    P03 - Early Stage/Localized Disease - Clinical Trials in Progress (ID 112)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Early Stage/Localized Disease
    • Presentations: 3
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P03.02 - Neoadjuvant Osimertinib with/without Chemotherapy vs Chemotherapy for EGFR Mutated Resectable NSCLC: NeoADAURA  (ID 3386)

      00:00 - 00:00  |  Presenting Author(s): Masahiro Tsuboi

      • Abstract
      • Slides

      Introduction

      Background

      Approximately 30% of patients with NSCLC present with resectable disease. Primary treatment for resectable NSCLC is curative surgery; patient prognosis following surgery alone remains poor. Neoadjuvant chemotherapy is recommended in resectable stage-III NSCLC, regardless of EGFR mutation status, and has demonstrated clinical benefit. However, improved treatment options for stage II/III are needed. Recent studies indicate that EGFR-TKI therapy could potentially achieve tumour size reduction and clearance of micrometastases in the neoadjuvant setting; treatment effect can be assessed in resected specimens. Osimertinib is a third-generation, CNS-active EGFR-TKI, with superior efficacy to comparator EGFR-TKI in treatment-naïve EGFR mutation-positive (EGFRm) advanced NSCLC. In the Phase III ADAURA study (NCT02511106), osimertinib showed statistically significant DFS improvement (hazard ratio: 0.20 [99.12% confidence interval 0.14, 0.30; p<0.001) in resected stage IBꟷIIIA EGFRm NSCLC following adjuvant chemotherapy, when indicated. A recent study (NCT03433469) found neoadjuvant osimertinib was well tolerated in patients with Stage IꟷIIIA NSCLC. Efficacy and tolerability of osimertinib in advanced and adjuvant settings support its investigation as neoadjuvant treatment in resectable disease. NeoADAURA (NCT04351555) is a Phase III, controlled, randomised study assessing efficacy and safety of osimertinib (with/without chemotherapy) versus chemotherapy plus placebo as neoadjuvant treatment in resectable stage IIꟷIIIB EGFRm NSCLC.

      Methods

      Trial Design

      Eligible patients: ≥18 years (≥20 years, Japan), ECOG PS 0/1, primary non-squamous stage IIꟷIIIB (IASLC Cancer Staging Manual v8) NSCLC and confirmed EGFRm (Ex19del/L858R), deemed completely resectable. Prior treatment with systemic anti-cancer therapy for NSCLC is not allowed. Approximately 351 patients will be randomised 1:1:1 (Figure) to receive platinum-based chemotherapy (pemetrexed 500 mg/m2 plus carboplatin AUC5 or cisplatin 75 mg/m2) plus placebo (Arm 1; double-blind), platinum-based chemotherapy plus osimertinib 80 mg once-daily (Arm 2; double-blind) or osimertinib 80 mg once-daily alone (Arm 3; open-label). Patients will be stratified by disease stage (II/III), race (non-Asian/Chinese/other Asian) and EGFR mutation (Ex19del/L858R).

      Following three cycles of chemotherapy (Arms 1 and 2) or nine weeks of osimertinib (Arm 3), patients will undergo complete surgical resection of primary NSCLC. Treatment with osimertinib or placebo may continue until surgery, unless unacceptable toxicity/withdrawn consent/other discontinuation criterion. Post-surgery, patients will receive optimal care (investigator-defined); this may include adjuvant osimertinib treatment for three years (maximum)/until disease recurrence or unmanageable toxicity.

      The primary endpoint is MPR, (≤10% residual cancer cells in surgical specimen post-surgery) centrally assessed. Secondary endpoints include pCR, EFS, downstaging, DFS, OS and safety. MPR and EFS will be tested using hierarchal testing procedure at MPR primary analysis.

      fig_for upload.png

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      P03.03 - MERMAID-1: A Phase III Study of Adjuvant Durvalumab plus Chemotherapy in Resected NSCLC Patients with MRD+ Post-Surgery (ID 3322)

      00:00 - 00:00  |  Author(s): Masahiro Tsuboi

      • Abstract
      • Slides

      Introduction

      30% of non-small-cell lung cancer (NSCLC) patients present with surgically resectable disease at diagnosis. To reduce disease recurrence, adjuvant chemotherapy is standard of care (SoC) for patients with completely (R0) resected stage II/III NSCLC. However, 5-year disease-free survival (DFS) rates remain low (~40%), with a 5-year absolute benefit of only 5.4% derived from chemotherapy (Pignon et al. JCO 2008;26:3552-9). Determining who will benefit from adjuvant chemotherapy remains challenging. Identifying minimal residual disease (MRD) through detection of circulating tumour (ct) DNA post-surgery could predict early disease recurrence. Durvalumab is a selective, high‑affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. In the phase III PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression following radical platinum-based concurrent chemoradiotherapy, durvalumab improved progression-free survival (PFS) and overall survival (OS), demonstrating its efficacy in situations of residual disease. Further, initial data from POSEIDON showed durvalumab plus chemotherapy prolongs PFS versus chemotherapy in first line treatment of metastatic NSCLC. In the adjuvant setting (i.e. following complete tumour resection), this regimen could provide additional DFS benefit versus chemotherapy alone. MRD assessment could facilitate earlier, more selective adjuvant therapy for MRD+ patients, allowing for treatment intensification for this potentially biologically distinct disease, while minimising overtreatment of MRD– patients. MERMAID‑1 will investigate the efficacy and safety of adjuvant durvalumab + SoC chemotherapy versus placebo + SoC chemotherapy in patients with completely resected stage II/III NSCLC, to assess the benefits of adjuvant therapy in patients with MRD+ status.

      Methods

      MERMAID-1 (NCT04385368) is a phase III, parallel-arm, placebo-controlled, double‑blind, multicentre study, conducted across 16 countries. Patients aged ≥18 years with histologically confirmed EGFR-/ALK- Wild-type, stage II/III NSCLC will enter the first screening period; a personalised MRD panel will be created. Before randomisation, and following assessment of MRD status post-surgery, patients will be further screened for full eligibility (no evidence of disease recurrence, WHO/ECOG performance status 0/1). Patients who have received prior adjuvant therapy or durvalumab, and those with mixed small cell and NSCLC histology or evidence of post-operative disease recurrence are ineligible. MRD status will be determined via ctDNA analysis of plasma samples, collected 3–4 weeks post-surgery, and based on personalised panels (comprised of ≤50 tumour-specific DNA variants) created by whole exome sequencing analysis of the patient’s resected tumour tissue. Approximately 332 patients will be randomised 1:1 (stratified by disease stage, MRD status, and PD-L1 expression) to durvalumab (1500 mg, intravenously) or placebo, plus concurrent SoC chemotherapy, once every three weeks (Q3W) for 12 weeks. Patients will continue with durvalumab monotherapy/placebo Q4W thereafter, until Week 48 or disease recurrence, whichever occurs first. Following a baseline radiological scan prior to randomisation, patients will be assessed Q12W until disease recurrence (per RECIST v1.1). The primary endpoint is DFS in the MRD+ analysis set (investigator-assessed). Secondary endpoints include DFS in the full analysis set (FAS; investigator-assessed); DFS in the MRD+ analysis set and FAS (blinded independent central review); OS in the MRD+ analysis set and FAS; and safety and tolerability, and patient-reported outcomes.

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      P03.05 - CANOPY-N: Neoadjuvant Canakinumab and Pembrolizumab in Patients With Surgically Resectable Non-Small Cell Lung Cancer (ID 2981)

      00:00 - 00:00  |  Author(s): Masahiro Tsuboi

      • Abstract
      • Slides

      Introduction

      Complete surgical resection is the standard treatment for patients with stage I-IIIA non-small cell lung cancer (NSCLC). 5-year survival rates range from 19-50%, with most patients dying from distant recurrence. Neoadjuvant or adjuvant chemotherapy improves overall survival by only 5% in patients with NSCLC, and new treatment options are needed. Preliminary data with PD-1 or PD-L1 inhibitors as neoadjuvant therapy has shown major pathologic responses (MPR) or pathologic complete responses (pCR) in patients with early stage NSCLC. CANTOS study demonstrated reduced incidence of NSCLC and decreased lung cancer-related mortality with canakinumab (an IL-1β inhibitor) versus placebo, in dose-dependent manner for patients with atherosclerosis. In preclinical NSCLC humanized models, treatment with canakinumab with or without an anti PD-1 inhibitor demonstrated anti-tumor activity. Combination of canakinumab and pembrolizumab is expected to enhance efficacy of PD-1 inhibition by inhibiting dysregulated inflammation in tumor microenvironment. Based on available evidence, CANOPY-N study was designed to evaluate effect of canakinumab and pembrolizumab as monotherapy or in combination as neoadjuvant treatment for patients with resectable NSCLC.

      Methods

      CANOPY-N (NCT03968419) is a phase II, randomized, open-label study evaluating effect of canakinumab or pembrolizumab monotherapy or in combination as neoadjuvant treatment in resectable NSCLC patients. Patients will be randomized (stratified by histology [squamous/non-squamous]) to receive a total of 2 doses of canakinumab alone or in combination with pembrolizumab or pembrolizumab with safety follow-up up to 130 days from last study drug dose (Figure 1). Patient eligibility criteria is listed in Table 1. Primary endpoint is to determine MPR rate (≤10% of residual viable tumor cells at time of surgery). Secondary endpoints include determination of overall response rate, MPR rate based on local review, surgical feasibility rates, anti-drug antibodies incidence and pharmacokinetic parameters. Surgery-related safety is one of the exploratory endpoints.

      Table 1: Eligibility Criteria

      Key Inclusion Criteria

      Key Exclusion Criteria

      Age ≥18 years

      Histologically confirmed stage IB–IIIA NSCLC

      Eastern Cooperative Oncology Group performance status 0 or 1

      Eligible for surgery, with a planned surgical resection in ~4–6 weeks from the first dose of study treatment

      Availability of archival (if obtained up to 5 months before 1 day of treatment) or new biopsy

      Unresectable or metastatic disease, including brain metastases

      History of severe hypersensitivity reactions to monoclonal antibodies

      Patients who received prior systemic therapy in the past 3 years before screening

      Clinically significant, uncontrolled cardiac disease and/or a recent cardiac event

      Major surgery within 4 weeks prior to randomization

      Figure 1: Study Design

      canopy-n study design.png

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    PL04 - A Vision for Clinical Trials in 2020 and Beyond (Japanese, Mandarin, Spanish Translation Available) (ID 145)

    • Event: WCLC 2020
    • Type: Plenary
    • Track: N.A.
    • Presentations: 1
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      PL04.08 - The Future of Clinical Trials - The Surgical Perspective (ID 3924)

      07:00 - 09:00  |  Presenting Author(s): Masahiro Tsuboi

      • Abstract
      • Slides

      Abstract not provided

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