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Pasi A Jänne



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    MS23 - What's New in Targeted Therapy? (ID 801)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 106
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      MS23.01 - Novel Combinations of Targeted Therapies (Now Available) (ID 11496)

      10:30 - 10:45  |  Presenting Author(s): Pasi A Jänne

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      Information from this presentation has been removed upon request of the author.

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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
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
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      OA02.07 - Updated Results of Phase 1 Study of DS-8201a in HER2-Expressing or –Mutated Advanced Non-Small-Cell Lung Cancer (Now Available) (ID 13325)

      11:35 - 11:45  |  Author(s): Pasi A Jänne

      • Abstract
      • Presentation
      • Slides

      Background

      DS-8201a is a HER2-targeting antibody-drug conjugate with a novel peptide-based cleavable linker, a topoisomerase I inhibitor payload, and a high drug-to-antibody ratio (7 to 8). In preclinical studies, DS-8201a showed broad antitumor activity, in a wide range of tumors. The ongoing phase 1 trial has a dose-escalation (part 1) and -expansion (part 2) and includes subjects with advanced breast cancer, gastric cancer, and other HER2-expressing/-mutated solid tumors. Here, we present updated results for subjects with HER2-expressing or -mutated non-small cell lung cancer (NSCLC).

      Method

      Subjects with HER2-expressing (defined as IHC ≥1+ or amplified) or –mutated (detected by NGS or other platforms) NSCLC were eligible to enroll. HER2 expression and mutation were assessed using archival tissue. Adverse events (AEs), objective response rate (ORR), disease control rate (DCR: CR + PR + SD), and duration of response (DOR) were assessed.

      Result

      [Results will be updated for presentation at meeting] As of Apr 18, 2018, 12 subjects with HER2-expressing and/or -mutated NSCLC received ≥1 dose of DS-8201a at 6.4 mg/kg. Median age was 58.5 y with median of 3 prior regimens. At data cutoff, 8 of 12 (66.7%) subjects remain on treatment. HER2 IHC status was available for 7 subjects. Median duration of treatment was 3.66 months (range 0.69, 14.19). Eight of 10 (80.0%) subjects with ≥1 post-baseline scan (ps) experienced tumor shrinkage (100.0% of them at 1st ps at 6 weeks). Overall, confirmed ORR and DCR in the evaluable subjects was 5 of 8 (62.5%) and 6 of 8 (75.0%), respectively. Among subjects with HER2 IHC 2+ or IHC 3+ expression, 2 of 5 (40.0%) had a PR. Overall, median DOR was 11.5 months (range 0.03+, 11.53). Three of 12 (25.0%) subjects experienced a grade ≥3 AE. Common AEs included decreased appetite 66.7% (0.0% grade ≥3), nausea 58.3% (0.0% grade ≥3), alopecia 41.7% (0.0% grade ≥3), and fatigue 41.7% (0.0% grade ≥3). One fatal case of interstitial lung disease was reported in this subgroup.

      Conclusion

      DS-8201a demonstrated promising antitumor activity in heavily pretreated NSCLC subjects.

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    OA05 - Clinical Trials in IO (ID 899)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 106
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      OA05.01 - Efficacy/Safety of Entinostat (ENT) and Pembrolizumab (PEMBRO) in NSCLC Patients Previously Treated with Anti-PD-(L)1 Therapy (Now Available) (ID 12922)

      13:30 - 13:40  |  Author(s): Pasi A Jänne

      • Abstract
      • Presentation
      • Slides

      Background

      Treatment options are limited for lung cancer patients whose disease has progressed on anti-PD-(L)1 therapy. HDAC inhibitors may synergize with PD-(L)1 inhibition to overcome resistance. We report the interim results of a Phase 2 trial of entinostat (ENT), a class I selective histone deacetylase (HDAC) inhibitor, plus pembrolizumab (PEMBRO) in patients with NSCLC previously treated with anti-PD-(L)1 therapy.

      Method

      ENCORE-601 is an open-label study evaluating the combination of ENT + PEMBRO in patients with recurrent or metastatic NSCLC and prior progression on anti-PD-1/PD-L1 therapy. Patients were eligible irrespective of histology or baseline PD-L1 expression. Patients were treated with ENT 5 mg PO weekly and PEMBRO 200 mg IV Q3W. The primary endpoint was ORR as assessed by irRECIST. Tumor biopsies and blood samples for immune correlates were taken prior to and during treatment in a subset of patients. A total of 70 patients will be enrolled.

      Result

      Of 57 patients with anti-PD-(L)1 resistant/refractory NSCLC, the confirmed objective response rate with ENT + PEMBRO was 11% (6 of 57, 95% CI: 4-21%). Of 49 patients with post-baseline tumor measurements, 47% had at least some reduction in tumor. Anti-PD-(L)1 therapy was the most recent line of therapy in 38 of 57 patients, and the median time from last dose of prior anti-PD-(L)1 to study entry was 67 days. The median duration of response with ENT + PEMBRO was 5 months, with the longest over 14 months. Of the 6 responders, four were PD-L1 negative at study entry. Response was associated with a higher median baseline level of peripheral classical monocytes (CD14+CD16-HLA-DRhi) with 16.9% of total live PBMCs in responders (n=6) compared to 8.2% in non-responders (n=45). 5 patients (8.8%) experienced Grade 3/4 related irAEs (2 events each of pneumonitis and colitis, 1 event of hyperthyroidism). In addition, 19 patients (33.3%) experienced other Grade 3/4 related AEs with only fatigue, anemia, hypophosphatemia, and hyponatremia occurring in more than 1 patient. Additional correlative analyses to identify biomarkers of response, including whole exome sequencing and RNAseq, are in progress.

      Conclusion

      ENT + PEMBRO demonstrated anti-tumor activity and acceptable safety in patients with NSCLC who have progressed on prior PD-(L)1 blockade. Ongoing analysis of immune correlates may identify strategies for effective patient selection.

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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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      P1.01-41 - A Phase 2 Study of DS-8201a in HER2-Overexpressing or -Mutated Advanced Non-Small-Cell Lung Cancer (ID 12939)

      16:45 - 18:00  |  Presenting Author(s): Pasi A Jänne

      • Abstract
      • Slides

      Background

      Approximately 30% of non-small-cell lung cancers (NSCLC) are human epidermal growth factor receptor 2 (HER2)-overexpressing (immunohistochemistry [IHC] 2+ or 3+) and approximately 2% have HER2-activating mutations. Although HER2 is considered a potential target for NSCLC, no HER2-targeted therapies are approved for the treatment of NSCLC. DS-8201a is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload (DXd) by a cleavable peptide-based linker, and with a high drug-to-antibody ratio of 7 to 8. In preliminary results from the ongoing phase 1, DS8201-A-J101 trial, DS-8201a (5.6 and 6.4 mg/kg) had a confirmed objective response rate (ORR) of 20.0% (1/5) in HER2-expressing NSCLC (Tsurutani et al, ESMO 2017). In addition to NSCLC, DS-8201a also showed substantial antitumor activity with a manageable safety profile in multiple other HER2-expressing tumors such as breast, gastric, and colorectal cancers.

      Method

      This multicenter, open-label, 2-cohort, phase 2 study will assess the efficacy and safety of DS-8201a in subjects with HER2-overexpressing or -mutated unresectable and/or metastatic nonsquamous NSCLC that is relapsed/refractory to standard treatment or for which no standard treatment is available (NCT03505710). Overall, approximately 80 subjects will be enrolled; 40 subjects in each of 2 cohorts (cohort 1: HER2-overexpressing [IHC 3+ or IHC 2+]; cohort 2: HER2-mutated including exon 20 insertions and single-nucleotide variants in kinase, transmembrane, and extracellular domains [eg, L755S, V659E, S310F]). To be eligible for inclusion in cohort 1, HER2-overexpression must be assessed and confirmed by central testing based on archival samples. To be eligible for inclusion in cohort 2, any HER2-activating mutation must be documented based on archival tumor samples analyzed by Clinical Laboratory Improvement Amendment-certified laboratory or equivalent. All enrolled subjects will receive a 6.4 mg/kg dose of DS-8201a once every 3 weeks; study treatment will be continued until progressive disease or unacceptable toxicity. The primary endpoint is ORR based on RECIST version 1.1 (percentage of complete and partial response) by an independent radiologic facility. Secondary efficacy endpoints include progression-free survival, duration of response, disease control rate, and overall survival. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. The study will enroll subjects in North America, Europe, and Japan. Recruitment began in May, 2018.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • 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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      P1.13-44 - Safety, PK, and Preliminary Antitumor Activity of the Oral EGFR/HER2 Exon 20 Inhibitor TAK-788 in NSCLC (ID 12373)

      16:45 - 18:00  |  Author(s): Pasi A Jänne

      • Abstract
      • Slides

      Background

      TAK-788 (AP32788) is an investigational tyrosine kinase inhibitor (TKI) with potent, selective preclinical activity against activating EGFR and HER2 mutations, including exon 20 insertions. We report early results of a phase 1/2 first-in-human, open-label, multicenter study of TAK-788 (NCT02716116).

      Method

      Patients with advanced non-small cell lung cancer (NSCLC) refractory to standard therapy received daily oral doses (5–120 mg) of TAK-788 in the ongoing dose-escalation phase (3+3 design). Preliminary antitumor activity (by RECIST v1.1), safety, and PK are reported for patients who received ≥1 dose.

      Result

      As of 8-Sep-2017, 34 patients (median age, 60 y; female, 65%; ≥2 prior anticancer therapies, 88%; Table) were treated with TAK-788; 10 remain on treatment at data cutoff. AUC0‑24,ss increased in a dose-proportional manner over the dose range evaluated; the effective t1/2 was ~16 (range 6–28) h. The most common treatment-emergent AEs (TEAEs; ≥20%) were diarrhea (47%), nausea (26%), and fatigue (21%). Grade ≥3 TEAEs in ≥2 patients (excluding disease progression) were dyspnea (n=3, 9%) and anemia, asthenia, dehydration, lung infection, pleural effusion, pneumonia, and pneumonitis (n=2 each, 6%). Two DLTs, both pneumonitis, were reported (80 mg, grade 3; 120 mg, grade 5). Of 14 evaluable patients, 3 had PR (80 mg, n=2, both confirmed; 120 mg, single PR awaiting confirmation), 6 had SD (40 mg, n=3; 80 mg, n=2; 120 mg, n=1), and 5 had PD as best response (40 mg, n=3; 80 mg, n=1; 120 mg, n=1). All patients with PR had EGFR exon 20 insertions.

      Conclusion

      TAK-788 exhibits antitumor activity in patients with EGFR exon 20 insertions with an AE profile consistent with other EGFR TKIs. Phase 2 will begin after determination of the RP2D, with 4 molecularly defined cohorts in NSCLC. Updated data will be presented, including the recommended phase 2 dose (RP2D).

      Baseline Characteristics

      5 mg

      (n=4)

      10 mg

      (n=5)

      20 mg

      (n=5)

      40 mg

      (n=6)

      80 mg

      (n=7)

      120 mg

      (n=7)

      Total

      (n=34)

      Mutation type,a %

      Common EGFR mutations (exon 19 deletion / L8585R) 25 20 0 0 0 0 6
      EGFR-T790M+ 0 0 0 0 14 0 3
      EGFR exon 20 insertion 50 40 60 83 71 57 62
      HER2 0 20 40 17 14 29 21
      a One patient (20 mg) had both EGFR and HER2 mutations; 1 patient (80 mg) had EGFR exon 20 insertion + T790M.

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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
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-43 - Phase 1 Study of the Anti-HER3 Antibody Drug Conjugate U3-1402 in Metastatic or Unresectable EGFR-Mutant NSCLC (ID 13484)

      16:45 - 18:00  |  Presenting Author(s): Pasi A Jänne

      • Abstract
      • Slides

      Background

      While outcomes for patients with EGFR-mutant NSCLC have significantly improved with the use of EGFR tyrosine kinase inhibitors, there remain limited treatment options for many patients once they develop resistance to these agents. The HER3/ERBB3 oncogene is overexpressed in many cancers, including NSCLC, and higher expression is correlated with poor outcomes. U3-1402 is a novel HER3-targeting antibody-drug conjugate (ADC) comprised of a recombinant fully human anti-HER3 antibody (patritumab) covalently conjugated via a cleavable peptide linker to a derivative of the topoisomerase I inhibitor exatecan. After U3-1402 binds to HER3 on the tumor cell surface, it is internalized and leads to apoptosis via inhibition of topoisomerase I. This ADC achieves a high drug-to-antibody ratio (DAR) of ~8:1. In vivo xenograft mouse model studies with human tumor cell lines indicate that U3-1402 exhibits HER3 expression-dependent tumor growth inhibition activity.

      Method

      This is a multicenter Phase 1, Dose Escalation and Dose Expansion study of U3-1402 in metastatic or unresectable adenocarcinoma NSCLC subjects harboring EGFR-activating mutation who (a) are T790M mutation-negative after disease progression during treatment with erlotinib, gefitinib, or afatinib or (b) develop disease progression while on osimertinib. Eligible subjects are at least 18 years of age, have ECOG PS 0 or 1, have radiological documentation of disease progression while receiving continuous treatment with an EGFR TKI, have at least one measurable lesion per RECIST v1.1, have adequate bone marrow and organ function, do not have LVEF < 45%, do not have QTc prolongation, and do not have spinal cord compression or clinically active brain metastases. In Dose Escalation, subjects receive U3-1402 via intravenous infusion in 21-day cycles. In Dose Escalation, escalation of U3-1402 dosing is based on dose-limiting toxicity data in subjects, guided by the modified Continuous Reassessment Method (mCRM) using a Bayesian logistic regression model (BLRM) following the escalation with overdose control (EWOC) principle. Additionally, intra-subject dose escalation may be considered in subjects who have completed at least 4 cycles of treatment without ≥ Grade 2 treatment-emergent adverse events. In Dose Expansion, subjects receive U3-1402 at the recommended dose for expansion (RDE) determined in Dose Escalation. Primary objectives are to determine the safety, tolerability, and RDE of U3-1402. Secondary objectives are to assess the pharmacokinetic parameters of U3-1402 and its components, and to assess antitumor activity of U3-1402 (RECIST v1.1). Enrollment to Dose Escalation cohort 1 was completed in April 2018. Clinicaltrials.gov identifier: NCT03260491

      Result

      Section not applicable - CTIP

      Conclusion

      Section no applicable

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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 (Now Available) (ID 11349)

      16:45 - 18:00  |  Author(s): Pasi A Jänne

      • 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.

      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

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    YI01 - Young Investigators Session (ID 988)

    • Event: WCLC 2018
    • Type: Young Investigator Session
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/23/2018, 08:00 - 11:30, Room 106
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      YI01.04 - Planning a Career in Lung Cancer - Bench to Beside (Now Available) (ID 14673)

      08:30 - 08:40  |  Presenting Author(s): Pasi A Jänne

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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