Abstract 1916P
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. Table: 1916P
| Differentiated (N=21) | Anaplastic (N=7) | All patients (N=28) | |
| ORR, % (95% CI)† | 90 (70–99) | 29 (4–71) | 75 (55–89) |
| CR, n (%) | 2 (10) | 0 | 2 (7) |
| PR, n (%) | 17 (81) | 2 (29) | 19 (68) |
| SD, n (%) | 2 (10) | 1 (14) | 3 (11) |
| PD, n (%) | 0 | 3 (43) | 3 (11) |
| ND, n (%) | 0 | 1 (14) | 1 (4) |
†Per investigator assessment. CI, confidence interval; CR, complete response; ND, not determined; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.
Clinical trial identification
NCT02122913, April 25, 2014; NCT02576431, October 15, 2015.
Editorial acknowledgement
Medical writing provided by Francesca Murphy of Scion Medica, London, UK Editorial assistance provided by Annabel Ola and Ian Norton, Scion Medica, London, UK.
Legal entity responsible for the study
Bayer and Loxo Oncology.
Funding
Bayer and Loxo Oncology.
Disclosure
M.E. Cabanillas: Research grant/Funding (self), Research (PI) Starting July 27, 2017 - >$25,000: Genentech; Advisory/Consultancy, Advisory Board October 2, 2017 $1-$10,000; Advisory Board September 27, 2018 $1-$10,000: LOXO; Advisory/Consultancy, Advisory Board April 17, 2018 $1-$10,000: Ignyta; Advisory/Consultancy, Advisory Board May 1, 2019 $1-$10,000: Larotrectinib. A. Drilon: Honoraria (self), Advisory/Consultancy: Loxo/Bayer/Lilly, Ignyta/Genentech/Roche; Honoraria (self), Advisory/Consultancy: Takeda/Ariad/Millenium; Honoraria (self), Advisory/Consultancy: TP Therapeutics; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Honoraria (institution), Advisory/Consultancy: WebMD; Honoraria (self): Physicians Education Resources, Targeted Oncology; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Blueprint Medicines; Honoraria (self), Advisory/Consultancy: Helsinn; Honoraria (self), Advisory/Consultancy: Beigene; Honoraria (self), Advisory/Consultancy: BergenBio; Honoraria (self), Advisory/Consultancy: Hengrui Therapeutics; Honoraria (self), Advisory/Consultancy: Exelixis; Honoraria (self), Advisory/Consultancy: Tyra Biosciences; Honoraria (self), Advisory/Consultancy: Verastem; Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: MORE Health; Honoraria (self), Advisory/Consultancy: 14ner/Elevation Oncology; Honoraria (self), Advisory/Consultancy: Axis; Honoraria (self), Advisory/Consultancy: Peerview Institute; Honoraria (self), Advisory/Consultancy: OncLive, Medscape; Honoraria (self), Advisory/Consultancy: Paradigm Medical Communications; Honoraria (self), Advisory/Consultancy: LLC; Honoraria (self), Advisory/Consultancy: Remedica Ltd, ArcherDX; Travel/Accommodation/Expenses, Food and beverage: Merck, Puma, Merus, Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Foundation Medicine; Honoraria (self), Advisory/Consultancy: Research to Practice; Honoraria (self), Advisory/Consultancy: PeerVoice; Licensing/Royalties: Wolters Kluwer; Research grant/Funding (institution): Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, PharmaMar. A.F. Farago: Research grant/Funding (self): Bayer, Loxo Oncology, Genentech, Roche, Bristol-Myers Squibb, AstraZeneca, AbbVie, PharmaMar, Merck, Ignyta, Amgen and Lilly; Advisory/Consultancy: Bayer, Genentech, Roche, Bristol-Myers Squibb, AstraZeneca, AbbVie, Boehringer Ingelheim, Merck, Pfizer, and H3 Biomedicine; Honoraria (self): Clinical Care Options, Medscape, Onclive, Research to Practice, and PeerView. M.S. Brose: Advisory/Consultancy, Research grant/Funding (institution), Research support to the University of Pennsylvania School of Medicine: Loxo Oncology; Advisory/Consultancy, Research grant/Funding (institution), Research support to the University of Pennsylvania School of Medicine: Genentech; Research grant/Funding (institution), Research support to the University of Pennsylvania School of Medicine: Eisai; Research grant/Funding (institution), Research support to the University of Pennsylvania School of Medicine: Blueprint Medicines; Advisory/Consultancy, Research grant/Funding (institution), Research support to the University of Pennsylvania School of Medicine: Lilly; Research grant/Funding (institution), Research support to the University of Pennsylvania School of Medicine: Novartis; Advisory/Consultancy, Research grant/Funding (institution), Research support to the University of Pennsylvania School of Medicine: Bayer; Advisory/Consultancy: AstraZeneca; Honoraria (self): Clinical Care Options; Honoraria (self): Medscape; Honoraria (self): OncLive; Honoraria (self): PeerView. R. McDermott: Travel/Accommodation/Expenses: Janssen-Cilag, Pfizer; Honoraria (self): Bayer, Sanofi, Janssen, Astellas, BMS, MSD, Pfizer, Novartis, Clovis; Research grant/Funding (self): Sanofi, Janssen, Bayer, Astellas. D. Sohal: Advisory/Consultancy: Perthera, Ability Pharmaceuticals; Honoraria (self): Foundation Medicine; Research grant/Funding (self): Agios, Bayer, Bristol-Myers Squibb, Celgene, Genentech, InCyte Loxo, OncoMed, Rafael. D-Y. Oh: Advisory/Consultancy: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, Aslan, Halozyme, Zymeworks, Celgene; Research grant/Funding (self): AstraZeneca, Novartis, Array, Eli Lilly. J. Bauman: Advisory/Consultancy: Pfizer; Bayer; Kura Consulting: Pfizer; AstraZeneca; Research grant/Funding (self): BMS. E. Chu: Advisory/Consultancy: Proteus Digital Health. S. Kummar: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer. S. Leyvraz: Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer. K. Park: Advisory/Consultancy: Loxo. J.A. Reeves, L. Dima, P. Maeda, L. Rodrigues, N. Brega: Full/Part-time employment: Bayer. D.S. Hong: Research grant/Funding (self): AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, Loxo Oncology, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer; Travel/Accommodation/Expenses: Loxo Oncology, MiRNA, ASCO, AACR, SITC, Genmab; Advisory/Consultancy: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, and Trieza Therapeutics; Shareholder/Stockholder/Stock options, Molecular Match (advisor), OncoResponse (founder), and Presagia Inc (advisor).: Molecular Match, OncoResponse, Presagia Inc. S.G. Waguespack: Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer. All other authors have declared no conflicts of interest.