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PMID
Authors M.E. Cabanillas, A. Drilon, A.F. Farago, M.S. Brose, R. McDermott, D. Sohal, D. Oh, M. Almubarak, J. Bauman, E. Chu, S. Kummar, S. Leyvraz, K. Park, J.A. Reeves, L. Dima, P. Maeda, L. Rodrigues, N. Brega, D.S. Hong, S.G. Waguespack
Title Larotrectinib treatment of advanced TRK fusion thyroid cancer
Journal Annals of Oncology
Vol 31
Issue suppl_4
Date
URL https://www.sciencedirect.com/science/article/pii/S0923753420414000
Abstract Text Background: Larotrectinib is a first-in-class, central nervous system-active, highly selective tropomyosin receptor kinase (TRK) inhibitor approved by the EMA and FDA for the treatment of adult and paediatric patients (pts) with TRK fusion cancer. Larotrectinib produced an objective response rate (ORR) of 79% and a median duration of response (DoR) of 35.2 months in pts with TRK fusion cancer across various tumour types (Hong et al. Lancet Oncol. 2020). Here, we report the efficacy and safety of larotrectinib in the subset of pts with TRK fusion thyroid cancer. Methods: Data in pts with locally advanced or metastatic thyroid cancer harbouring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion were pooled from two larotrectinib clinical trials (NCT02122913 and NCT02576431). Adult and paediatric patients received larotrectinib 100 mg and 100 mg/m2 twice daily, respectively, on a continuous 28-day schedule. Responses were investigator-assessed per RECIST v1.1 (data cut-off: 15 July 2019). Results: A total of 28 pts with TRK fusion thyroid cancer were included: 19 papillary, 7 anaplastic and 2 follicular. Median age was 62 years (range 6–80). Twelve (43%) pts had a NTRK1 fusion and 16 (57%) pts had a NTRK3 fusion. All pts had received prior treatment, including surgery (100%), radiotherapy (61%), radioiodine (75%) and ≥1 prior systemic therapy (89%). Eleven (44%) pts had received ≥3 prior systemic therapies. ORR was 75% (95% confidence interval [CI] 55–89), including 29% for pts with anaplastic disease (Table). DoR ranged from 1.9+ to 41.0+ months. Median progression-free survival (PFS) was not reached (95% CI 16.6–NE) and the 12-month PFS rate was 81%. Adverse events (AEs) were mostly Grade 1–2. Grade ≥3 AEs occurred in 46% of pts and 7% of pts had Grade ≥3 AEs related to larotrectinib. Conclusions: Larotrectinib was highly efficacious and demonstrated a favourable safety profile. These findings support routine testing for NTRK gene fusions in pts with non-medullary, advanced thyroid cancer. Clinical trial identification: NCT02122913, April 25, 2014; NCT02576431, October 15, 2015.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NTRK1 fusion thyroid gland cancer predicted - sensitive Larotrectinib Phase II Actionable In a combined analysis of two clinical trials, Vitrakvi (larotrectinib) treatment demonstrated a favorable safety profile, resulted in an objective response rate of 75% (21/28, 2 complete responses, 19 partial responses) in patients with non-medullary, advanced thyroid cancer harboring NTRK1 (n=12) or NTRK3 (n=16) fusions, with median progression-free survival (PFS) not reached and a 12-month PFS rate of 81% (Annals of Oncology (2020) 31 (suppl_4): S1086; NCT02122913, NCT02576431). detail...