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Byoung Chul Cho



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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA04.07 - Mutations Associated with Sensitivity or Resistance to Immunotherapy in mNSCLC: Analysis from the MYSTIC Trial (Now Available) (ID 901)

      15:15 - 16:45  |  Author(s): Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Background

      In the Phase 3 MYSTIC study (NCT02453282), blood tumour mutational burden, at various thresholds from ≥12 to ≥20 mut/Mb (bTMB≥20), has been associated with improved OS and PFS with first-line durvalumab (D; anti-PD-L1) +/- tremelimumab (T; anti-CTLA-4) versus platinum-based chemotherapy (CT). Specific gene mutations have been associated with resistance (STK11 and KEAP1) or sensitisation (ARID1A) to anti-PD-(L)1 monotherapy. However, the relationship between gene alterations and response to anti-PD-(L)1 ± anti-CTLA-4 are not well characterised. Here we explore associations between mutations and survival outcomes in the MYSTIC patient population.

      Method

      Circulating tumour DNA from baseline blood specimens was profiled using the GuardantOMNI platform. Samples were available from 1003 patients (89.7% of ITT; 943 mutation-evaluable). Survival outcomes were analysed in patients with (m) or without (wt) non-synonymous somatic mutations in STK11, KEAP1, or ARID1A.

      Result

      In the mutation-evaluable population, STK11m, KEAP1m, and ARID1Am frequencies were 16%, 18% and 12%, respectively (19%, 20%, and 11% [nonsquamous]; 7%, 13%, and 15% [squamous]). Across treatment arms, patients with STK11m or KEAP1m had a shorter median OS (mOS) than patients with STK11wt (D, 10.3 vs 13.3 mo; D+T, 4.4 vs 11.3 mo; CT, 6.7 vs 13.1 mo) or KEAP1wt (D, 7.6 vs 14.6 mo; D+T, 9.2 vs 11.3 mo; CT, 6.3 vs 13.3 mo) mNSCLC. In the D+T arm, patients with ARID1Am had a longer mOS than patients with ARID1Awt mNSCLC (D, 8.6 vs 13.7 mo; D+T, 23.2 vs 9.8 mo; CT, 10.6 vs 12.4 mo). Additional mutational analyses will be presented.

      Conclusion

      In these analyses from the MYSTIC study, poorer outcomes were observed across treatment arms in patients with mNSCLC and mutations in STK11 or KEAP1 compared with those without the corresponding mutations. In patients receiving D+T, ARID1Am was associated with survival benefits compared with ARID1wt. These data are exploratory and require further validation.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-94 - JNJ-61186372, an EGFR-cMet Bispecific Antibody, in EGFR Exon 20 Insertion-Driven Advanced NSCLC (ID 1802)

      09:45 - 18:00  |  Presenting Author(s): Byoung Chul Cho

      • Abstract

      Background

      JNJ-61186372 (JNJ-372), a bispecific antibody that targets the EGFR and cMet receptors, is currently being explored in a first-in-human study in patients with non-small cell lung cancer (NSCLC). Preliminary JNJ-372 clinical data have suggested activity in patients with diverse EGFR mutations, including Exon 20 insertions (Exon20ins), which carry primary resistance to tyrosine kinase inhibitors (TKIs; Cho BC et al. Ann Oncol 2018;29(suppl_8):mdy292.118). To better understand the mechanism of JNJ-372 activity in this patient population, we conducted preclinical studies exploring the activity of JNJ-372 in different EGFR Exon20ins models.

      Method

      BaF3 cells were transduced with retrovirus expressing various EGFR Exon20ins, as described. Cell titer glo assays were used to measure cell proliferation; western blot analysis was used to study EGFR and cMet signaling cascade events. For mouse tumor models, JNJ-372 was administered i.p. daily at 10mg/kg or 30mg/kg. Referenced patients with Exon20ins disease were administered 1050mg JNJ-372 i.v. weekly for the first 4-week cycle, then biweekly for each subsequent cycle (Park et al. J Thorac Oncol 2018;13:S344-5).

      Result

      In a dose-dependent manner, JNJ-372 inhibited the growth of BaF3 cells harboring diverse Exon20ins mutations. Mechanistic assays revealed down-modulation of EGFR and cMet receptor levels and decreases in phospho-EGFR and cMet, as well as inhibition of downstream signaling events including p-ERK, p-Akt and p-S6. Cleaved caspase-3 and BIMEL were upregulated at antiproliferative doses, suggesting caspase-mediated cell death as part of the mechanism of action. JNJ-372 demonstrated corresponding antitumor activity in PDC and PDX models harboring different Exon20ins mutations with concomitant inhibition of EGFR signaling and induction of apoptosis. In the ongoing first-in-human trial, two patients with Exon20ins disease (P772_H773insPNP and H773delinsNPY) continue to demonstrate durable clinical benefit (13 and 22 cycles), with maximum tumor reductions of –23% and –63%, respectively, as demonstrated by baseline and postbaseline CT scans.

      Conclusion

      In EGFR Exon20ins disease, JNJ-372 demonstrates preclinical antitumor activity and initial clinical responses. Preclinically, JNJ-372 induces antitumor activity in models of EGFR Exon20ins disease by decreasing EGFR and cMet receptor levels, inhibiting downstream signaling cascades, and activating apoptotic signaling. These results provide an understanding of the activity of JNJ-372 being observed in the ongoing clinical study and support the continued examination of JNJ-372 in NSCLC patients with Exon20ins and other EGFR mutations.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-02 - CANOPY-A: A Phase 3 Study of Canakinumab as Adjuvant Therapy in Patients with Surgically Resected NSCLC (ID 1569)

      10:15 - 18:15  |  Author(s): Byoung Chul Cho

      • Abstract

      Background

      Overexpression of interleukin (IL)-1β has been described in solid tumors, including lung. IL-1β can promote angiogenesis, tumor invasiveness, and induces tumor-associated immunosuppression through myeloid-derived suppressor cell (MDSC) accumulation in tumors. Pre-clinical data has shown that IL-1β inhibition reduced tumor growth, by limiting pro-tumorigenic inflammation and polarization of MDSCs into M1 phenotype. Canakinumab is a human monoclonal antibody with high affinity and specificity for IL-1β. Recently, it was found that canakinumab was associated with a significant and dose-dependent reduction in incidence and mortality from lung cancer based on CANTOS study.

      Method

      CANOPY-A (NCT03447769) is a phase III, randomized, double-blind, placebo-controlled study designed to evaluate efficacy and safety of adjuvant canakinumab versus placebo in patients with surgically resected NSCLC. This trial will enroll adult patients, with completely resected (R0) AJCC/UICC v.8 stages II-IIIA and IIIB (T >5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or neoadjuvant radiotherapy is not permitted. Approximately 1500 patients will be randomized 1:1 to receive canakinumab (200 mg Q3W, s.c) or placebo (Q3W, s.c.) for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, death, or loss to follow-up. Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region. The primary objective is disease-free survival, per investigator assessment. Secondary objectives include overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient-reported outcomes. Enrollment is ongoing.CANOPY-A (NCT03447769) is a phase III, randomized, double-blind, placebo-controlled study designed to evaluate efficacy and safety of adjuvant canakinumab versus placebo in patients with surgically resected NSCLC. This trial will enroll adult patients, with completely resected (R0) AJCC/UICC v.8 stages II-IIIA and IIIB (T >5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or neoadjuvant radiotherapy is not permitted. Approximately 1500 patients will be randomized 1:1 to receive canakinumab (200 mg Q3W, s.c) or placebo (Q3W, s.c.) for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, death, or loss to follow-up. Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region. The primary objective is disease-free survival, per investigator assessment. Secondary objectives include overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient-reported outcomes. Enrollment is ongoing.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-59 - Osimertinib in EGFR T790M Advanced NSCLC: Analysis of Uncommon/Complex EGFR Mutations in a Real-World Study (ASTRIS) (ID 1263)

      10:15 - 18:15  |  Author(s): Byoung Chul Cho

      • Abstract
      • Slides

      Background

      The challenges of treating uncommon/complex EGFR mutations impact treatment decisions in clinical practice. Osimertinib is a third-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-TKI sensitising (EGFRm) and EGFR T790M mutations and has demonstrated efficacy in NSCLC CNS metastases. ASTRIS is an ongoing, international, real-world study of osimertinib in EGFR T790M positive advanced NSCLC (NCT02474355). We report a subset-analysis of patients with uncommon/complex mutations.

      Method

      Patients with stage IIIB/IV T790M positive NSCLC previously treated with an EGFR-TKI were enrolled and received osimertinib 80 mg once-daily. Progression-free survival (PFS), clinical response and time to treatment discontinuation (TTD) were analysed in both full analysis set (FAS) and patients with uncommon/complex EGFR mutations. Uncommon mutation combinations included: T790M+G719X, T790M+S768I, T790M+ex20ins; complex mutations included T790M+two or more mutation(s).

      Result

      From 18 September 2015 to 15 October 2018 data cut-off, 3015 patients across 16 countries had received ≥1 dose of osimertinib (FAS), 53(2%) of these patients had uncommon/complex EGFR mutations. Baseline demographics between this patient subset and the FAS were similar (Asian: 55%/69%; female: 57%/64%; median age: 59 [30–80] years/62 [range, 27–92]; WHO performance status 2: 9%/11%, respectively). Baseline EGFR mutation status at enrolment of the FAS is shown in Table 1. Clinical outcomes appeared to be lower in the uncommon/complex mutation subset than in the FAS: response rate (measured in a FAS subset with ≥1 documented response assessment) was 50% [95% CI, 35.2, 64.8] in the uncommon/complex mutation group, and 57% [55.2, 58.9] in the FAS; median PFS was 8.1 [5.4, 10.1] and 11.1 [11.0, 12.0] months; median TTD was 9.0 [6.7, 11.5] and 13.5 [12.6, 13.9] months, respectively. Overall survival data are immature.

      astris table 1.png

      Conclusion

      Whilst clinical outcomes appeared to be lower in the uncommon/complex mutation subset than the FAS, they were favourable and support use of osimertinib 80mg in this heterogeneous population.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)

      08:00 - 10:15  |  Author(s): Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Background

      No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.

      Method

      This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.

      Result

      As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.

      Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.

      The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

      Conclusion

      LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

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