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Everett E. Vokes



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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA14.03 - EGFR M+ Subgroup of Phase 1b Study of Telisotuzumab Vedotin (Teliso-V) Plus Erlotinib in c-Met+ Non-Small Cell Lung Cancer (Now Available) (ID 1622)

      15:45 - 17:15  |  Author(s): Everett E. Vokes

      • Abstract
      • Presentation
      • Slides

      Background

      Telisotuzumab vedotin (ABBV-399; teliso-v) is an anti-c-Met antibody conjugated with monomethyl auristatin E, a tubulin polymerization inhibitor. Preliminary activity was reported for the teliso-v + erlotinib combination in c-Met overexpressing (c-MET+) non-small cell lung cancer (NSCLC) patients, with an activating EGFR mutation and for whom prior EGFR TKI failed. We present mature data from the EGFR M+ subgroup of the teliso-v + erlotinib cohort of a phase 1b study (NCT02099058).

      Method

      Teliso-v was administered at 2.4 mg/kg (dose-escalation phase) or 2.7 mg/kg intravenously once every 3 weeks, and erlotinib at 150 mg orally once a day/prior tolerated dose in adult patients with advanced NSCLC. For efficacy analysis, c-Met+ was defined as central lab IHC H-score ≥150 or local lab MET amplification (MET/CEN7 ≥2); EGFR M+ was defined as del19 or L858R by local lab. Pharmacokinetics were assessed. All patients who received teliso-v + erlotinib were evaluated for safety.

      Result

      As of Dec 2018, 42 NSCLC patients received teliso-v + erlotinib; 37 were c-MET+ (36 evaluable: 35 H-score≥150, 1 MET amplified). Median age was 65 years, 25 patients (69%) had ECOG PS 1, 29 (81%) were EGFR M+ (of these: 48% had T790M, 10% had MET amplification, 3% had polysomy, 97% had prior EGFR TKI, 55% 3rd-generation TKI, 69% TKI as last prior therapy, and 62% platinum doublet). All-grade (≥20%) adverse events (AEs) were dermatitis acneiform (38%), diarrhea (36%), peripheral motor/sensory neuropathy (52%; 7% Grade 3), dyspnea, fatigue, hypoalbuminemia (31% each), decreased appetite, nausea (24% each), asthenia, vomiting (21% each). Grade ≥3 (≥10%) AE: pulmonary embolism (14%). Pharmacokinetics of teliso-v for the combination were similar to single-agent teliso-v. The table presents efficacy data.

      Patients with EGFR mutation
      (n=29)

      Objective response rate*, % (95% CI)
      Complete response, n

      34.5 (17.9, 54.3)
      1

      Median duration of response, months
      (95% CI)

      NR
      (2.8, NE)

      Median PFS, months (95% CI)

      NR
      (2.8, NE)

      Median follow-up, months 4
      6-month PFS rate, % (95% CI)

      51 (30, 69)

      Median treatment duration, month (range)
      Teliso-v
      Erlotinib


      3.5 (0.71–10.4)
      5.3 (0.71–25.4)

      Objective response rate by subgroup of interest, n (%)
      Received prior 3rd generation EGFR TKI
      C-met amplified, copy number gain, or polysomy
      EGFR TKI-containing regimen as last-line therapies


      6/16 (37.5)
      5/7 (71.4)
      8/20 (40.0)

      *RECIST version 1.1.

      EGFR, epidermal growth factor receptor; NE, not estimable; NR, not reached; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; TKI, tyrosine kinase inhibitor;

      Conclusion

      These data suggest acceptable safety and promising activity of teliso-v + erlotinib in patients with c-Met+ NSCLC with an activating EGFR mutation and for whom EGFR TKI has failed.

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    OA12 - Profiling the Multidisciplinary Management of Stage III NSCLC (ID 144)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      OA12.04 - Discussant - OA12.01, OA12.02, OA12.03 (Now Available) (ID 3789)

      15:45 - 17:15  |  Presenting Author(s): Everett E. Vokes

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Author(s): Everett E. Vokes

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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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
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-133 - Randomized Open-Label Study of Bintrafusp Alfa (M7824) vs Pembrolizumab in Patients with PD-L1 Expressing Advanced 1L NSCLC (Now Available) (ID 741)

      09:45 - 18:00  |  Author(s): Everett E. Vokes

      • Abstract
      • Slides

      Background

      Transforming growth factor β (TGF- β) promotes tumor progression via immune- and non–immune-related processes. Bintrafusp alfa* (M7824) is an innovative first-in-class bifunctional fusion protein composed of 2 extracellular domains of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody against PD-L1. Targeting these independent and complementary pathways may restore and enhance antitumor responses. An expansion cohort of the NCT02517398 study of patients with advanced NSCLC (n=80) treated with bintrafusp alfa in the second-line setting presented at ESMO 2018 showed an objective response rate of 86% in the subgroup with high PD-L1 tumor expression at the recommended phase 2 dose (1200 mg intravenously [IV] every 2 weeks [Q2W]). Observed data support the hypothesis that bintrafusp alfa may be superior to other PD-(L)1 inhibitors, including pembrolizumab, for the treatment of NSCLC. Based on the promising antitumor activity and manageable safety profile, this study will evaluate bintrafusp alfa treatment in patients with advanced NSCLC in the 1L setting.

      Method

      Here we present a global, randomized trial comparing bintrafusp alfa vs pembrolizumab in the 1L treatment of patients with metastatic NSCLC with high PD-L1 expression levels. Patients in this study must have a histologically confirmed diagnosis of advanced NSCLC with high PD-L1 expression on tumor cells (defined as either ≥80% by the Dako 73-10 pharmDx kit or ≥50% by the Dako 22C3 pharmDx kit since both assays are expected to select a similar patient population at their respective cut-offs). ECOG performance status must be 0 or 1. Patients must not have received prior systemic treatment for advanced NSCLC. Patients with tumors with actionable mutations (for which targeted therapy is locally approved) are not eligible. Patients will receive 1200 mg Q2W or pembrolizumab 200 mg Q3W as an IV infusion until confirmed disease progression, unacceptable toxicity, or trial withdrawal. Dual primary endpoints are progression-free survival and best overall response; key secondary endpoints include overall survival, duration of response, and safety. Estimated enrollment is 300 patients. Clinical trial information: NCT03631706. *Proposed INN.

      © 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO-SITC Clinical Immuno-Oncology Meeting. All rights reserved.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-12 - Ph I Trial of Concurrent or Sequential Ipilimumab, Nivolumab, and SBRT to Multiple Sites in Patients with Stage IV NSCLC  (ID 2903)

      10:15 - 18:15  |  Author(s): Everett E. Vokes

      • Abstract

      Background

      Despite the promise of immunotherapy for the treatment of advanced NSCLC, only a fraction of patients experience significant benefit from immunotherapy alone. Previous studies have shown that SBRT can stimulate innate and adaptive immunity to potentially augment immunotherapy. In addition, SBRT is used in patients with limited metastatic disease as consolidative approach, showing an improvement overall survival when compared to systemic treatment alone. Combining immunotherapy with ablative therapy is being studied by a number of investigators. While many of these pre-clinical and clinical studies are promising, timing of immunotherapy with SBRT has not be formally studied. Further, few of these studies have addressed treatment of multiple sites of disease and little is known about what molecular changes occur in the tumor microenvironment immediately after ablative therapy. This trial is designed to evaluate the safety and efficacy of the combination of nivolumab (N) and ipilimumab (I) plus sequential(S) or concurrent(C) SBRT in patients with stage IV NSCLC.

      Method

      This is a single-center phase I, open-label, two-arm, randomized platform trial. Eligible patients include those with stage IV NSCLC with >2 metastatic lesions that meet criteria for SBRT (0.2 cc to 65 cc of viable tumor, larger tumors able to be partially treated up to 65 cc). Eligible patients are simultaneously accrued on arm I (S) and arm II (C) in a 1:1 ratio. Participants in arm I complete SBRT to 2-4 sites followed by initiation of N/I 1-7 days after completion of SBRT. Participants in arm II are treated with N/I within 24-48 hours of SBRT with required SBRT completion to 2-4 sites within two weeks (prior to the second dose of N). Protocol therapy consists of treatment with N 3mg/kg every 2 weeks and I 1mg/kg every 6 weeks for a maximum of 24 months. The primary endpoint is dose-limiting toxicity defined as a >33% rate of grade ≥3 toxicity. DLT is defined as any grade ≥3 toxicity possibly, likely, or definitely related to SBRT plus N/I (the combination and not the individual components). 
Secondary endpoints include response rate and progression free survival at 6 months, control rate of treated lesions and non-treated lesions, and comparison of efficacy and toxicity between the arms. Biopsies and blood draws performed pre- and post-SBRT will facilitate molecular correlative studies including investigation of changes in the immune microenvironment induced by the two approaches.

      Result

      Current enrollment includes 27 of the 40-80 participants: 15 patients are enrolled on arm 1 (sequential) and 12 patients are enrolled on arm 2 (concurrent). SBRT safety cohorts, to which patients can contribute to more than one, include the following: central lung (n=20), peripheral lung (n=7), abdominal (n=5), osseous (n=9), and liver (n=5). All patients have paired pretreatment and posttreatment biopsies of at least one irradiated lesion. 79% of post-ablative biopsies are suitable for DNA/RNA sequencing.

      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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      P2.14-12 - Tyrosine Kinase Inhibitor Resistance Mechanisms in EGFR T790M-Positive Lung Cancer: The University of Chicago Experience (ID 2709)

      10:15 - 18:15  |  Author(s): Everett E. Vokes

      • Abstract
      • Slides

      Background

      Acquired resistance to osimertinib in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is a poorly understood phenomenon and presents an ongoing challenge. Previously described mechanisms include emergence of mutations at EGFR C797S, MET amplification, transformation to small cell lung cancer, and BRAF mutation. Next-generation sequencing (NGS) of tumors at progression through osimertinib may help to illuminate novel mechanisms of resistance to osimertinib.

      Method

      We surveyed University of Chicago Medicine case records for osimertinib-treated NSCLC patients treated who progressed through therapy. Panels utilized for NGS included, among others, the University of Chicago’s validated panel (the UCM-OncoPlus, surveying greater than 1,100 genes) and Guardant (Guardant Health; Redwood City, CA). Patients were stratified according to presence of EGFR T790M mutation at the initiation of osimertinib therapy.

      Result

      28 patients were identified to have progressed through osimertinib. 23 patients (82.1%) had next-generation performed at the time of progression. Among osimertinib-resistant patients who had NGS, 17 (73.9%) demonstrated at least one resistance mechanism, of which 8 (34.8% of tested patients) were subsequently treated with tyrosine kinase inhibitor-containing regimens or clinical trial of targeted therapy. Mutational profile at progression through osimertinib included: 2 patients (11.8%) with EGFR C797 mutation, 2 patients (11.8%) with MET amplification, 2 patients (11.8%) with RET fusion protein, 2 patients (11.8%) with MET point mutation, 1 patient (5.9%) with EGFR amplification, and 1 patient (5.9%) with small cell transformation. Newly identified resistance mechanisms (n = 1 for each) included mutation to EGFR G724 and L718 residues, ROS1 fusion protein, and in the same patient CBLB Q371* and SMAD4 loss. Of the 23 patients undergoing NGS at progression, 11 (47.8%) harbored EGFR T790M mutations prior to treatment, 3 (27.3%) of whom demonstrated resistance mutations susceptible to additional tyrosine kinase inhibitor therapy.

      Conclusion

      On the basis of these data, we confirm many previously described mechanisms of osimertinib resistance, including EGFR amplification, MET amplification, fusions involving RET, and transformation to small cell lung cancer, as well as novel resistance mechanisms including ROS1 fusion protein. We demonstrate the utility of NGS at the time of progression through osimertinib in our practice, regardless of the patient’s EGFR T790M status. We conclude that re-biopsy and utilization of NGS identifies a significant subset of osimertinib-resistant patients in whom well-tolerated tyrosine kinase inhibitor therapies remain an option and, in the interests of both patient well-being and clinical trial enrollment, should be considered standard practice at progression.

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    P2.18 - Treatment of Locoregional Disease - NSCLC (ID 191)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.18-01 - A Multicenter, Double-Blind, Randomized, Controlled Study of Bintrafusp Alfa (M7824) in Unresectable Stage III NSCLC (Now Available) (ID 2200)

      10:15 - 18:15  |  Presenting Author(s): Everett E. Vokes

      • Abstract
      • Slides

      Background

      The TGF-β pathway promotes tumor immunosuppression, and its inhibition may enhance the antitumor activity of PD-(L)1 monoclonal antibodies and reduce radiation-induced lung fibrosis. Bintrafusp alfa is an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In a phase 1 study, second-line bintrafusp alfa therapy demonstrated promising antitumor activity in advanced non-small cell lung cancer (NSCLC) (NCT02517398). In preclinical studies, bintrafusp alfa plus radiotherapy showed enhanced antitumor activity compared with radiotherapy alone in mouse models. This study is evaluating the efficacy and safety of bintrafusp alfa with concurrent chemoradiation (cCRT) followed by bintrafusp alfa vs cCRT plus placebo followed by durvalumab in patients with unresectable stage III NSCLC.

      Method

      This global, multicenter, double-blind, randomized, controlled study of bintrafusp alfa (NCT03840902) includes adults with histologically documented stage III locally advanced, unresectable NSCLC, ECOG performance status ≤1, adequate pulmonary function, and life expectancy ≥12 weeks. Patients with tumors with actionable mutations (EGFR, ALK translocation, ROS-1 rearrangement) are also eligible. Mixed small cell lung cancer and NSCLC histology; pleural effusions greater than minimal, exudative, or cytologically positive; significant acute or chronic infections; prior chemotherapy or immune checkpoint inhibitor therapy for NSCLC; and current use of immunosuppressive medication are exclusion criteria. Patients are randomized to receive either bintrafusp alfa 1200 mg IV every 2 weeks (Q2W) with cCRT for 6 weeks followed by bintrafusp alfa 1200 mg IV Q2W (arm A) or placebo with cCRT for 6 weeks followed by durvalumab 10 mg/kg IV Q2W (arm B) until confirmed disease progression, unacceptable toxicity, or treatment ≤1 year. The primary endpoint is progression-free survival; secondary endpoints include overall survival, safety, lung function assessment, objective response, duration of response, pharmacokinetics, and immunogenicity. This phase 2 trial was activated on April 2, 2019 and first patient in is anticipated for May 22, 2019. Target enrollment: 350 patients.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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