Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase fusion sarcomas Journal Article


Authors: Kummar, S.; Shen, L.; Hong, D. S.; McDermott, R.; Keedy, V. L.; Casanova, M.; Demetri, G. D.; Dowlati, A.; Melcón, S. G.; Lassen, U. N.; Leyvraz, S.; Liu, T.; Moreno, V.; Patel, J.; Patil, T.; Mallick, A. B.; Sousa, N.; Tahara, M.; Ziegler, D. S.; Norenberg, R.; Arvis, P.; Brega, N.; Drilon, A.; Tan, D. S. W.
Article Title: Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase fusion sarcomas
Abstract: Background: Larotrectinib, a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor, has demonstrated efficacy in adult and pediatric patients with various solid tumors harboring NTRK gene fusions. This subset analysis focuses on the efficacy and safety of larotrectinib in an expanded cohort of adult patients with TRK fusion sarcomas. Methods: Patients (≥18 years old) with sarcomas harboring NTRK gene fusions were identified from three clinical trials. Patients received larotrectinib 100 mg orally twice daily. Response was investigator-assessed per RECIST v1.1. Data cutoff was July 20, 2021. Results: At the data cutoff, 36 adult patients with TRK fusion sarcomas had initiated larotrectinib therapy: two (6%) patients had bone sarcomas, four (11%) had gastrointestinal stromal tumors, and 30 (83%) had soft tissue sarcomas. All patients were evaluable for response and demonstrated an objective response rate of 58% (95% confidence interval, 41–74). Patients responded well to larotrectinib regardless of number of prior lines of therapy. Adverse events (AEs) were mostly grade 1/2. Grade 3 treatment-emergent AEs (TEAEs) occurred in 15 (42%) patients. There were no grade 4 TEAEs. Two grade 5 TEAEs were reported, neither of which were considered related to larotrectinib. Four (11%) patients permanently discontinued treatment due to TEAEs. Conclusions: Larotrectinib demonstrated robust and durable responses, extended survival benefit, and a favorable safety profile in adult patients with TRK fusion sarcomas with longer follow-up. These results continue to demonstrate that testing for NTRK gene fusions should be incorporated into the clinical management of adult patients with various types of sarcomas. Plain Language Summary: Tropomyosin receptor kinase (TRK) fusion proteins result from translocations involving the NTRK gene and cause cancer in a range of tumor types. Larotrectinib is an agent that specifically targets TRK fusion proteins and is approved for the treatment of patients with TRK fusion cancer. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. Over half of patients had a durable response to larotrectinib, with no unexpected side effects. These results show that larotrectinib is safe and effective in adult patients with TRK fusion sarcomas. © 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.
Keywords: adolescent; adult; child; clinical article; controlled study; treatment response; aged; bone neoplasms; survival analysis; bone tumor; genetics; fatigue; diarrhea; drug efficacy; drug safety; cancer patient; follow up; cancer grading; neoplasm; neoplasms; gastrointestinal stromal tumor; pain; anemia; protein kinase inhibitor; nausea; vomiting; myalgia; cohort analysis; genetic association; gene function; cancer therapy; abdominal pain; arthralgia; backache; coughing; dizziness; dyspnea; sarcoma; protein kinase inhibitors; oncogene; insomnia; thorax pain; adverse outcome; pyrazole derivative; pyrazoles; data analysis; gene fusion; oncogene proteins, fusion; muscle weakness; peripheral edema; soft tissue sarcoma; anxiety disorder; liver disease; headache; genetic screening; treatment withdrawal; soft tissue neoplasms; soft tissue tumor; upper respiratory tract infection; rhinopharyngitis; bone sarcoma; protein tyrosine kinase a; tropomyosin; response evaluation criteria in solid tumors; stomach distension; body weight disorder; receptor, trka; trk; humans; human; male; female; article; larotrectinib; ntrk gene fusion; ntrk gene; trk inhibitors; oncogene fusion protein
Journal Title: Cancer
Volume: 129
Issue: 23
ISSN: 0008-543X
Publisher: Wiley Blackwell  
Date Published: 2023-12-01
Start Page: 3772
End Page: 3782
Language: English
DOI: 10.1002/cncr.35036
PUBMED: 37769113
PROVIDER: scopus
PMCID: PMC11265530
DOI/URL:
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus
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  1. Alexander Edward Drilon
    636 Drilon