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Stephen V Liu



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    MA02 - Improving Outcomes for Patients with Lung Cancer (ID 895)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 201 BD
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      MA02.01 - ROS1 Gene Rearrangements Are Associated with an Exaggerated Risk of Peri-Diagnosis Thromboembolic Events (ID 12442)

      10:30 - 10:35  |  Author(s): Stephen V Liu

      • Abstract
      • Presentation
      • Slides

      Background

      Based on clinical observation, we hypothesized that ROS1 gene-rearranged non-small cell lung cancer (ROS1+ NSCLC) has a higher than expected thromboembolic event (TEE) rate. A multicenter, retrospective cohort study of TEE in advanced ROS1+, KRAS+, ALK+ and EGFR+ NSCLC was conducted.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Venous (DVT / PE) and arterial (MI/TIA/CVA) TEE within +/- 365 days of diagnosis of ROS1+, KRAS+, ALK+ or EGFR+ advanced NSCLC at 4 academic centers in USA and China from October 2002 to January 2018 were captured. The primary endpoint was the incidence of TEE in ROS1+ compared to KRAS+ NSCLC as a control group within +/- 90 days of diagnosis. Secondary endpoints compared TEE incidence between ROS1+ and ALK+, and ROS1+ and EGFR+. Fine-Gray Model was used to detect differences in TEE incidence while accounting for death as a competing risk.

      4c3880bb027f159e801041b1021e88e8 Result

      105 ROS1+, 101 ALK+, 112 EGFR+, and 114 KRAS+ NSCLC patients were enrolled. Incidence rate of TEE within +/- 90 days of diagnosis was 30.5% (32/105), 12.9% (13/101), 7.1% (8/112), and 12.3% (14/114) in the respective molecular cohorts. Compared to the ROS1+ cohort, the risk of TEE was significantly lower in the three other cohorts (KRAS+ HR 0.334, 95% CI: 0.18-0.62, p=0.001; ALK+ HR 0.357, 95% CI: 0.188-0.68, p=0.002; EGFR+ HR 0.193, 95% CI: 0.089-0.421, p<0.001) (Figure 1). First event TEEs were venous as opposed to arterial in 59.5% (22/37) ROS1+, 87.1% (27/31) ALK+, 80.6% (25/31) EGFR+, and 80% (16/20) KRAS+ cases. The median time (Interquartile Range) to TEE from the time of diagnosis for ROS1+/ALK+/EGFR+/ KRAS+ was 0 days (-6.75 to 7.0), 0 days (-20.0 to 35.0), 0.50 days (-43.7 to 21.3), and 13 days (0.49 to 32.0), respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Among common molecular subtypes of NSCLC, ROS1+ oncogene is associated with a significantly higher risk of developing TEE within +/- 90 days of advanced NSCLC diagnosis.

      figure 1 ros1 90 day.tif

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA21 - Molecular Subtyping, CBL3, and Non Coding RNA (ID 924)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 205 BD
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      MA21.01 - Cbl Mutations (mt) as Important Mediators of Oncogenic RTK Signaling in NSCLC (ID 12377)

      15:15 - 15:20  |  Author(s): Stephen V Liu

      • Abstract
      • Presentation
      • Slides

      Background

      Casitas B-lineage lymphoma (Cbl), an E3 ubiquitin ligase, selectively regulates receptor tyrosine kinase (RTKs), e.g. EGFR, MET. Cbl loss of function (LOF) mt can can prevent ubiquitination of EGFR and potentiate EGFR signaling. Cbl mt have been described in cases of EGFR-TKI resistance but because EGFR signaling can activate signaling of fusion kinases and other ERBB family members, the implications of Cbl mt warrant broad characterization

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Biopsies from NSCLC pts tested with Next-Generation Sequencing on a 592-gene panel (Illumina NextSeq, ArcherDx) were analyzed retrospectively. Cbl domains of interest: LOF [tyrosine kinase binding (TKB), linker (L), ring finger (RF) and ubiquitin-associated (UBA)] and unclear function [N-terminal (NT) and proline-rich (PR)]. Chi-square analysis was used to compare co-alteration rates.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 4,484 NSCLC pts’ tumors (50% M/50% F; age range: 20-90, profiled 11/16-12/17), 222 had Cbl mt (5%), of which 65 (29% of mt, 1.4% of cohort) were LOF: 13% TKB (29), 7% L (15), 5% RF (13), and 3.6% UBA (8). Cbl LOF mt were primarily observed in adenocarcinomas (48/65), metastatic sites (35/65) and equal between M/F. Cbl mt in other domains: 23% PR (51) and 14% NT (31). Co-mutation distribution is shown in table below. Cbl LOF mt that disrupt Cbl function (H398N, S407C, C396R, Y371D, T377I/H) or interactions w/ RTK (S216G, P288S, F325L) co-occurred w/ oncogenes in nine pts: EGFR (L858R, S768I, exon19del+T790M), ERBB3 (V104M, G284R), EML4-ALK (n = 2), CD74-ROS1 (n = 1), and HER2 (D1125E).

      LOF

      WT

      Oncogene

      pos/total (%)

      P

      ERBB3 mt

      2/65 (3.1)

      6/4329 (0.1)

      < 0.001

      EGFR mt

      3/65 (4.6)

      491/4329 (11.3)

      0.08

      METex14

      0/65 (0)

      100/4329 (2.3)

      0.2

      ROS

      1/60 (1.7)

      22/3976 (0.6)

      0.2

      KRAS mt

      14/65 (21)

      1242/3086 (29)

      0.2

      BRAF V600E

      0/65 (0)

      56/4312 (1.3)

      0.3

      ALK

      2/60 (3.3)

      97/4175 (2.3)

      0.6

      ERBB4 mt

      0/65 (0)

      6/4329 (0.1)

      0.7

      HER2 mt

      1/65 (1.5)

      58/4328 (1.3)

      0.9

      8eea62084ca7e541d918e823422bd82e Conclusion

      Regulation of RTK signaling through Cbl-mediated degradative pathways represents an important node for dysregulation in cancer. Presence of Cbl LOF mt in oncogene-driven tumors may provide a bypass signaling-enabled molecular landscape. Further analysis of the role of Cbl LOF mt in de-novo or acquired TKI resistance in pts identified is planned.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • 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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      P1.01-47 - Phase I/II Trial of Dasatinib and Osimertinib in Patients with Advanced EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 14220)

      16:45 - 18:00  |  Author(s): Stephen V Liu

      • Abstract

      Background

      The presence of epidermal growth factor receptor (EGFR) mutations is associated with sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but a subset of patients (pts) do not respond to EGFR-TKIs or have very short duration of response, suggesting intrinsic resistance. Moreover, acquired resistance to EGFR-TKIs is inevitable for most patients. We showed that overexpression of Cripto-1, a member of the EGF–CFC family, contributes to the development of intrinsic resistance to EGFR-TKIs through the activation of the Src pathway and that the combination of EGFR-TKI therapy and Src inhibition works synergistically in preclinical models.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This was an open-label, phase I/II trial of osimertinib and dasatinib, a multi-kinase inhibitor with activity against Src, in EGFR-TKI treatment-naïve pts with advanced EGFR-mutant NSCLC (NCT02954523). Pts with pleural or pericardial effusions at study entry were excluded. The primary endpoint of the phase I part was to establish a safe and tolerable phase II dose of osimertinib and dasatinib. Dose escalation included 2 dose levels (dose level 1: osimertinib 80 mg QD, dasatinib 50 mg BID, dose level 2: osimertinib 80 mg QD, dasatinib 70 mg BID). In addition, 2 dose levels below the starting dose level could be explored if dose reductions were necessary.

      4c3880bb027f159e801041b1021e88e8 Result

      7 pts (4 at dose level 1, 3 at dose level 2) were enrolled to date. None of them had dose limiting toxicities (DLTs), but given frequent dose reductions and toxicities beyond the DLT period at dose level 2, dose level 1 is being further assessed (up to 6 pts at dose level 1). The most common treatment-related adverse events (TRAEs) included pleural effusion (n=6), AST elevation (n=5), ALT elevation (n=5), rash (n=5), and diarrhea (n=4), most of which were grade 1 or 2. 3/2/1 pts had grade 1/2/3 pleural effusion, respectively. 4 pts had grade 3 TRAEs, which included pleural effusion, fatigue, neutropenia, anemia, and headaches. No grade 4 or 5 toxicities were observed. Among 6 evaluable pts, 4 confirmed partial response (PR)/1 unconfirmed PR/1 stable disease were observed. Responses were durable with all the PRs ongoing.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The combination of dasatinib and osimertinib showed no new safety signals and demonstrated evidence of anticancer activity. Treatment-related toxicities were manageable with dasatinib dose reductions and supportive measures. The safety and efficacy of dasatinib and osimertinib will continue to be explored.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 961)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.12-03 - Phase I/II Trial Of 177Lu-DOTA0-Tyr3-Octreotate (Lutathera) And Nivolumab for Patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC) (ID 12015)

      16:45 - 18:00  |  Author(s): Stephen V Liu

      • Abstract

      Background

      Despite initial sensitivity to chemotherapy, most patients with ES-SCLC relapse quickly. Studies have shown that somatostatin receptors are expressed in SCLC. Lutathera is a 177Lutetium-labeled somatostatin analog that targets somatostatin receptor positive cancer cells, which is approved for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Lutathera and nivolumab, an anti-PD-1 antibody, may have synergistic effects on the generation of anticancer immunity and this combination given as maintenance treatment may delay progression in patients with ES-SCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a multicenter phase I/II trial of Lutathera and nivolumab in patients with ES-SCLC (NCT03325816). The phase I portion includes patients with either relapsed/refractory ES-SCLC or non-progressing ES-SCLC after first-line platinum-based chemotherapy, or advanced grade I-II pulmonary neuroendocrine tumors. The primary objective is to determine the recommended phase 2 dose (RP2D) of Lutathera when given with nivolumab. The phase I portion follows the standard 3+3 design, assessing two dose levels (dose level 1: Lutathera 3.7 GBq Q8W for 4 doses with nivolumab 240 mg Q2W; dose level 2: Lutathera 7.4 GBq Q8W for 4 doses with nivolumab 240 mg Q2W). In the phase II portion, patients with ES-SCLC not progressing after completion of first-line platinum-based chemotherapy are randomly assigned to either maintenance combination with Lutathera and nivolumab or observation. The primary endpoint for the phase II part is progression-free survival. Crossover is allowed at progression for those assigned to the observation group.

      4c3880bb027f159e801041b1021e88e8 Result

      Three patients were enrolled at dose level 1. All patients had ES-SCLC at study entry with 2 patients with progressive disease and 1 patient with stable disease after platinum-based chemotherapy. No dose-limiting toxicities (DLTs) were observed at dose level 1. Treatment-related adverse events include anemia (n=1), arthralgia (n=1), and non-cardiac chest pain (n=1), all of which were grade 1 events per CTCAE 4.03. At first tumor assessment performed 8 weeks after starting treatment, one patient achieved a partial response and two patients had progressive disease per RECIST. Assessment of dose level 2 is underway. Updated safety and efficacy results will be presented.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Early evidence from the phase I/II trial of Lutathera and nivolumab suggests that the combination is safe, well tolerated and showed initial signs of antitumor activity. The safety and efficacy of the combination will be further explored.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • 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 (ID 12892)

      09:00 - 09:10  |  Presenting Author(s): Stephen V Liu

      • 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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