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Daniel S.W. Tan



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    JCSE01 - Perspectives for Lung Cancer Early Detection (ID 779)

    • Event: WCLC 2018
    • Type: Joint IASLC/CSCO/CAALC Session
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/23/2018, 07:30 - 11:15, Room 202 BD
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      JCSE01.12 - Discussant Oral Abstracts (ID 11681)

      10:45 - 11:00  |  Presenting Author(s): Daniel S.W. Tan

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA02 - Novel Therapies in ROS1, HER2 and EGFR (ID 893)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
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      OA02.01 - Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC) (ID 13903)

      10:30 - 10:40  |  Author(s): Daniel S.W. Tan

      • Abstract
      • Presentation
      • Slides

      Background

      Entrectinib is a central nervous system (CNS) active, potent, and selective inhibitor of ROS1, TRKA/B/C and ALK. Entrectinib is more potent against ROS1 than crizotinib, the only agent currently approved for the treatment of ROS1-positive NSCLC. Interim data demonstrated that entrectinib was tolerable and achieved high objective response rates (ORR) in patients with ROS1-positive, ROS1 inhibitor-naive NSCLC, including patients with baseline CNS disease (Ahn MJ WCLC 2017).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Phase 1/2 studies of entrectinib (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267) enrolled patients with locally advanced or metastatic solid tumors. The safety-evaluable population included patients who received ≥1 dose of entrectinib. The integrated efficacy analysis included ROS1-positive NSCLC patients enrolled based on identification of ROS1 fusions via nucleic acid-based diagnostic platforms. Safety was assessed by monitoring adverse events (AEs), laboratory tests, and physical examination. Tumor assessments were performed at the end of cycle 1 and every 8 weeks thereafter. All scans were submitted for blinded independent central review (BICR) using RECISTv1.1. Primary endpoints were ORR and duration of response (DOR) by BICR. Key secondary objectives were progression-free survival (PFS), overall survival (OS), and safety. Additional endpoints evaluated in patients with baseline CNS disease were intracranial ORR (defined as complete or partial responses in patients with baseline CNS lesions per BICR using RECISTv1.1), intracranial DOR, and PFS. For intracranial assessments, the CNS subgroup was derived per BICR; for systemic analyses, the CNS subgroup was derived per investigator.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 53 efficacy-evaluable patients with treatment-naïve, ROS1-positive NSCLC. BICR ORR was 77.4% (95% CI 63.8–87.7) with complete responses in three patients (5.7%); median BICR DOR was 24.6 months (95% CI 11.4–34.8). Per baseline CNS status (as determined by investigator), median BICR PFS was 26.3 months (95% CI 15.7–36.6) and 13.6 months (95% CI 4.5–NR) for patients without (n=30) and with CNS disease (n=23), respectively. Intracranial ORR was 55.0% (95% CI 31.5–76.9) and median intracranial DOR was 12.9 months (95% CI 5.6–not reached [NR]) in patients with baseline CNS disease per BICR (n=20). In the overall safety-evaluable population (n=355), most treatment-related AEs were grade 1–2. Few patients required dose reduction (27.3%) or discontinued treatment (3.9%) due to treatment-related AEs.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Entrectinib was tolerable with a manageable safety profile, and showed clinically meaningful, deep and durable systemic responses in ROS1-positive NSCLC. Clinically meaningful intracranial activity was also demonstrated in patients with baseline CNS disease.

      Study Sponsor: Ignyta, Inc., a wholly owned subsidiary of F. Hoffmann-La Roche Ltd.

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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
    • 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 (ID 13922)

      16:20 - 16:30  |  Author(s): Daniel S.W. Tan

      • 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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    P1.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 948)

    • 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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      P1.16-07 - Cost-Effectiveness of Pembrolizumab as 1st Line Treatment for Metastatic NSCLC Patients with High PD-L1 Expression in Singapore (ID 11719)

      16:45 - 18:00  |  Author(s): Daniel S.W. Tan

      • Abstract
      • Slides

      Background

      Pembrolizumab, an immune checkpoint inhibitor, has been approved as monotherapy for 1st line treatment of metastatic NSCLC with PD-L1 tumor proportion score (TPS) ≥50% based on the pivotal Keynote (KN)-024 study. This study aims to evaluate the cost-effectiveness of pembrolizumab compared with standard-of-care (SoC) platinum-based chemotherapy in patients with TPS≥50% from a societal perspective in Singapore based on results from KN024.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A known partitioned-survival model was adapted to estimate progression-free survival, overall survival, costs of treatments, adverse events and disease management, and health utilities over a time horizon of 20 years. The maximum treatment duration of 2 years was applied for pembrolizumab. Clinical and resource utilization inputs were based on data from KN024 study and input from local oncologists. Unit costs captured both patients’ payments and government subsidies. Utility scores in different health states were based on EQ-5D data from KN024 with weighting indices suggested by a local quality-of-life study. An annual discount rate of 3% was applied and a series of sensitivity and scenario analyses were conducted to address uncertainty.

      4c3880bb027f159e801041b1021e88e8 Result

      For 1st line treatment for NSCLC patients with TPS≥50%, pembrolizumab monotherapy is estimated to result in 0.91 quality-adjusted-life-years (QALY) gained. The projected incremental cost for pembrolizumab is S$141,979 compared to SoC, leading to an incremental cost-effectiveness ratio (ICER) of S$155,630 per QALY gained. A similar ICER of S$156,862 is observed in a scenario analysis whereby all patients are tested for PD-L1 and those with high PD-L1 expression are treated with pembrolizumab. With a Pembrolizumab Patient Access Program (PAP), the ICER is estimated to be S$95,279 per QALY. In another scenario analysis where government subsidies and claim limits of Medishield / Medisave are considered, the estimated ICER is S$46,308 per QALY from the Ministry of Health (MOH) perspective.

      8eea62084ca7e541d918e823422bd82e Conclusion

      For NSCLC patients with TPS≥50%, the ICER in the base-case for pembrolizumab as 1st-line treatment is $155,630 – which is between 2-3x gross domestic product (GDP) per capita of Singapore (S$73,167) in 2016, whereas the estimated ICER with Pembrolizumab PAP is 1-2x GDP per capita. Depending on threshold boundaries adopted, 1st line pembrolizumab for patients with similar profile (TPS ≥50%) as those in KN024, would be a cost-effective treatment compared to SoC in Singapore.

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-21 - MET Addiction Can be Circumvented Through EGFR Inhibition Via AXL in MET-Amplified Primary Resistant EGFR-Mutant NSCLC (ID 14384)

      16:45 - 18:00  |  Author(s): Daniel S.W. Tan

      • Abstract
      • Slides

      Background

      Primary resistance to EGFR-TKI is observed in approximately 10% of patients with activating EGFR mutations. In a patient harboring L858R mutation and high cMET amplification (MET copy number 7.3, CEP7 ratio 3.4) who progressed after just 4 weeks of erlotinib (ERL), significant tumor regression was achieved with MET inhibition alone (Crizotinib, CRZ). We confirmed this phenotype in the corresponding patient-derived cell line model (A482) and identified EGFR-AXL interaction as a mechanism that can circumvent clonal cMET addiction.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We generated patient-derived cell lines from the patient’s baseline neck excision biopsy (A482) and evaluated the effect of mono and combination therapy (ERL, CRZ, ERL-CRZ) on A482, including viability (CellTiter-Glo Luminescent Assay, Promega), colony forming (Crystal Violet Assay), downstream signaling (Western blots) and adaptive pathways (Human Phosho-Receptor Tyrosine Kinase Array Kit, R&D systems). AXL was identified as a key mediator of resistance and subsequently subjected to further functional validation. Finally, we examined the prevalence of this clinical phenomenon in a retrospective series of MET amplified EGFR-mutant NSCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      Cell viability assays confirmed the patient-derived cell line to be more sensitive to CRZ as compared to ERL alone or with combination CRZ-ERL. Upregulation of AXL, RET and FGFR3 expression were identified as adaptive changes 24 hours upon ERL exposure. A targeted pharmacologic screen revealed A482 to be exquisitely sensitive to combination EGFR and AXL inhibition. Immunoprecipitation revealed a direct interaction between EGFR and AXL, which upon treatment with ERL resulted in attenuation of cMET addiction. Co-existing cMET amplification with demonstrated suboptimal response to EGFR TKI was found in 3% of EGFR-mutant NSCLC in a retrospective series of patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Targeting the EGFR-AXL axis through EGFR inhibition alone can lead to paradoxical MET pathway activation, while the combination of EGFR and AXL inhibition can circumvent downstream signaling in MET amplified EGFR-mutant NSCLC. AXL expression levels can potentially identify patients in whom combination or monotherapy with MET inhibitors may be most beneficial. Our data highlights the challenge in interpreting genomic alterations alone; and how cellular context can lead to differential sensitivities to EGFR and MET inhibitors alone and/or in combination in MET amplified EGFR-mutant NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.13-45 - SHERLOC: A Phase 2 Study of Seribantumab in Combination with Docetaxel in Patients with Heregulin Positive, Advanced NSCLC (ID 11349)

      16:45 - 18:00  |  Author(s): Daniel S.W. Tan

      • Abstract
      • Slides

      Background

      HER3 and its ligand, heregulin (HRG), have been identified as a critical activator of PI3K and Akt signaling and a key pro-survival pathway in cancer cells. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. Preclinical data suggest that seribantumab reverses HRG-mediated drug resistance across multiple cancer models. In retrospective analyses of prior seribantumab Phase 2 studies, high levels of HRG mRNA appeared to predict poor outcome to standard of care (SOC) treatment. Addition of seribantumab to SOC appeared to improve progression-free survival (PFS) in patients with HRG positive (HRG+) tumors, consistent with the hypothesis that the blockade of HRG-induced HER3 signaling by seribantumab can restore drug sensitivity.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In the current randomized, open-label, international, Phase 2 study, patients with locally advanced or metastatic NSCLC histologically classified as adenocarcinoma are screened for HRG using an RNA in situ hybridization assay on a recent biopsy tissue sample. Approximately 100 HRG+ patients will be enrolled and randomized in a 2:1 ratio to receive seribantumab plus docetaxel (experimental treatment Arm), or docetaxel alone (control Arm). Eligible patients must have no EGFR and ALK mutations and have progressed following one to two SOC for locally advanced and/or metastatic disease, including platinum-based therapy and anti-PD-1/PD-L1 therapy where available and clinically indicated. Primary trial endpoint is PFS. Secondary endpoints include overall survival, objective response rate, time to progression, and pharmacokinetic profile. The study has ≥ 80% power to detect a 3-month improvement in median PFS over 3 months (hazard ratio ≤ 0.50), using a one-sided, stratified log-rank test at a significance level of 0.025. Study is ongoing and enrolling patients in seventy nine sites worldwide. Clinical trial information: NCT02387216

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    PC04 - Targeted Therapy for NSCLC (ID 843)

    • Event: WCLC 2018
    • Type: Pro-Con Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 106
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      PC04.05 - NGS/Whole Exome Sequencing for Routine Use (ID 11618)

      16:03 - 16:15  |  Presenting Author(s): Daniel S.W. Tan

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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