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S. Popat

Moderator of

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    ISS03 - Industry Supported Symposium: Non-Small Cell Lung Cancer: The Programmed Death-Ligand 1 (PD-L1) Receptor as a Target for Monotherapy and in Combination – Merck-Pfizer Alliance (ID 437)

    • Event: WCLC 2016
    • Type: Industry Supported Symposium
    • Track:
    • Presentations: 6
    • Moderators:S. Popat
    • Coordinates: 12/04/2016, 03:30 PM - 05:00 PM, Hall C2
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      ISS03.01 - Welcome and Overview (ID 7037)

      S. Popat

      • Abstract

      Abstract not provided

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      ISS03.02 - Anti-PD-L1 Monotherapy in Non-Small Cell Lung Cancer (NSCLC): Overview of the Trials Examining anti-PD-L1 Monotherapy in NSCLC (ID 7038)

      R.A. Juergens

      • Abstract

      Abstract not provided

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      ISS03.03 - Anti-PD-L1 Combined with Other Agents in NSCLC: Combinations with non-Immunooncology Agents (ID 7039)

      J.E. Gray

      • Abstract

      Abstract not provided

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      ISS03.04 - Anti-PD-L1 Combined with Other Agents in NSCLC: Immuno-Oncology Combinations (ID 7040)

      S.I. Rothschild

      • Abstract

      Abstract not provided

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      ISS03.05 - Anti-PD-L1 Agents: Opportunities for Differentiation (ID 7041)

      H. Borghaei

      • Abstract
      • Slides

      Abstract not provided

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      ISS03.06 - Summary, Questions and Close (ID 7042)

      S. Popat

      • Abstract

      Abstract not provided



Author of

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    ED11 - Advanced NSCLC: State-of-the-Art Treatment (ID 280)

    • Event: WCLC 2016
    • Type: Education Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      ED11.01 - Systemic Therapy for Advanced Oncogene-Driven NSCLC (Now Available) (ID 6485)

      S. Popat

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Oncogene-driven lung cancer remains the embodiment of personalized medicine. Since the first description of EGFR activating mutations found in patients with what was then called bronchiolalveolar carcinoma of the lung (BAC) in 2004, the topic of oncogene-driven lung cancer has grown rapidly and expanded to now encompass a number of additional mutation- and fusion-related entities. Recent updates to molecular testing guidelines, such as those of IASLC, have added several new oncogenes to the initial EGFR and ALK recommendations, including ROS1 and RET fusions, MET amplification or mutation, and HER2 mutations (1,2,3). Although the efficacy of tyrosine kinase inhibitors (TKI) in the treatment of some of these disease subsets is well established, the treatment decision-making process at the time of each relapse is becoming more complex as our knowledge of resistance pathways grows and more treatment options become available, with 2[nd] and 3[rd] generation drugs now in play. Subtping of progressive disease (PD) in oncogene-driven lung cancer into systemic PD versus oligo-PD or CNS-santuary PD can assist in determining the most appropriate therapeutic approach, as shown in Figure 1 below(4).Further, the methods by which we assess tumor at the time of initial or re-biopsy are also rapidly evolving, from single gene or multiplexed gene panels to highly sensitive and specific next generation sequencing (NGS). Lastly, we and others (4,5) have proposed algorithms for possible substitution of plasma cell free DNA by NGS platforms for tissue re-biopsy or for serial monitoring in plasma, as demonstrated in Figure 2.In this presentation we will present a step-wise approach to molecular testing and personalizing treatment for patients with oncogene-driven NSCLC, focusing on EGFR-mutated and ALK-rearranged subsets, since the treatment paradigms are most well established. We will emphasize some of the real world challenges faced by treating physicians. Decision criteria for selecting the best first-line therapy will be reviewed, the importance of re-biopsy upon disease progression to determine the most appropriate next-line therapy highlighted, and third line therapy and beyond discussed. The emerging role of liquid biopsy for assessment of plasma cell free DNA will be discussed, as well as a rationale for substituting liquid biopsy for initial or repeat tumor biopsy in some clinical settings. Algorithms designed to facilitate treatment decision-making will be presented. Two examples in EGFR-mutated lung cancer are shown below.Figure 1: Algorithm for management by Progressive Disease SubtypingEGFR-mutated NSCLCFigure 1Figure 2: Algorithm for Re-Biopsy and/or Plasma cf DNA AnalysisIn EGFR-mutated NSCLCFigure 2 References 1. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J et al: Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2013, 8(7):823-859. 2. Leighl NB, Rekhtman N, Biermann WA, Huang J, Mino-Kenudson M, Ramalingam SS, West H, Whitlock S, Somerfield MR: Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Society for the Study of Lung Cancer/Association of Molecular Pathologists Guideline. Journal of Clinical Oncology 2014. 3. Ettinger, D. S., Akerley, W., Borghaei, H., Chang, A. C., Cheney, R. T., Chirieac, L. R., ... & Grant, S. C. Non–small cell lung cancer, version 2.2013. Journal of the National Comprehensive Cancer Network, 2013, 11(6), 645-653. 4. Gandara DR, Li T, Lara PN, Kelly K, Riess JW, Redman MW, Mack PC: Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: approach to subtyping progressive disease and clinical implications. Clinical lung cancer 2014, 15(1):1-6. 5. Oxnard, G. R., Thress, K. S., Alden, R. S., Lawrance, R., Paweletz, C. P., Cantarini, M., ... & Jänne, P. A. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non–small-cell lung cancer. Journal of Clinical Oncology, 2014, JCO667162.





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    ISS03 - Industry Supported Symposium: Non-Small Cell Lung Cancer: The Programmed Death-Ligand 1 (PD-L1) Receptor as a Target for Monotherapy and in Combination – Merck-Pfizer Alliance (ID 437)

    • Event: WCLC 2016
    • Type: Industry Supported Symposium
    • Track:
    • Presentations: 2
    • Moderators:S. Popat
    • Coordinates: 12/04/2016, 03:30 PM - 05:00 PM, Hall C2
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      ISS03.01 - Welcome and Overview (ID 7037)

      S. Popat

      • Abstract

      Abstract not provided

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      ISS03.06 - Summary, Questions and Close (ID 7042)

      S. Popat

      • Abstract

      Abstract not provided

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    MA16 - Novel Strategies in Targeted Therapy (ID 407)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
    • Now Available
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      MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (Now Available) (ID 4325)

      S. Popat

      • Abstract
      • Presentation
      • Slides

      Background:
      GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.

      Methods:
      A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).

      Results:
      165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.

      Conclusion:
      RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.

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    OA22 - Novel Trials and Biomarkers in Malignant Pleural Mesothelioma (ID 403)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
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      OA22.02 - Nintedanib plus Pemetrexed/Cisplatin in Patients with MPM: Phase II Findings from the Placebo-Controlled LUME-Meso Trial (Now Available) (ID 4191)

      S. Popat

      • Abstract
      • Presentation
      • Slides

      Background:
      Standard first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin, yielding a median overall survival (OS) of only ~1 year, thus new approaches are required. As demonstrated by the bevacizumab MAPS study, inhibition of the VEGF pathway is of interest as a treatment approach for MPM. Nintedanib is an oral, triple angiokinase inhibitor of VEGFR, PDGFR and FGFR. This study will evaluate the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with advanced MPM.

      Methods:
      Patients with unresectable MPM (chemo-naïve, ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomised (1:1) to receive up to 6 cycles of pemetrexed (500 mg/m[2])/cisplatin (75 mg/m[2]) on Day 1 plus nintedanib (200 mg bid)/placebo on Days 2–21. Patients without disease progression received maintenance treatment with nintedanib/placebo. The primary endpoint was progression-free survival (PFS).

      Results:
      87 patients were randomised to receive pemetrexed/cisplatin, plus nintedanib/placebo. Patient characteristics were comparable between the groups. PFS was longer in the nintedanib vs the placebo arm, in both the overall study population and in epithelioid patients (Table 1). Preliminary OS data also favour nintedanib. All patients experienced at least one adverse event (AE, any grade), with 7% of patients in the nintedanib arm discontinuing due to AEs, vs 15% with placebo. Serious AEs occurred in 36% vs 42% of patients in the nintedanib and placebo arms, respectively. The most common ≥grade 3 AEs occurring in nintedanib vs placebo patients were neutropenia (34% vs 10%), ALT increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%).

      Conclusion:
      Nintedanib plus pemetrexed/cisplatin demonstrated clinical efficacy with improved PFS and a tolerable safety profile in patients with unresectable MPM. Based on these promising findings, this Phase II study was extended to a confirmatory Phase III trial, which is currently enrolling patients. Clinical trial identifier: NCT01907100.

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    P3.02a - Poster Session with Presenters Present (ID 470)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      P3.02a-016 - Pooled Efficacy and Safety Data from Two Phase II Studies (NP28673 and NP28761) of Alectinib in ALK+ Non-Small-Cell Lung Cancer (NSCLC) (Now Available) (ID 5044)

      S. Popat

      • Abstract
      • Slides

      Background:
      Alectinib is an FDA-approved ALK TKI, for treatment of patients with ALK+ metastatic NSCLC who have progressed on, or are intolerant to, crizotinib. Systemic and CNS efficacy was demonstrated in two single-arm, phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]). We report the pooled systemic efficacy and safety analysis of alectinib from 2016 cut-offs 22 January, NP28761 and 1 February, NP28673.

      Methods:
      Patients were ≥18 years, had locally advanced or metastatic ALK+ NSCLC [FDA-approved FISH test] and had progressed on, or were intolerant to, crizotinib. Patients received oral alectinib 600mg twice daily until disease progression, death or withdrawal. The pooled analysis assessed objective response rate (ORR) by an independent review committee (IRC) using RECIST v1.1 (primary endpoint in both studies); disease control rate (DCR); duration of response (DOR); progression-free survival (PFS); overall survival (OS); and safety.

      Results:
      The pooled dataset included 225 patients, (n=138 NP28673; n=87 NP28761). Median age was 53 years, 60% of patients had baseline CNS metastases and 77% had received prior chemotherapy. The response-evaluable (RE) population by IRC included 189 patients (84%). Median follow-up was 18.8 months (0.6–29.7). In the RE population (n=189) ORR by IRC was 51.3% (95% CI 44.0–58.6; all partial responses), a DCR of 78.8% (95% CI 72.3–84.4), with a median DOR of 14.9 months (95% CI 11.1–20.4) after 58% of events. In patients with prior chemotherapy (n=148), IRC ORR was 49.3% (95% CI 41.0–57.7); DCR: 79.1% (95% CI 71.6–85.3); median DOR: 14.9 months (95% CI 11.0–21.9) after 59% of events. In patients who were chemotherapy-naïve (n=41), IRC ORR was 58.5% (95% CI 42.1–73.7); DCR: 78.0% (95% CI 62.4–89.4); median DOR: 11.2 months (95% CI 8.0–NE) after 54% of events. In the total pooled population (n=225) median PFS by IRC was 8.3 months (95% CI 7.0–11.3) after 69% of events and median OS was 26.0 months (95% CI 21.4–NE) after 43% of events. Grade ≥3 adverse events (AEs) occurred in 40% of patients and the most common were dyspnoea (4%), elevated levels of blood creatine phosphokinase (4%) and alanine aminotransferase (3%). The mean dose intensity was 94.6%. Fourteen patients withdrew due to AEs; 20.9% had AEs leading to dose interruptions/modification.

      Conclusion:
      This pooled analysis confirmed alectinib has robust systemic efficacy with a durable response in this population and in patients with or without prior chemotherapy. Alectinib had an acceptable safety profile.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      P3.02b-046 - Afatinib Benefits Patients with Confirmed/Suspected EGFR Mutant NSCLC, Unsuitable for Chemotherapy (TIMELY Phase II Trial) (Now Available) (ID 4195)

      S. Popat

      • Abstract
      • Slides

      Background:
      Afatinib is licensed for EGFR-mutant NSCLC without prior TKI therapy, but its efficacy and toxicity in patients unsuitable for platinum-doublet chemotherapy is unknown. One previous study suggested that TKIs could benefit medically unfit EGFR-mutant East Asian patients. We conducted the first such study in a Western population.

      Methods:
      Single arm phase-II trial. Eligible patients with histologically confirmed NSCLC, comorbidities precluding chemotherapy, with either: (i) confirmed EGFR-mutation and PS 0-3, or (ii) suspected EGFR-mutation (no suitable tissue for genotyping or failed genotyping), but never/former-light smoker, adenocarcinoma and PS 0-2. Patients received oral afatinib (20-40mg daily) until disease progression/toxicity. CT scans performed 4 weeks after starting treatment then every 8 weeks in first year until progression, thereafter every 12 weeks. Primary endpoint was 6-month RECIST-defined progression-free-survival (target 30%).

      Results:
      39 patients were recruited across 14 UK centres (March 2013-August 2015). Median age 72 years (range 36-90); 30 females, 9 males; 20 confirmed and 19 suspected EGFR-mutant; 8 former and 11 never smokers (among suspected EGFR-positives); 1,1,7,30 in each stage IA,IIIA,IIIB,IV; and 27 PS 0-1, 12 PS 2-3. As of July 2016, 7 patients were still taking afatinib (median time on drug 11 months, range 10-16), and 11 stopped for toxicity. 23/39 patients had at least one grade ≥3 afatinib-related toxicity (all gd3, except two with gd4 [sepsis and hypokalemia], one fatal pneumonitis), mainly: n=13 diarrhoea; n=4 vomiting; n=3 dehydration; n=3 mouth ulcer, all expected for afatinib, and unsurprising in this unfit group. The table shows efficacy. 6-month PFS rate (58%) far exceeded the 30% target; similarly for patients with confirmed (74%) or suspected (41%) EGFR-mutation.

      Efficacy (26 PFS events, 21 deaths)
      Rate (95%CI) at month Alive & progression-free Overall-survival
      All patients (n=39)
      6 58% (43-74) 74% (60-88)
      12 34% (18-50) 64% (48-80)
      Median, months (95%CI) 7.9 (4.6-10.2) 15.5 (10.9-25.1)
      Confirmed EGFR mutant (n=20)
      6 74% (55-94) 85% (69-100)
      12 47% (24-70) 85% (69-100)
      Median, months 10.2 (5.9-not estimable) Not reached
      Suspected EGFR mutant (n=19)
      6 41% (19-64) 63% (41-85)
      12 21% (0.1-41) 42% (18-66)
      Median, months 4.4 (2.6-8.0) 10.9 (3.9-21.0)
      Lower 95%CI for all 6-month PFS-rates exceed the pre-specified 15% minimum rate.
      13% patients survived ≥18 months. 23% patients did not progress <12 months


      Conclusion:
      The toxicity rate was higher compared to that in fitter patients, but afatinib seems to improve PFS and OS in unfit EGFR-mutant NSCLC, and in suspected-positive patients who would otherwise only receive best supportive care.

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    P3.05 - Poster Session with Presenters Present (ID 475)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Palliative Care/Ethics
    • Presentations: 1
    • Now Available
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      P3.05-006 - Anxiolytic Effect of Acupuncture in a Phase II Study of Acupuncture and Morphine for Dyspnoea in Lung Cancer and Mesothelioma (Now Available) (ID 4056)

      S. Popat

      • Abstract
      • Slides

      Background:
      Anxiety is common in cancer patients. Treatments include psychological therapies, psychotropic drugs and complementary therapies including acupuncture. Evidence for acupuncture for treating anxiety in cancer patients is lacking.

      Methods:
      A single-centre, randomised phase II study of patients with non-small cell lung cancer (NSCLC) or mesothelioma assessed the use of acupuncture for control of dyspnoea. One-hundred and seventy-three patients were randomised to acupuncture alone (A), morphine alone (M) or the combination (AM). Acupuncture was administered at upper sternal, thoracic paravertebral, trapezius trigger points and thumb points (LI4). Manubrial semi-permanent acupuncture studs were inserted for patient massage when symptomatic. Arm A patients received rescue morphine.

      Results:
      There was no statistically significant difference in the dyspnea control rate between arms. Secondary outcomes included measures of anxiety. The trial population had high levels of anxiety and depression with all patients having depression hospital anxiety and depression (HAD) score of >7 and 71.5% having anxiety HAD score of >7. VAS relaxation improved in arms A (1.06 points) and AM (1.48 points) compared to arm M (-0.19 points; p<0.001). Of those patients whom were anxious at baseline (HAD anxiety > 7), 78% of arm AM, 52% of arm A and 38% of arm M achieved a 1.5 point improvement in VAS relaxation (chi-squared p=0.002). At 7 days, the Lar anxiety score improved in arm A (1.5 points), arm AM (1.2 points) with no change in arm M (0 points, p=0.003).

      Conclusion:
      Acupuncture has an anxiolytic effect seen on two scoring systems in this trial. Further research in this area is warranted.

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