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.

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.
Competing Interests: 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. The funders and Flatiron Health, Inc. also provided support in the form of salaries for authors and funding for medical writing assistance. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare. DPH and SLM report employment from Genentech, Inc. GDD reports honoraria from M.J. Hennessey / OncLive, MEDSCAPE, AACR/ASCO; consulting/advisory role for F. Hoffmann-La Roche Ltd, Ikena Therapeutics, Genentech, Inc., Bayer, EMD-Serono, Daiichi-Sankyo, WCG/Arsenal Capital, Blueprint Medicines, PharmaMar, Pfizer, Novartis, GlaxoSmithKline, Janssen, Mirati, MEDSCAPE, Relay Therapeutics, CellCarta; research funding to institution from F. Hoffmann-La Roche Ltd, Bayer, Loxo Oncology at Lilly, Daiichi-Sankyo, Janssen, Pfizer, Novartis; travel, accommodations, expenses from F. Hoffmann-La Roche Ltd; shareholder/stakeholder/stock options from Blueprint Medicines, G1 Therapeutics, Ikena Therapeutics, CARIS Life Sciences, Bessor Pharmaceuticals, ERASCA Pharmaceuticals, Translate BIO, Relay Therapeutics, CellCarta; licensing/royalties from Novartis to Dana-Farber Cancer Institute; board of directors membership for Blueprint Medicines, Translate BIO; non-remunerated activities for Alexandria Real Estate Equities. SP reports honoraria from F. Hoffmann-La Roche Ltd, Bristol-Myers Squibb, Novartis, Pfizer, MSD, AstraZeneca, Takeda, Illumina; consulting/advisory role for F. Hoffmann-La Roche Ltd/Genentech, Inc., Novartis, Bristol-Myers Squibb, Pfizer, MSD, Amgen, AstraZeneca, Janssen, Regeneron, Merck Serono, Boehringer Ingelheim, Takeda, Lilly, Abbvie, Bayer, Biocartis, Debiopharm Group, Illumina, PharmaMar, Sanofi, Seattle Genetics, Blueprint Medicines, Daiichi Sankyo, Incyte, Bioinvent, Clovis Oncology, Vaccibody; research funding from F. Hoffmann-La Roche Ltd, Bristol-Myers Squibb, MSD, Amgen, Lilly, AstraZeneca, Pfizer, Illumina, Merck Serono, Novartis, Biodesix, Boehringer Ingelheim, Iovance Biotherapeutics; travel, accommodations, expenses from F. Hoffmann-La Roche Ltd, Bristol-Myers Squibb, MSD, Sanofi, Incyte; non-remunerated activities for Journal of Thoracic Oncology, ESMO, European Thoracic Oncology Platform (ETOP), Annals of Oncology. JD and LP report employment at F. Hoffmann-La Roche Ltd. OH reports employment at Flatiron Health, Inc., which is an independent subsidiary of the Roche Group, as well as stock ownership in Roche.