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Edward S Kim



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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): Edward S Kim

      • 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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      P1.01-28 - Impact of Afatinib Dosing on Safety and Efficacy Real-World in Patients with EGFR Mutation-Positive Advanced NSCLC (ID 13276)

      16:45 - 18:00  |  Author(s): Edward S Kim

      • Abstract
      • Slides

      Background

      Tolerability-guided dose adjustment of afatinib reduced incidence and severity of adverse drug reactions (ADRs) without affecting efficacy in the LUX-Lung (LL) studies in patients with EGFR mutation-positive (EGFRm+) NSCLC. We evaluated the impact of modifying the recommended starting dose of afatinib (40mg) on efficacy and safety in a real-world setting.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This non-interventional, observational, multi-country/site study used medical records of TKI-naïve patients with EGFRm+ (Del19/L858R) NSCLC treated with first-line afatinib. Primary outcomes were % patients with ADRs by severity, time on treatment (TT), and time to progression (TTP), relative to LL3. Secondary outcomes were % of patients with/reasons for modified starting dose.

      4c3880bb027f159e801041b1021e88e8 Result

      228 patients from 13 countries were included. Baseline characteristics were generally similar to LL3, but with more Del19 patients (78% vs 49%) and fewer Asian patients (44% vs 72%); 12% had ECOG PS 2–3. 31% of patients received an afatinib starting dose of <40 mg; 20% of patients starting with <40 mg increased their dose during the study. 67% of 40 mg starters underwent dose reductions, with 86% of those occurring in the first 6 months. Dose reductions were more frequent in females, Eastern Asian patients, and those with lower body weight. The main reason for dose modification was ADRs. In <40 mg starters, overall ADR incidence was similar to that in ≥40 mg starters, with fewer G3 (17% vs 25%) and no G4 ADRs. There were no new safety signals, and fewer ≥G3 ADRs and serious adverse events (SAEs) than in LL3 (28% vs 49% and 5% vs 14%, respectively). >60% of patients received medications to treat diarrhea and manage skin AEs. Median TT and TTP were 18.7 months and 20.8 months, respectively, and were not impacted by reduced starting dose or dose modification (19.4/17.7/19.5 and 25.9/20.0/29.0 months for patients who started on ≤30 mg/reduced to <40 mg/remained on ≥40 mg, respectively). The efficacy of afatinib was demonstrated across all patient subgroups analysed (ECOG PS 0/1 vs 2/3, age <75 yrs vs ≥75 yrs, EGFR mutational status); TT and TTP were significantly longer in patients with ECOG PS0/1 versus PS2/3.

      8eea62084ca7e541d918e823422bd82e Conclusion

      As in pivotal trials, dose adjustments with afatinib in real-world practice reduced the frequency and intensity of ADRs without impacting efficacy. RealGido demonstrated long TT/TTP regardless of afatinib dose adjustment or reduced starting dose, and an acceptable safety profile. The results highlight the benefit of tailoring afatinib dose based on individual patient characteristics and ADRs to optimize outcomes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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