30 / 32
PRIMARY AND ACQUIRED RESISTANCE
TO LAROTRECTINIB
Primary resistance in 6/ 55 patients (11%)
•
NTRK3
G623R mutation in one patient
•
3/5 had material available. In all three patients, central pan-TRK immunohistochemical testing did not confirm the
presence of an expressed TRK fusion, ( false positive or fusion was not expressed at the protein level?)
Secondary resistance in 10/55 patients (objective response or stable disease for at least 6 months)
•
mutations affecting the
NTRK
gene involved in the fusion were identified in tumor or plasma samples
•
Mutations: substitutions in the solvent front position (
NTRK1
G595R or
NTRK3
G623R in 7 patients), the gatekeeper
position (
NTRK1
F589L in 2), and the xDFG position (
NTRK1
G667S or
NTRK3
G696A in 2
Specifically designed to address acquired kinase domain mutations ,
LOXO-195
is currently being evaluated in a phase 1–2 study
involving children and adults
Drilon A. NEJM 2018, Kummar S Targeted Oncology 2018