Real-world survival outcomes in patients with locally advanced or metastatic NTRK fusion-positive solid tumors receiving standard-of-care therapies other than targeted TRK inhibitors

PLoS One. 2022 Aug 8;17(8):e0270571. doi: 10.1371/journal.pone.0270571. eCollection 2022.

Abstract

The clinical profiles and outcomes of patients with neurotrophic tropomyosin receptor kinase fusion-positive (NTRK+) solid tumors receiving standard of care other than tropomyosin receptor kinase inhibitor (TRKi) targeted therapy have not been well documented. Here, we describe the clinical characteristics of patients with NTRK+ tumors treated in clinical practice using information from a United States electronic health record-derived clinicogenomic database. We also compared survival outcomes in NTRK+ patients and matched NTRK fusion-negative (NTRK-) patients and investigated the clinical prognostic value of NTRK fusions. NTRK positivity was defined by the presence of a fusion or rearrangement involving NTRK1/2/3, determined using NGS (Foundation Medicine, Inc.). NTRK+ patients (n = 28) were diagnosed with locally advanced/metastatic solid tumors between January 1, 2011 and December 31, 2019 and had received no TRKis (e.g., entrectinib or larotrectinib) during their patient journey. The unselected NTRK-population comprised 24,903 patients, and the matched NTRK-cohort included 280 patients. NTRK+ patients tended to be younger, were more commonly not smokers, and had a shorter time from advanced diagnosis to first NGS report, compared with unselected NTRK-patients; however, these differences were not significant. Median overall survival (OS) from advanced/metastatic diagnosis was 10.2 months (95% CI, 7.2-14.1) for the NTRK+ cohort versus 10.4 months (95% CI, 6.7-14.3) for the matched NTRK-cohort; hazard ratio for death in NTRK+ versus matched NTRK-patients was 1.6 (95% CI, 1.0-2.5; P = 0.05). Genomic co-alterations were rare in the NTRK+ cohort (only two of 28 patients had a co-alteration). Overall, while hazard ratios suggest NTRK fusions may be a negative prognostic factor of survival, there are no significant indications of any favorable impact of NTRK fusions on patient outcomes. TRKis, with their high response rate and good tolerability, are likely to improve outcomes for patients compared with existing standard-of-care treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Fusion
  • Humans
  • Neoplasms* / drug therapy
  • Neoplasms* / genetics
  • Neoplasms* / pathology
  • Neoplasms, Second Primary* / drug therapy
  • Oncogene Proteins, Fusion / genetics
  • Protein Kinase Inhibitors / therapeutic use
  • Receptor, trkA / genetics
  • Tropomyosin / genetics

Substances

  • Oncogene Proteins, Fusion
  • Protein Kinase Inhibitors
  • Tropomyosin
  • Receptor, trkA

Grants and funding

This study was funded by F. Hoffmann-La Roche Ltd/Genentech, Inc.: F. Hoffmann-La Roche used Flatiron Health’s services for data acquisition and preparation. F. Hoffmann-La Roche and Genentech were involved in the design and funding of the study and also provided support in the form of salaries for authors: JD and LP report employment from F. Hoffmann-La Roche Ltd and DPH and SLM report employment from Genentech, Inc. OH reports employment from Flatiron Health Inc. The specific role of all authors is articulated in the “Author contributions” section. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Laura Vergoz, PhD and Lietta Nicolaides, PhD, of Ashfield MedComms, an Ashfield Health company, and funded by F. Hoffmann-La Roche Ltd.