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Matthew G Krebs



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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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      MA14.02 - Entrectinib in Patients with ROS1-Positive NSCLC or NTRK Fusion-Positive Solid Tumors with CNS Metastases (Now Available) (ID 1631)

      15:45 - 17:15  |  Author(s): Matthew G Krebs

      • Abstract
      • Presentation
      • Slides

      Background

      Entrectinib potently inhibits kinases encoded by NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated analysis data (31 May 2018 data cut-off) from three Phase 1/2 entrectinib trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]) for a large cohort of adult patients with NTRK fusion-positive solid tumors (NTRK+) or ROS1 fusion-positive NSCLC (ROS1+), with baseline CNS metastases.

      Method

      Patients had locally advanced/metastatic NTRK+ solid tumors or ROS1+ NSCLC by nucleic acid-based assays confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were performed at baseline, week 4, and then every 8 weeks by blinded independent central review (RECIST v1.1). Primary endpoints were overall response rate (ORR), duration of response (DOR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy in patients with CNS metastases, safety.

      Result

      Most patients were treated first-line or after one line of prior therapy; baseline characteristics relating to measurable CNS metastases for patients with NTRK+ solid tumors and ROS1+ NSCLC are presented (Table). Intracranial outcomes for the NTRK+ solid tumors (n=54; 18% NSCLC) and ROS1+ NSCLC (n=53) efficacy evaluable populations are reported (Table). Durability of treatment effect and potential delayed progression in the CNS was observed; time to CNS progression was 17.0 months (95% CI: 14.3–NE) for NTRK+ solid tumor patients and NE (95% CI: 15.1–NE) for ROS1+ NSCLC. In the subset of patients with NTRK+ NSCLC (n=10), 6 patients had CNS metastases at baseline (by BICR); IC-ORR was 66.7% (4/6), 2 CR; IC-DOR was NE. In both the NTRK+ and ROS1+ populations, entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2.

      Conclusion

      Entrectinib induced clinically meaningful durable responses in patients with NTRK+ solid tumors or ROS1+ NSCLC with CNS disease at baseline.

      Funding: This study was funded by F. Hoffmann-La Roche

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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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      P1.01-83 - Comparative Efficacy Analysis Between Entrectinib Trial and Crizotinib Real-World ROS1 Fusion-Positive (ROS1+) NSCLC Patients (ID 2215)

      09:45 - 18:00  |  Author(s): Matthew G Krebs

      • Abstract

      Background

      Entrectinib is an oral tyrosine kinase inhibitor for ROS1 fusion-positive (ROS1+) NSCLC. Three phase 1/2 single-arm studies showed entrectinib efficacy in this population (Doebele WCLC 2018). Due to the rarity of ROS1+ patients generating direct comparative evidence in prospective randomized trials is difficult. We identified a retrospective real-world cohort of ROS1+ NSCLC patients from electronic health records (EHR), to compare crizotinib, the current standard of care, to entrectinib as reported in clinical trials

      Method

      Crizotinib-treated patients with advanced ROS1+ NSCLC diagnosed 1 Jan 2011 to 30 Jun 2018, were identified with technology-enabled abstraction in the Flatiron Health EHR-derived database (>2.1 million cancer patients from US oncology practice). Entrectinib trial inclusion/exclusion criteria were applied to match the crizotinib cohort as closely as possible. Primary endpoint: time to treatment discontinuation (TTD), adapted from Gong (ASCO 2018); real-world progression-free survival (rwPFS; physician/scan report) and overall survival (OS) were secondary outcomes. Time-to-event analyses used Kaplan-Meier survival curves and Cox proportional hazard models on propensity score weighted populations; age, gender, race/ethnicity, smoking status, brain metastasis and previous lines of therapy were prognostic factors.

      Result

      We analyzed 53 entrectinib and 69 crizotinib ROS1+ NSCLC patients. Median weighted TTD: entrectinib, 14.6 months (95% CI: 8.3–23.8); crizotinib, 8.8 months (95% CI: 8.2–9.9). When rwPFS from crizotinib was compared to trial PFS, entrectinib had longer PFS vs crizotinib (weighted HR: 0.44; 95% CI: 0.27–0.74). Median OS with entrectinib was not reached (median follow-up: 15.5 months); weighted median OS with crizotinib was 18.5 months (95% CI: 15.1–19.9). Findings were consistent across multiple sensitivity analyses.

      Conclusion

      Entrectinib was associated with longer TTD and PFS in ROS1+ NSCLC patients vs a matched real-world crizotinib population. Control populations derived from real-world cohorts can supplement evidence from clinical trials in settings where new standards of care are needed, but where only limited data are available and randomization is not feasible.

      Funding: This study was funded by F. Hoffmann-La Roche

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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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      P2.01-08 - Clinical Trial in Progress: CONCORDE - A Phase 1B Study of Novel Agents in Combination with Conventional Radiotherapy in NSCLC (ID 600)

      10:15 - 18:15  |  Author(s): Matthew G Krebs

      • Abstract

      Background

      The majority of patients with locally advanced non-small cell lung cancer (NSCLC) treated with curative intent receive radiotherapy (RT) as part of their treatment. Despite considerable technological advances in RT delivery, the survival of these patients has barely changed over the last 60 years. A major factor in this failure to improve outcomes is the relative radioresistance of NSCLC. Attempts to overcome radioresistance by escalating RT doses have demonstrated inferior outcome likely secondary to normal tissue toxicity. Therefore an alternate approach is to exploit genetic dependencies in the DNA damage response of NSCLC, using biological inhibitors to selectively radiosensitise tumours whilst sparing normal tissues. The CONCORDE study is a multi-arm phase 1B platform study to investigate the combination of radical RT with DNA damage response inhibitors (DDR-i) targeting five different proteins: PARP, ATR, WEE1, ATM, DNA-PK.

      Method

      CONCORDE is a hypothesis-driven combination study of novel therapeutics and RT using an innovative adaptive early-phase trial design. The study will address two main research questions:

      - What are the recommended phase 2 doses (RP2D) of individual DDR-i in combination with curative RT in patients with stage IIB/III NSCLC?

      - What are the safety profiles of individual DDR-i combined with curative RT in this population?

      Key inclusion criteria are stage IIB and III NSCLC planned to receive curative intent RT doses (+/- neoadjuvant chemotherapy) and PS 0-1. Participants will be randomised on a 3:1 basis between DDR-i with RT or RT alone. Patients receiving RT alone will be pooled across the arms to provide contemporary data on toxicity. All patients will receive external beam RT with a planned dose of 60 Gy in 30 fractions.

      The study will use a Bayesian adaptive model-based approach to dose-escalation, with separate Time-To-Event Continual Reassessment Method (TiTE-CRM) models in each experimental arm. The primary endpoints are dose-limiting toxicities occurring within 12 months of the start of radiotherapy. Secondary endpoints include safety and toxicity (acute and late toxicity up to 2 years including using patient reported outcome (PRO) measures), treatment compliance, and best overall response (using RECIST 1.1, progression-free, and overall survival).

      Correlative studies will be carried out to identify biomarkers of toxicity and response. We have secured high-level agreement from leading pharmaceutical partners to invest in 5 treatment arms and funding approval from Cancer Research UK is pending. The first participant is estimated to commence treatment in late 2019

      Result

      Section not applicable

      Conclusion

      Section not applicable