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Tony S. Mok



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    MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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      MA26.11 - Effects of Dose Modifications on the Safety and Efficacy of Dacomitinib for EGFR Mutation-Positive NSCLC (Now Available) (ID 13318)

      14:40 - 14:45  |  Author(s): Tony S. Mok

      • Abstract
      • Presentation
      • Slides

      Background

      In patients with EGFR mutation-positive advanced stage NSCLC, first-line dacomitinib significantly improved PFS, OS, DoR and time to treatment failure vs gefitinib (ARCHER 1050; NCT01774721).1,2 Dacomitinib starting dose was 45 mg QD for all patients, with reductions to 30 or 15 mg QD permitted. We explored effects of dacomitinib dose reduction on safety and efficacy in this ongoing study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with newly diagnosed stage IIIB/IV or recurrent NSCLC harboring an EGFR mutation (exon 19 del or exon 21 L858R) randomized to dacomitinib received 45 mg PO QD. Study endpoints and protocol-defined dose reduction parameters were previously described.1 We evaluated reasons for dose reductions, and their effects on incidence and severity of common adverse events (AEs) and key efficacy endpoints (PFS, OS, ORR). Data cutoff dates: 17-Feb-2017 (OS), 29-Jul-2016 (other endpoints).

      4c3880bb027f159e801041b1021e88e8 Result

      Overall, 150 (66.1%) patients dose reduced for AEs (87 and 63 reduced to 30 and 15 mg QD as lowest dose, respectively); most commonly for skin toxicities (62.6%) and diarrhea (14.0%). Median time to each successive dose reduction was ~12 weeks. Incidence and severity of AEs declined following dose reduction, including grade ≥3 diarrhea (11.3% before vs 4.0% after), dermatitis acneiform (15.3% vs 6.7%), stomatitis (3.3% vs 2.7%) and paronychia (7.3% vs 4.7%).

      PFS was similar in dose-reduced and all dacomitinib-treated patients (Figure).

      pfzusdt200581 dacomitinib dose reduction figure 02.jpg

      Median OS results were also similar (dose-reduced patients: 36.7 mo [95% CI: 32.6, NR]; all dacomitinib-treated patients: 34.1 mo [95% CI: 29.5, 37.7] as were ORRs (dose-reduced patients: 79.3% [95% CI: 72.0, 85.5]; all dacomitinib-treated patients: 74.9% [95% CI: 68.7, 80.4]).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Efficacy was similar in the dose-reduced patients and the overall study population. Incidence/severity of dacomitinib-related AEs decreased with dose reduction, thereby allowing patients to continue treatment.

      References:

      Wu, et al. Lancet Oncol. 2017.

      Mok, et al. J Clin Oncol. 2018.

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    OA07 - Oligometastasis: What Should Be the State-Of-The-Art? (ID 905)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Oligometastatic NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 107
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      OA07.02 - ATOM: A Phase II Study to Assess Efficacy of Preemptive Local Ablative Therapy to Residual Oligometastases After EGFR TKI (Now Available) (ID 12977)

      15:25 - 15:35  |  Author(s): Tony S. Mok

      • Abstract
      • Presentation
      • Slides

      Background

      NSCLC patients (Pts) harboring EGFR mutation invariably develop resistance to EGFR TKI at a median time of 9-13 months. Prior studies have showed that local ablative therapy (LAT) upon oligoprogression (OP) can extend the duration of TKI therapy effectively. We postulate that residual positron emission tomography (PET) avid lesions after initial treatment of EGFR TKI may harbor resistant clones and preemptive LAT may improve progression free survival (PFS).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This single-arm phase II study aims to determine the efficacy of preemptive LAT to residual metabolic active oligo-metastases after initial TKI. Pts with stage IIIB/ IV EGFR M+ NSCLC who possessed oligoresidual (OR) disease (≤ 4 PET-avid lesions with SUV ≥2.5) after a 3-mth TKI therapy were enrolled. Those with initial PR underwent screening PET-CT. PET avid ORs would be treated by LAT, either by stereotactic ablative radiotherapy (SABR) or surgery per clinicians’ discretion. TKI was continued after LAT until it was considered ineffective. PET-CT was done on the 3rd and 12th month post-LAT (or at progression), apart from regular imaging. Further LAT was allowed if OP was detected. Primary endpoint was PFS rate at 1 year from enrollment. Overall survival (OS), treatment safety and comparison with screen failure cohorts were secondary endpoints.

      4c3880bb027f159e801041b1021e88e8 Result

      18 Pts were enrolled from 2014-17. Recruitment was stopped before the planned number (n = 34) due to slow accrual. Two were not analyzed due to consent withdrawal and significant protocol violation. Median follow up was 28.7 mth. Among the 16 analyzed Pts, the 1 year PFS rate (i.e. 15 mth post TKI) was 62.5%. OS data was not yet mature. All LAT were done by SABR, and none experienced ≥grade 3 SABR related toxicities. Compared with screen failure cohort (n = 43, metabolic CR or PR with residual disease not fulfilling LAT criteria), the 1 year and 2 year PFS favored treatment arm, though statistically not significant (62.5% vs 47.1%, 30.0% vs 7.9%; p = 0.15).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The 1-yr PFS rate is encouraging. A trend of improved long term PFS is noted in Pts receiving preemptive LAT to residual PET-avid OM after initial TKI compared with Pts without LAT. Further studies are warranted.

      Clinical Trial information: NCT01941654

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA12 - Novel Therapies in MET, RET and BRAF (ID 921)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 106
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      OA12.07 - Clinical Activity of LOXO-292, a Highly Selective RET Inhibitor, in Patients with RET Fusion+ Non-Small Cell Lung Cancer (Now Available) (ID 13922)

      16:20 - 16:30  |  Author(s): Tony S. Mok

      • Abstract
      • Presentation
      • Slides

      Background

      RET kinase gene fusions are actionable drivers that occur in ~2% of non-small cell lung cancers (NSCLC). However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET fusion+ NSCLC patients has been limited. LOXO-292 is a highly selective RET inhibitor, with preclinical activity against diverse RET fusions, potential acquired resistance mutations, and against brain metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      LIBRETTO-001 is a multicenter global phase 1/2 study (26 sites, 9 countries) enrolling patients w/ advanced solid tumors (NCT03157128) including RET fusion+ NSCLC. Patients are dosed orally in 28-day cycles with dose escalation following a 3+3 design. The primary endpoint is MTD/recommended dose determination. Secondary endpoints include safety, overall response rate (ORR, RECIST 1.1) and duration of response (DoR). Initial data were presented at the ASCO 2018 Annual Meeting.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 02-April 18, 82 solid tumor patients (including 38 RET fusion+ NSCLC) were treated at 8 doses (20 mg QD-240 mg BID). The MTD was not reached. AEs (≥10% of patients) were fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%), and dyspnea (11%); most were grade 1-2. 2 TEAEs ≥ grade 3 were attributed to LOXO-292 (Gr3 tumor lysis syndrome, Gr3 increased ALT). Of the 38 RET fusion+ NSCLC pts, 30 had at least 1 post-baseline assessment or discontinued LOXO-292 prior to such assessment. 26 of 30 patients (87%) had >20% radiographic tumor reduction (range: -21 to -72%). The ORR was 77% (23/30, 3 responses pending confirmation) with a confirmed ORR of 74% (20/27, excluding 3 patients with unconfirmed responses). The response rate was similar regardless of prior MKI treatment (12/15 MKI-naïve, 11/15 MKI pretreated). Responses occurred independent of upstream fusion partner when known (13/16 KIF5B vs 9/11 other) and included patients w/ baseline brain metastases. Most patients remained on treatment (33/38), including all responders. The median DoR was not reached (longest response was the first responder: >10+ months). Rapid plasma clearance of RET variants was observed, with complete clearance by day 15 in 10 of 17 (59%) NSCLC patients with assessable baseline and day 15 ctDNA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      LOXO-292 was well-tolerated and had marked antitumor activity in RET-fusion+ NSCLC patients, including those w/ resistance to prior MKIs and brain metastases. Phase 2 cohorts are now open globally (160 mg BID). Updated safety and efficacy data as of 19 Jul 2018 will be presented.

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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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      P1.13-02 -  eXalt3: Phase 3 Randomized Study Comparing Ensartinib to Crizotinib in Anaplastic Lymphoma Kinase Positive Non-Small Cell Lung Cancer Patients (ID 13294)

      16:45 - 18:00  |  Author(s): Tony S. Mok

      • Abstract
      • Slides

      Background

      Ensartinib (X-396) is a novel, potent ALK small molecule tyrosine kinase inhibitor (TKI). It is well-tolerated and has shown promising activity in NSCLC patients in a phase 1/2 study in patients that were both ALK TKI naïve and patients that received prior crizotinib, as well as those with CNS metastases. The safety profile of ensartinib appears to be different from other ALK TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this global, phase 3, open-label, randomized study, approximately 270 patients with ALK+ NSCLC who have received no prior ALK TKI and up to one prior chemotherapy regimen will be randomized with stratification by prior chemotherapy (0/1), performance status (0-1/2), brain metastases at screening (absence/presence), and geographic region (Asia /other), to receive oral ensartinib (225 mg, once daily) or crizotinib (250mg, twice daily) until disease progression or intolerable toxicity.

      Eligibility also includes patients ≥ 18 years of age, stage IIIB or IV ALK+ NSCLC. Patients are required to have measurable disease per RECIST 1.1, adequate organ function, and an ECOG PS of ≤2. Adequate tumor tissue (archival or fresh biopsy) must be available for central testing. The primary endpoint is progression-free survival assessed by independent radiology review based on RECIST v. 1.1 criteria. Secondary efficacy endpoints include overall survival, response rates (overall and central nervous system [CNS]), PFS by investigator assessment, time to response, duration of response, and time to CNS progression. The study has > 80% power to detect a superior effect of ensartinib over crizotinib in PFS at a 2-sided alpha level of 0.05.

      Phase 3 recruitment began in June, 2016 and currently has 98 active sites in 21 countries. The duration of recruitment will be approximately 28 months. This study is registered with ClinicalTrials.Gov as NCT02767804.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    PL01 - Patients First (ID 849)

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 08:15 - 09:45, Plenary Hall
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      PL01.03 - Trials that Matter! (Now Available) (ID 11645)

      08:40 - 08:55  |  Presenting Author(s): Tony S. Mok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    PL02 - Presidential Symposium - Top 5 Abstracts (ID 850)

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 08:15 - 09:45, Plenary Hall
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      PL02.07 - IMpower 133: Primary PFS, OS and Safety in a PH1/3 Study of 1L Atezolizumab + Carboplatin + Etoposide in Extensive-Stage SCLC (Now Available) (ID 12892)

      09:00 - 09:10  |  Author(s): Tony S. Mok

      • Abstract
      • Presentation
      • Slides

      Background

      First-line (1L) standard-of-care treatment for extensive-stage small cell lung cancer (ES-SCLC) is platinum (carboplatin or cisplatin) with etoposide. Despite high initial response rates, there has been limited progress in the last two decades and outcomes remain poor with a median overall survival (OS) of ~10 months. IMpower133 (NCT02763579), a global Phase 1/3, double-blind, randomized, placebo-controlled trial evaluated efficacy and safety of adding atezolizumab, a humanized monoclonal anti–PD-L1 antibody, or placebo to 1L carboplatin and etoposide in ES-SCLC.

      Patients with measurable (RECIST v1.1) ES-SCLC, ECOG performance status 0 or 1, who had not received prior systemic treatment for ES-SCLC were enrolled. PD-L1 immunohistochemical testing was not required. Patients were randomized 1:1 to receive four 21-day cycles of carboplatin (AUC 5 mg/mL/min IV, Day 1) plus etoposide (100 mg/m2 IV, Days 1-3) with either atezolizumab (1200 mg IV, Day 1) or placebo, followed by maintenance therapy with atezolizumab or placebo until intolerable toxicity or progressive disease per RECIST v1.1. Patients meeting predefined criteria could receive treatment beyond progression. Co-primary endpoints were OS and investigator-assessed progression-free survival (PFS). Adverse events (AEs) were graded per NCI-CTCAE v4.0. Blood-based tumor mutation burden (bTMB) was assessed using prespecified cutoffs of ≥16 vs. <16 and ≥10 vs. <10 mutations/Mb.

      In total, 201 patients were randomized to the atezolizumab group, and 202 to the placebo group. Median follow-up was 13.9 months. Median OS was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio [HR] 0.70 [95% confidence interval (CI): 0.54, 0.91; P=0.0069]). Median PFS was 5.2 months and 4.3 months, respectively (HR 0.77 [95% CI: 0.62, 0.96; P=0.017]). OS and PFS benefits were consistent across key patient subgroups. Investigator-assessed confirmed objective response rates were 60.2% and 64.4% in the atezolizumab and placebo groups, respectively; median duration of response, 4.2 and 3.9 months. Exploratory analyses showed OS survival benefits in subgroups above and below prespecified bTMB cutoffs. Grade 3-4 treatment-related AEs were reported in 56.6% vs. 56.1% patients in atezolizumab vs. placebo groups, respectively; serious treatment-related AEs occurred in 22.7% and 18.9% patients, respectively.

      Addition of atezolizumab to carboplatin and etoposide provided a significant improvement in OS and PFS in 1L ES-SCLC in an all-comer patient population. No unexpected safety signals were identified. Atezolizumab plus carboplatin and etoposide may represent a new standard regimen for patients with untreated ES-SCLC.

      a9ded1e5ce5d75814730bb4caaf49419

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    YI01 - Young Investigators Session (ID 988)

    • Event: WCLC 2018
    • Type: Young Investigator Session
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/23/2018, 08:00 - 11:30, Room 106
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      YI01.13 - How to give a Great Presentation (Now Available) (ID 14682)

      10:30 - 10:45  |  Presenting Author(s): Tony S. Mok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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