Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach

Date 21 October 2018
Event ESMO 2018 Congress
Session Proffered paper session - Developmental therapeutics
Topics Clinical Research
Personalised/Precision Medicine
Presenter Ulrik Lassen
Citation Annals of Oncology (2018) 29 (suppl_8): viii133-viii148. 10.1093/annonc/mdy279
Authors U.N. Lassen1, C.M. Albert2, S. Kummar3, C.M. van Tilburg4, S.G. Dubois5, B. Geoerger6, L. Mascarenhas7, N. Federman8, R.J. Schilder9, F. Doz10, J.D. Berlin11, D. Oh12, S.S. Bielack13, R. McDermott14, D.S.W.S. Tan15, S. Cruickshank16, N.C. Ku16, M.C. Cox16, A. Drilon17, D.S. Hong18
  • 1Finsen Center, Dept. Of Oncology, Phase 1 Unit, Copenhagen University Hospital - Rigshospitalet, 2100 - Copenhagen/DK
  • 2Pediatric Oncology, Seattle Children’s Hospital, University of Washington, Fred Hutchinson Cancer Research Center, Seattle/US
  • 3Medical Oncology, Stanford Cancer Institute, Stanford University, 94305 - Stanford/US
  • 4Pediatric Oncology, Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg/DE
  • 5Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston/US
  • 6Department Of Pediatric And Adolescent Oncology, Institut Gustave Roussy, 94800 - Villejuif/FR
  • 7Oncology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles/US
  • 8Pediatric Oncology, University of California, Los Angeles, Los Angeles/US
  • 9Medical Oncology, Thomas Jefferson University, Philadelphia/US
  • 10Pediatric Oncology, Institut Curie and University Paris Descartes, Paris/FR
  • 11Medicine, Vanderbilt Ingram Cancer Center, 37232-6307 - Nashville/US
  • 12Medical Oncology, Seoul National University Hospital, 110-744 - Seoul/KR
  • 13Pediatric Oncology, Klinikum Stuttgart - Olgahospital, 70174 - Stuttgart/DE
  • 14Medical Oncology, AMNCH Adelaide and Meath Hospital, 24 - Dublin/IE
  • 15Medical Oncology, National Cancer Center, 16910 - Singapore/SG
  • 16Clinical Development, Loxo Oncology, 94080 - South San Francisco/US
  • 17Medical Oncology, Memorial Sloan-Kettering Cancer Center, 10065 - New York/US
  • 18Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 77035 - Houston/US

Abstract

Background

TRK fusion cancer results from gene fusions involving NTRK1, NTRK2 or NTRK3. Larotrectinib, the first selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% with a favorable safety profile in the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancer (Drilon et al.,NEJM2018). Here, we report the clinical activity of larotrectinib in an additional 35 TRK fusion cancer patients and provide updated follow-up of the primary analysis set (PAS) of 55 patients as of 19thFeb 2018.

Methods

Patients with TRK fusion cancer detected by molecular profiling from 3 larotrectinib clinical trials (NCT02122913, NCT02637687, and NCT02576431) were eligible.Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed using RECIST version 1.1.

Results

As of Feb 2018, by independent review, 6 PRs in the PAS deepened to CRs. The median duration of response (DoR) and progression-free survival in the PAS had still not been reached, with 12.9 months median follow-up. At 1 year, 69% of responses were ongoing, 58% of patients remained progression-free and 90% of patients were alive. An additional 19 children and 25 adults (age range, 0.1-78 years) with TRK fusion cancer were enrolled after the PAS, and included cancers of the salivary gland, thyroid, lung, colon, melanoma, sarcoma, GIST and congenital mesoblastic nephroma. In 35 evaluable patients, the ORR by investigator assessment was 74% (5 CR, 21 PR, 6 SD, 2 PD, 1 not determined). In these patients, with median follow-up of 5.5 months, median DoR had not yet been reached, and 88% of responses were ongoing at 6 months, consistent with the PAS. Adverse events (AEs) were predominantly grade 1, with dizziness, increased AST/ALT, fatigue, nausea and constipation the most common AEs reported in ≥ 10% of patients. No AE of grade 3 or 4 related to larotrectinib occurred in more than 5% of patients.

Conclusions

TRK fusions are detected in a broad range of tumor types. Larotrectinib is an effective age- and tumor-agnostic treatment for TRK fusion cancer with a positive safety profile. Screening patients for NTRK gene fusions in solid- and brain tumors should be actively considered.

Clinical trial identification

NCT02122913, NCT02637687, and NCT02576431.

Legal entity responsible for the study

Loxo Oncology, Inc.

Funding

Loxo Oncology, Inc.

Editorial Acknowledgement

Disclosure

S.G. Dubois: Fees for consulting and advisory board roles: Loxo Oncology. N. Federman: Honoraria from ad boards: Bayer AG and Loxo Oncology. S. Cruickshank: Paid consultant: Loxo Oncology, Inc. N.C. Ku, M.C. Cox: Employee and stockholder: Loxo Oncology, Inc. All other authors have declared no conflicts of interest.