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Proffered paper session - Developmental therapeutics

5033 - Efficacy and Safety of Entrectinib in Patients with NTRK Fusion-Positive (NTRK-fp) Tumors: Pooled Analysis of STARTRK-2, STARTRK-1 and ALKA-372-001

Date

21 Oct 2018

Session

Proffered paper session - Developmental therapeutics

Presenters

George Demetri

Authors

G.D. Demetri1, L. Paz-Ares2, A.F. Farago3, S.V. Liu4, S.P. Chawla5, D. Tosi6, E.S. Kim7, C. Blakely8, J.C. Krauss9, D. Sigal10, L. Bazhenova11, T. John12, B. Besse13, J. Wolf14, T. Seto15, E. Chow-Maneval16, P.S. Multani17, A.D. Johnson18, B. Simmons19, R.C. Doebele20

Author affiliations

  • 1 Centre For Sarcoma And Bone Oncology, Dana-Farber Cancer Institute, 02215 - Boston/US
  • 2 Medical Oncology, Hospital Universitario Virgen del Rocío, 28041 - Sevilla/ES
  • 3 Department Of Medicine, Division Of Hematology/oncology, Massachusetts General Hospital, 02114 - Boston/US
  • 4 Medical Oncology, Georgetown University, 20007 - Washington/US
  • 5 Medical Oncology, Sarcoma Oncology Center, 90403 - Santa Monica/US
  • 6 Medical Oncology, Institut du Cancer de Montpellier, 34290 - Montpellier/FR
  • 7 Solid Tumor Oncology, Levine Cancer Institute, 23204 - Charlotte/US
  • 8 Medicine, University of California San Francisco, 94115 - San Francisco/US
  • 9 Division Of Hematology/oncology, Department Of Internal Medicine, Michigan Medicine, 48109-5912 - Ann Arbor/US
  • 10 Hematology/oncology, Scripps Clinic, 92037 - La Jolla/US
  • 11 Medicine, Moores UCSD Cancer Center, 92093 - La Jolla/US
  • 12 Medical Oncology, Olivia Newton-John Cancer Research Institute, Austin Health, 3084 - Heidelberg/AU
  • 13 Dept Of Cancer Medicine, Gustave Roussy Institut de Cancérologie, 94805 - Villejuif/FR
  • 14 Oncology, Centrum fur Integrierte Onkologie (CIO) Koln Bonn, 50937 - Cologne/DE
  • 15 Department Of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka/JP
  • 16 Clinical Development, Ignyta, 92121 - San Diego/GB
  • 17 Clinical Development, Ignyta, CA 92121 - San Diego/US
  • 18 Clinical Development, Ignyta, 92121 - San Diego/US
  • 19 Product Development Oncology, Genentech (Roche), 94080 - South San Francisco/US
  • 20 Medical Oncology, University of Colorado, 80045 - Aurora/US
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Abstract 5033

Background

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions lead to the transcription of chimeric TRK proteins with overexpressed kinase function; this confers oncogenic potential across several tumor types. Entrectinib is a central nervous system (CNS)-active, potent inhibitor of TRKA/B/C and ROS1. We show integrated efficacy and safety analyses from entrectinib clinical trials.

Methods

Patients (pts) with locally advanced/metastatic NTRK-fusion positive (fp) tumors confirmed by nucleic acid-based methods and enrolled in global (>150 sites, 15 countries) phase 1/2 entrectinib trials (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267) were included. Tumors were assessed after cycle 1 (4 wk) then every 8 wk. Scans underwent blinded independent central review (BICR) using RECISTv1.1. Primary endpoints: overall response rate (ORR); duration of response (DOR) by BICR. Secondary endpoints: progression-free survival (PFS), overall survival (OS) in pts with and without baseline CNS disease; safety.

Results

The efficacy-evaluable population comprises 54 adult pts with advanced/metastatic NTRK-fp solid tumors (10 tumor types, >19 histopathologies), including pts with baseline CNS metastases. After 15.5 mo follow-up, BICR ORR was 57.4% (95% CI 43.2–70.8), complete responses n=4 (7.4%); responses seen in all tumor types. Median BICR DOR: 10.4 mo (95% CI 7.1–NR); median BICR PFS: 11.2 mo (95% CI 8.0–14.9); median OS: 20.9 mo (95% CI 14.9–NR). Per baseline CNS status (investigator assessed), median BICR PFS was 12.0 mo (95% CI 8.7–15.7) and 7.7 mo (95% CI 4.7–NR) for patients without (n=42) and with CNS disease (n=12), respectively. In the safety population (355 pts who received entrectinib across clinical trials), most treatment-related AEs were grade 1–2 and managed with dose reduction (27.3%); few pts discontinued (3.9%) due to treatment-related AEs.

Conclusions

In this multicenter, pooled analysis of global clinical trials, entrectinib was well tolerated overall and induced clinically meaningful, durable systemic responses in pts with NTRK-fp solid tumors, type agnostic, with and without CNS disease.

Clinical trial identification

EudraCT 2012-000148-88; NCT02097810; NCT02568267

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