Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children Journal Article
| Authors: | Drilon, A.; Laetsch, T. W.; Kummar, S.; DuBois, S. G.; Lassen, U. N.; Demetri, G. D.; Nathenson, M.; Doebele, R. C.; Farago, A. F.; Pappo, A. S.; Turpin, B.; Dowlati, A.; Brose, M. S.; Mascarenhas, L.; Federman, N.; Berlin, J.; El-Deiry, W. S.; Baik, C.; Deeken, J.; Boni, V.; Nagasubramanian, R.; Taylor, M.; Rudzinski, E. R.; Meric-Bernstam, F.; Sohal, D. P. S.; Ma, P. C.; Raez, L. E.; Hechtman, J. F.; Benayed, R.; Ladanyi, M.; Tuch, B. B.; Ebata, K.; Cruickshank, S.; Ku, N. C.; Cox, M. C.; Hawkins, D. S.; Hong, D. S.; Hyman, D. M. |
| Article Title: | Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children |
| Abstract: | BACKGROUND: Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. METHODS: We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progressionfree survival, and safety. RESULTS: A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events. CONCLUSIONS: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. Copyright © 2018 Massachusetts Medical Society. |
| Keywords: | adolescent; adult; child; preschool child; aged; child, preschool; disease-free survival; middle aged; young adult; unclassified drug; oncoprotein; gene mutation; major clinical study; genetics; clinical trial; constipation; fatigue; histopathology; diarrhea; drug efficacy; drug safety; side effect; treatment duration; antineoplastic agents; disease free survival; follow up; antineoplastic agent; prospective study; neoplasm; neoplasms; progression free survival; neutrophil count; phase 2 clinical trial; anemia; protein kinases; nausea; vomiting; antineoplastic activity; protein tyrosine kinase; pyrimidines; alanine aminotransferase blood level; arthralgia; aspartate aminotransferase blood level; coughing; dizziness; dyspnea; alanine aminotransferase; aspartate aminotransferase; chemistry; infant; pyrazole derivative; pyrazoles; drug response; fusion gene; oncogene proteins, fusion; headache; phase 1 clinical trial; receptor protein-tyrosine kinases; kaplan meier method; pyrimidine derivative; protein kinase; tumor resistance; kaplan-meier estimate; clinical outcome; humans; human; male; female; priority journal; article; antagonists and inhibitors; malignant neoplasm; larotrectinib; body weight gain; tropomyosin receptor kinase; arry-470; tropomyosin kinase; trk gene |
| Journal Title: | New England Journal of Medicine |
| Volume: | 378 |
| Issue: | 8 |
| ISSN: | 0028-4793 |
| Publisher: | Massachusetts Medical Society |
| Date Published: | 2018-02-22 |
| Start Page: | 731 |
| End Page: | 739 |
| Language: | English |
| DOI: | 10.1056/NEJMoa1714448 |
| PUBMED: | 29466156 |
| PROVIDER: | scopus |
| PMCID: | PMC5857389 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 April 2018 -- Source: Scopus |
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