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Tony S. Mok



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    FP14 - Targeted Therapy - Clinically Focused (ID 252)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP14.12 - Quality of Life and Subgroup Analysis in a Phase 3 Randomized Study of Ensartinib vs Crizotinib in ALK–Positive NSCLC Patients: eXalt3. (ID 3852)

      00:00 - 00:00  |  Author(s): Tony S. Mok

      • Abstract
      • Slides

      Introduction

      Ensartinib (X-396) is a novel second-generation ALK tyrosine kinase inhibitor (TKI). In a phase 3 study interim analysis, ensartinib showed statistically significant improvement of median PFS over crizotinib in patients with ALK+ NSCLC who were ALK TKI naive or received up to one prior chemotherapy line, including higher efficacy against brain metastases. Ensartinib was well tolerated, with low grade rash, pruritus, edema, and transaminitis as the most frequent treatment-related AEs. Here we plan to present subgroups analyses and the quality of life outputs of the phase 3 eXalt3 study (NCT02767804).

      Methods

      Patients with locally tested ALK+ NSCLC (ITT population) were randomized 1:1 to ensartinib (225 mg QD orally) or crizotinib (250 mg BID orally). No crossover was allowed. Patients were stratified by prior chemotherapy, ECOG PS, brain metastases, and geographic region. The modified ITT (mITT) population was prespecified to include all centrally ALK+ patients by Abbott FISH test. The primary endpoint was blinded independent review committee (BIRC)–assessed progression-free survival (PFS; RECIST v.1.1). Secondary endpoints included overall survival (OS), overall response rate (ORR), and time to treatment failure (TTF) in the brain and patients reported outcomes (PRO). PRO data collection included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30). A linear mixed model for repeated measures was used to analyze change from baseline in the Global Health Status/Quality of Life subscale (GHS/QOL), with a change of greater than or equal to ten points deemed meaningful. Time to symptom deterioration will be presented.

      Results

      In total, 290 patients were randomized (ensartinib [n=143]; crizotinib [n=147]).Median age was 54.1 y, 26% of patients had prior chemotherapy, and 36% of patients had baseline CNS metastases (5% had prior brain radiotherapy). The mITT population included 247 patients (ensartinib [n=121]; crizotinib [n=126]). At the July 1, 2020, data cutoff, 139 BIRC-assessed PFS events (73%) occurred in the ITT population and 119 (63%) in the mITT population. Median PFS was 25.8 months with ensartinib vs 12.7 months with crizotinib (HR, 0.52; P=.0003 by log-rank test) with a median follow-up of 23.8 and 20.2 months in the ITT population. Median PFS was not reached with ensartinib vs 12.7 months with crizotinib in the mITT population (HR, 0.48; P=.0002 by log-rank test). New subgroup analyses in mITT for ensartinib showed a trend for higher efficacy by prior chemotherapy vs no chemotherapy (mPFS NR vs 25.8). Both global health status (GHS) as well as 5 functional and 9 symptom domains within EORTC QLQ-C30 had clinical meaningful improvement over time for ensartinib. Ensartinib delays the time to worsening of GHS with HR =0.83 (95% CI [0.57, 1.20]) vs crizotinib. Complete subgroup analyses (forest plot and multivariate analyisis) will be presented at the conference as well as OS updates. Comprehenive EORTC QLQ-C30 and Lung Cancer Symptom Scale scores will also be reported at the conference.

      Conclusion

      In ALK+ NSCLC patients ensartinib represents a new option in first-line setting. QOLs data support its favorable safety profile. Relevant subgroups analyses to evaluate its clinical impact will be presented at the meeting.

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    IS03 - Industry Symposium Sponsored by Daiichi-Sankyo: Antibody Drug Conjugates (ADC) as Therapeutic Options for Advanced NSCLC: Opportunities and Challenges (ID 279)

    • Event: WCLC 2020
    • Type: Industry Symposium
    • Track:
    • Presentations: 2
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      IS03.01 - Welcome and Introduction (ID 4315)

      11:45 - 12:45  |  Presenting Author(s): Tony S. Mok

      • Abstract

      Abstract not provided

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      IS03.02 - Evolving Challenges for the Treatment of Advanced NSCLC (ID 4316)

      11:45 - 12:45  |  Presenting Author(s): Tony S. Mok

      • Abstract

      Abstract not provided

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    IS15 - Industry Symposium Sponsored by Amoy: Lung Cancer Biomarker Panel Testing (ID 292)

    • Event: WCLC 2020
    • Type: Industry Symposium
    • Track:
    • Presentations: 3
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      IS15.01 - Opening Remarks (ID 4370)

      13:00 - 14:00  |  Presenting Author(s): Tony S. Mok

      • Abstract

      Abstract not provided

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      IS15.02 - Biomarker for Lung Cancer: Right Patient, Right Time, Right Test (ID 4371)

      13:00 - 14:00  |  Presenting Author(s): Tony S. Mok

      • Abstract

      Abstract not provided

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      IS15.05 - Closing Remarks (ID 4374)

      13:00 - 14:00  |  Presenting Author(s): Tony S. Mok

      • Abstract

      Abstract not provided

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    JICC01 - Joint IASLC-CAALC-CSCO Session: The Truth and Myth of Oral Anti-VEGFR Inhibitors for Advance NSCLC (ID 276)

    • Event: WCLC 2020
    • Type: Workshop
    • Track: N.A.
    • Presentations: 1
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      JICC01.02 - Chair (ID 4261)

      07:00 - 09:00  |  Presenting Author(s): Tony S. Mok

      • Abstract

      Abstract not provided

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    MA11 - Expanding Targetable Genetic Alterations in NSCLC (ID 251)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
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      MA11.08 - Patient-Reported Outcomes from the Randomized Phase 3 CROWN Study of First-Line Lorlatinib versus Crizotinib in ALK+ NSCLC (ID 3257)

      14:15 - 15:15  |  Author(s): Tony S. Mok

      • Abstract

      The abstract for this presentation is currently under embargo or has not been submitted.

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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: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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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): Tony S. Mok

      • 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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    P19 - Locoregional and Oligometastatic Disease - Oligometastatic Disease (ID 129)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Locoregional and Oligometastatic Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P19.01 - Local Ablative Radiotherapy on Oligo-Progression while Continued on EGFR-TKI in Advanced NSCLC Patients: A Longer Cohort (ID 1505)

      00:00 - 00:00  |  Author(s): Tony S. Mok

      • Abstract
      • Slides

      Introduction

      Continuation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKI) in advanced Non-small cell Lung cancer (NSCLC) patients harboring sensitive mutation (Exon 19 deletion /Exon 21 L858R mutation) upon first progression according to RECIST criteria can prolong the use of EGFR-TKI for more than 3 months till change of therapy. Local ablative radiotherapy (LAR) on oligo-progression is widely used but actual benefit is yet to be quantified.

      Methods

      Health records of patients given LAR from 2012-2019 in a single centre were reviewed. Patients with stage IV NSCLC harboring epidermal growth factor receptor (EGFR) activating mutations having <5 sites of oligo-progression while on EGFR TKI and given LAR with 1-8 fractions were included. Demographics, site of oligo-progression, radiotherapy sites and dose/fractionation schedules were captured. Duration from start of TKI to oligo-progression was defined as PFS1. The primary endpoint was progression free survival from LAR to further progression that led to stop of EGFR TKI (PFS2). The secondary endpoint was overall survival from LAR. Potential factors affecting PFS2 and OS were analyzed with Cox regression model.

      Results

      There were total 55 eligible patients. The mean age at delivery of LAR was 62.7 (36-88) years. Majority (89%) had sensitive mutations (Exon 19 deletion and exon 21 L858R mutation). The median PFS1 was 17.2 months (95% CI 11.4 to 23.0). Total number of lesions treated were 75, including lung (n=45), bone (n=15), cervical lymph node (n=1), adrenal (n=1) and brain (n=13). The mean radiation doses with biological equivalent dose with α/β= 10 (BED10) were: lung: 112.2Gy (100.0-151.2Gy); bone: 47.8 Gy (41.6- 100Gy); brain: 61.7Gy (37.5-70.4Gy). The patient with metastatic lymph node was given 60Gy in 8 fractions (BED10= 105Gy) and with adrenal metastasis was given 40Gy in 5 fractions (BED 10= 72Gy). The mean time from diagnosis of oligo-progression to LAR was 2.2 months (0.6 to 4.6 months). No significant toxicities were reported. The median follow-up time was 13.3 months (1.5-51.6 months).

      The median PFS1 was 17.2 months (95% CI 11.4 to 23.0). Median PFS2 was 6.9 months (95% CI 3.1- 10.7 months). The 1-year and 2-year local control rate were 86% and 78%. The 1-year and 2-year distant control rates were 29% and 16%. The median OS from LAR was 25.1 months (95% CI 10.0-40.10 months). On multivariable analysis, it was found that patients with EGFR mutation type (exon 19 deletion or L858R mutation) had superior PFS2 (HR 0.11 95% CI 0.03-0.41, p =0.001) and OS (HR 0.099 95 CI 0.010-0.961, p=0046) compared with other less common mutations, while longer time to treatment (>70 days) and more lines of TKI before LAR negatively affected PFS2 (p=0.046; 0.004). Age, sex, smoking status, CNS involvement, number of radiation sites, PFS1 and treatment dose did not affect PFS2 and OS with statistical significance.

      Conclusion

      LAR is a safe and convenient modality in treatment of oligo-progressive disease for patients with EGFR mutations positive NSCLC. Patients with EGFR exon 19 deletion or Exon 21 L858R mutation, shorter time from diagnosis to treatment, and less prior lines of EGFR-TKI may benefit more from LAR.

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    P35 - Pathology - Genomics (ID 105)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P35.15 - Molecular Epidemiology of KRAS G12C Mutations in Chinese Lung Cancer Patients (ID 2498)

      00:00 - 00:00  |  Author(s): Tony S. Mok

      • Abstract
      • Slides

      Introduction

      The incidence of KRAS mutations are different between the Asian and non-Asian populations. Recent development of KRAS G12C targeting drugs has shown great promise. We report on the real-world genomic landscape of KRAS G12C in Chinese cancer patients (pts).

      Methods

      Sequencing data of samples from 186 comprehensive cancer centres in China performed at a single CAP-accredited laboratory were reviewed for KRAS mutation status. Additionally, smoking status and its correlation with KRAS were analysed within the lung cancer cohort. Concomitant genomic aberrations were identified in tumors with KRAS G12C mutations through a comprehensive cancer panel encompassing 450 cancer-related genes.

      Results

      11,951 tumour samples from individual pts were collected from 11/2016 to 7/2019. Lung cancer formed the largest cohort of pts, accounting for 42% (n=5063) of samples, followed by colorectal (CRC) (9.3%), liver (8.9%), biliary tract (BTC) (8.4%), and others. KRAS mutations were observed in 16.6% of all samples. Specifically, KRAS G12C was the most common KRAS mutation identified in 4.3% (n=218) of lung cancer pts. In addition, KRAS G12C was also identified in 2.5% and 2.3% of CRC and BTC pts’ samples. In lung adenocarcinoma (LUAD) pts, KRAS mutations were more commonly identified in current and former smokers vs. non-smokers (20.7%, 20.3% 8.9% respectively, p<0.001). This correlation was not seen in pts with squamous cell carcinoma of lung. 81 (54.7%) of KRAS G12C LUAD cases had at least one potentially actionable alteration in addition to KRAS G12C (level 1 to 4), with actionable EGFR and ALK mutations were identified in 8 cases (5.4%).

      Distribution of KRAS aberration subtypes in lung cancer (N=5063)
      KRAS Aberration N (Total 607 KRAS aberrations in 591 samples) Proportions of KRAS aberrations Frequencies in lung cancer (N=5063)
      G12C 218 35.9% 4.3%
      G12V 108 17.8% 2.1%
      G12D 99 16.3% 2.0%
      Amplification 57 9.4$ 1.1%
      G12A 37 6.1% 0.7%
      Q61H 18 3.0% 0.4%
      G13C 15 2.5% 0.3%
      G13D 13 2.1% 0.3%
      G12S 7 1.2% 0.1%
      Others 35 5.8% 0.7%

      Conclusion

      We report on the largest KRAS mutation landscape in Chinese cancer patients to date. KRAS G12C mutation remains uncommon. However, more than half of LUAD pts with KRAS G12C had co-alterations which are potentially actionable. This may form the basis for future combinational drug development strategies. Other histologies with KRAS G12C have also been identified.

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    P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P76.67 - Safety and Efficacy of First-Line Dacomitinib in Advanced Non-Small Cell Lung Cancer by EGFR Mutation SUBtype in ARCHER 1050 (ID 3335)

      00:00 - 00:00  |  Author(s): Tony S. Mok

      • Abstract
      • Slides

      Introduction

      ARCHER 1050 (NCT01774721) compared dacomitinib versus gefitinib in newly diagnosed patients with advanced EGFR-mutation positive non-small cell lung cancer (NSCLC). Updated overall survival (OS) analysis showed significant improvement in OS with dacomitinib versus gefitinib in the overall population and exon 21 L858R substitution mutation (L858R) subgroup. We report analysis of efficacy and safety by EGFR mutation subtype.

      Methods

      In this ongoing, open-label, phase III trial, eligible patients were randomized 1:1 to dacomitinib 45 mg/day (n = 227) or gefitinib 250 mg/day (n = 225), stratified by race and EGFR mutation subtype (exon 19 deletion [Del19] or L858R). The primary endpoint was PFS (blinded independent radiologic central review). Post-hoc exploratory efficacy analyses for patients with dacomitinib dose reductions were also conducted.

      Results

      Improvements in PFS and updated OS with dacomitinib over gefitinib were observed in patients with dacomitinib dose reduction in both EGFR mutation subgroups (Table 1). In responding patients, duration of response was longer with dacomitinib versus gefitinib in both EGFR mutation subgroups. Dacomitinib dose reduction was reported in 66% (Del19) and 67% (L858R) of patients for PFS (data cutoff date July 29, 2016) and 68% (Del19 and L858R) of patients for updated OS (data cutoff date May 13, 2019; extended median follow-up 47.9 months). Median duration of treatment with dacomitinib was 16.5 months (range 0.2-35.0) and 13.2 months (range 0.1-37.4) in the Del19 and L858R subgroups, respectively. Safety data are in Table 2.

      table 1.png105176 wclc 2020 daco archer mut sbgrp abs_table 2_updated 08 sep 2020.png

      Conclusion

      Dacomitinib is the first second-generation TKI to improve PFS and OS over gefitinib in patients with dose reduction in both Del19 and L858R subgroups. The difference in treatment durations of the dacomitinib subgroups may affect frequency of Grade ≥3 TEAEs. Potential differences in safety between EGFR mutation subgroups will warrant further exploration.

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      P76.78 - Evaluation of the Development of Brain Metastases in Patients Treated with Dacomitinib or Gefitinib from ARCHER 1050 Study (ID 3461)

      00:00 - 00:00  |  Author(s): Tony S. Mok

      • Abstract
      • Slides

      Introduction

      Dacomitinib (Vizimpro®) is a competitive, irreversible, small-molecule inhibitor of epidermal growth factor receptor (EGFR). ARCHER 1050 is a multicenter, Phase 3 study conducted in patients with metastatic or recurrent NSCLC harboring EGFR activating mutations (exon 19 deletion or exon 21 L858R substitution mutations) with no prior therapy for metastatic disease. Dacomitinib significantly improved progression-free survival (PFS) and overall survival (OS) against gefitinib with hazard ratios of 0.59 (p<0.001) and 0.75 (p=0.0155), respectively. The present analysis evaluated the risk factors of development of brain metastases from ARCHER 1050, including treatment, baseline characteristics, and dacomitinib exposure.

      Methods

      CNS imaging was performed in ARCHER 1050 at baseline for all patients and on treatment for patients with clinically suspected brain metastases at the discretion of investigators. Brain lesion data were recorded based on investigator (INV) and independent radiologic central (IRC) reviews. Patients, excluding any history or evidence of brain or leptomeningeal metastases as per the protocol exclusion criteria, were randomized to receive dacomitinib (starting dose of 45 mg QD with allowance of dose reduction to 30 mg or 15 mg) or gefitinib (250 mg QD). Dacomitinib exposure was measured by population PK model-based trough concentrations, average concentrations, or AUC at the end of Cycle 1. Other baseline characteristics were evaluated for its potential association with on treatment development of brain metastases using logistic regression (glm() function).

      Results

      Based on INV review, no patients in the dacomitinib arm (n=227) presented with baseline brain metastases and 1 patient presented with baseline brain metastases in the gefitinib arm (n=225). After median follow up of 22.1 months, total of 4 (1.8%) patients developed brain metastases in the dacomitinib arm comparing to 14 (6.2%) in the gefitinib arm [odds ratio (OR): 0.27 (95% CI: 0.08, 0.77; p=0.0229)]. Of the 4 patients with developed brain metastases in the dacomitinib arm, 1 patient had no dose reduction and the other 3 patients had dose reduced to 30 mg QD. Similarly, by IRC review, no patients presented with brain metastases at baseline in dacomitinib arm while 4 patients in gefitinib arm were retrospectively found to have baseline brain metastases. According to IRC, only 1 (0.4%) patient in dacomitinib arm and 9 (4.0%) patients in gefitinib arm developed new brain lesions [OR: 0.11 (95% CI: 0.01, 0.57; p=0.0341)]. No other covariates (eg., smoking status, race, sex, baseline ECOG performance status, EGFR mutation type, and baseline brain metastases) were associated with development of new brain lesions. Dacomitinib exposure was explored as a covariate for the INV reported new brain lesions and was not found to be associated with development of brain metastases.

      Conclusion

      Dacomitinib is associated with a lower incidence of symptomatic CNS progression in the ARCHER 1050 study.

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