40 / 48
of resistance mutation
Figure 6.
Lorlatinib potently inhibits
ALK
resistance mutations, including
ALK
G1202R. Absolute
IC
50
values of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib on cellular ALK
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Figure 1.
Overview of on-target mechanisms of resistance among ALK-positive specimens obtained
from patients progressing on: A) crizotinib, B) ceritinib, and C) alectinib. Pie charts depict
the frequency and distribution of
ALK
resistance mutations and
ALK
fusion gene
amplification in each cohort. Four patients underwent two separate biopsies while on
crizotinib; one patient underwent two separate biopsies while on ceritinib. Note: If a
specimen is listed as having ≥2
ALK
resistance mutations, the individual mutations are not
listed separately.
a
One post-crizotinib specimen harbored
ALK
G1269A and 1151Tins
mutations. Four post-ceritinib samples contained ≥2 ALK resistance mutations. These
included: I1171N+C1156Y, D1203N+F1174C, F1174L+G1202R, C1156Y+G1202del
+V1180L mutations.
b
ALK fluorescence in situ hybridization (FISH) to assess for fusion
gene amplification was performed in only crizotinib-resistant specimens (N=36), of which
8% had amplification. Ceritinib- and alectinib-resistant specimens were not assessed for
ALK
amplification by FISH. ALK, anaplastic lymphoma kinase; WT, wild-type.
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ROS1 Inhibitors : Better CNS penetration,
nst resistance kinase domain mutations
Drilon et al ASCO 2018
ALK G1202R
Lorlatinib > Ropotrectinib
ROS1 G2032R
Ropotrectinib > Lorlatinib
Drilon et al ASCO 2018 ; Gainor et al Cancer discov 2016