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Malapelle et al. J Transl Genet Genom 2019;3:3. I https://doi.org/10.20517/jtgg.2018.29 Page 7 of 9

Table 1. Tyrosine kinase inhibitors effectiveness against secondary resistance mutations
TKI Effectiveness against secondary resistance mutations
Crizotinib G1202R: IC50 = 381.6 nmol/L
L1196M: IC50 = 339.0 nmol/L
F1174C: IC50 = 115.0 nmol/L
I1171T/S: IC50 = 51.4/94.1 nmol/L
[33]
Ceritinib G1202R: IC50 = 124.4 nmol/L
L1196M: IC50 = 9.3 nmol/L
F1174C: IC50 = 38.0 nmol/L
I1171T/S: IC50 = 1.7/3.8 nmol/L
[33]
Alectinib G1202R: IC50 = 706.6 nmol/L
L1196M: IC50 = 117.6 nmol/L
F1174C: IC50 = 27.0 nmol/L
I1171T/S: IC50 = 33.6/117.0 nmol/L
[33]
Brigatinib G1202R: IC50 = 129.5 nmol/L
L1196M: IC50 = 26.5 nmol/L
F1174C: IC50 = 18.0 nmol/L
I1171T/S: IC50 = 6.1/17.8 nmol/L
[33]

TKI: tyrosine kinase inhibitors; IC: half maximal inhibitory concentration

one of the most promising third generation ALK-TKI, shows activity against all known ALK resistance
mutations ( including G1202R: IC50 = 49.9 nmol/L), succeeding were first and second generation ALK-TKI
failed, as well as excellent results in several different settings: crizotinib-pretreated patients (CNS ORR: 68%),
not crizotinib ALK-TKI pretreated patients (ORR: 33%, CNS ORR: 42%), patients pretreated with two or
three previous ALK-TKI (ORR: 39%, CNS ORR: 39%), naive patients (ORR: 90%, CNS ORR: 75%) [33,40] .

In the light of the latest ALK-TKI developments, it appears clear that in the near future these drugs will be
administered according to a multi-step strategy, based on the information coming from genomic analyses,
in order to choose the right drug for the right mutation at the right time, maximizing the benefits coming
from the best possible therapeutic sequence.

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