Abstract 536P
Background
Serious fractures have been reported in patients (pts) with tropomyosin receptor kinase (TRK) fusion cancer receiving non-selective TRK inhibitors (Frampton, Drugs 2021). Larotrectinib is a first-in-class, highly selective TRK inhibitor approved in over 40 countries for the treatment of adult and paediatric pts with TRK fusion cancer. Here we report the incidence of fractures in pts with cancer treated with larotrectinib.
Methods
Data on the incidence of fractures were pooled from three phase I/II trials of pts with solid and CNS tumours treated with larotrectinib monotherapy (NCT02122913, NCT02576431 and NCT02637687).
Results
As of July 20, 2020, a total of 331 pts (214 adults, 117 paediatric) were included in this analysis. Treatment-emergent fractures of any grade occurred in 15 adults (7.0%) and 9 children (7.7%). Among adults, fractures occurred in the rib (5 pts), face, femur, foot, hip, vertebra (2 pts each), and fibula, neck, sternum, tibia and wrist (1 pt each), with 5 adults experiencing 2 fractures. Among children, fractures involved the wrist, ulna (2 pts each), femur, fibula, humerus, upper limb not otherwise specified and spinal compression (1 pt each). The majority of the fractures were attributed to trauma due to a fall or were tumour-related. No fractures were considered larotrectinib-related by the investigator, and no pts discontinued treatment due to a fracture (table). Table: 536P
| Adult patients n=214 | Paediatric patients n=117 | |
| Patients with fractures, n (%) | 15 (7.0) | 9 (7.7) |
| Total fractures, n | 20 | 9 |
| Grade 1 or 2 | 12 | 8 |
| Grade 3 | 7† | 1 |
| Grade 5 | 1‡ | 0 |
| Larotrectinib-related fractures | 0 | 0 |
| Time to first fracture, months, median (range) | 13.0 (0.9–45.8) | 8.0 (0.9–40.5) |
| Treatment interruption due to fracture, n (%) | 5 (33.0) | 0 |
| Treatment discontinuation due to fracture, n (%) | 0 | 0 |
| Associated events by fracture, n | ||
| Trauma | 11§ | 5 |
| Tumour related | 3§ | 2 |
| Stress fracture | 1 | 1 |
| Not reported | 5 | 1 |
†One grade 3 fracture was downgraded to grade 2 on day 83.‡Cervical vertebral fracture unrelated to larotrectinib.§One patient had two fractures: one fall-related fracture and one tumour-related fracture.
Conclusions
The incidence of fractures in oncology pts is estimated to be up to 18% in adults and 6% in children with solid tumours (FDA, 2021). Therefore, the incidence of fractures in pts treated with larotrectinib was within the expected range for pts with solid tumours. Fractures were mainly grade 1–2 and associated with trauma (fall) or were tumour-related. Additional data are warranted to assess the potential association between larotrectinib and skeletal fractures, including ongoing long-term follow-up in paediatric pts.
Clinical trial identification
NCT02122913, first posted April 25, 2014 NCT02637687, first posted December 22, 2015 NCT02576431, first posted October 25, 2015.
Editorial acknowledgement
Medical writing assistance was provided by Michael Sheldon of Scion, London, UK, supported by Bayer HealthCare Pharmaceuticals Inc.
Legal entity responsible for the study
Bayer HealthCare Pharmaceuticals and LOXO Oncology.
Funding
Bayer HealthCare Pharmaceuticals and LOXO Oncology.
Disclosure
T.W. Laetsch: Financial Interests, Personal, Advisory Role: Novartis, Cellectis, Bayer, Loxo, Lilly, Deciphera, Jumo Health, Y-mAbs Therapeutics; Financial Interests, Personal, Research Grant: Pfizer, Novartis, Bayer, Loxo, AbbVie, Amgen, Atara, Biotherapeutics, BMS, Lilly, Epizyme, GSK, Janssen, Jubilant Pharmaceuticals, Novella Clinical, Servier. C.M. van Tilburg: Financial Interests, Personal, Advisory Board: Bayer, Novartis. S. Kummar: Financial Interests, Personal, Advisory Role: Boehringer Ingelheim, Springworks Therapeutics, Varian, Bayer, Genome & Company, HarbourBiomed, Seagen, Mundibiopharma Ltd, Gilead,; Financial Interests, Personal, Other, Travel support: Bayer; Financial Interests, Personal, Other, Editor-in-Chief, Current Problems in Cancer: Elsevier. A. Dowlati: Financial Interests, Personal, Advisory Role: Takeda, Abbvie, Seattle Genetics, AstraZeneca, Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Loxo, Bayer, Incuron, Takeda, Regeneron, Tesaro, Amgen, Seattle genetics, Symphogen, Abbvie and Ipsen. K. Guiver: Financial Interests, Personal, Full or part-time Employment: Bayer. M. Fellous: Financial Interests, Personal, Full or part-time Employment: Bayer. N. Brega: Financial Interests, Personal, Full or part-time Employment: Bayer. E. De La Cuesta: Financial Interests, Personal, Full or part-time Employment: Bayer. A. Shurshalina: Financial Interests, Personal, Full or part-time Employment: Bayer. A. Drilon: Financial Interests, Personal, Advisory Role: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, Abbvie, 14ner/Elevation Onco; Financial Interests, Institutional, Research Grant: Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, Food/Beverage: Merck, Puma, Merus, Boehringer Ingelheim; Financial Interests, Personal, Other, CME homoraria: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Medscape, Clinical Care Optio. D. Hong: Financial Interests, Personal, Research Grant: 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, Pfize; Financial Interests, Personal, Advisory Board: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, and Trieza Therapeutics; Financial Interests, Personal, Ownership Interest: Molecular Match (advisor), OncoResponse (founder), and Presagia Inc (advisor); Financial Interests, Personal, Other, Travel/accomadation: Loxo Oncology, MiRNA, ASCO, AACR, SITC, Genmab.