Table 2.

Pharmacologic properties of ALK inhibitors approved by the FDA or in clinical testing

ALK TKICrizotinib (PF-02341066)Ceritinib (LDK378)Alectinib (RO/CH5424802)Brigatinib (AP26113)Lorlatinib (PF-06463922)Entrectinib (RXDX-101)Ensartinib (X-396)
ManufacturerPfizerNovartisGenentechAriadPfizerIgnytaXcovery
Targets other than ALKROS1ROS1GAKROS1ROS1NTRK1ROS1
METIGF1RLTKNTRK2MET
IRRETNTRK3AXL
ROS1
Resistance mutations known to be targeted by TKIL1198FI1171T/NL1152P/RI1151TinsI1151TinsC1156Y/TC1156Y/T
L1196MC1156Y/TL1152P/RL1152P/RL1196ML1196M
S1206C/YF1174C/L/VC1156Y/TC1156Y/T
G1269A/SL1196MF1174C/L/VI1171T/N/S
S1206C/YL1196MF1174C/L/V
G1269A/SG1202RaL1196M
G1269A/SG1202Rb
S1206C/Y
E1210K
G1269A/S
Reported resistance mutations to the TKII1151TinsI1151TinsI1171T/N/SG1202RaL1198F + C1156YcG1202RN.D.
L1152P/RL1152P/RV1180LE1210K + S1206C
C1156Y/TC1156Y/TG1202RE1210K + D1203N
I1171T/N/SF1174C/L/V
F1174C/L/VG1202R
V1180L
L1196M
G1202R
S1206C/Y
E1210K
G1269A/S
Regulatory approvalApproved for 1L and beyondApproved for crizotinib-pretreatedApproved for crizotinib-pretreated; breakthrough therapy designation for 1LBreakthrough therapy designation for crizotinib-pretreatedN/AN/AN/A
Phase of testingPhase III completeIIIIIIIIIIIIIIIII
References(3, 4, 74, 78)(73, 78)(78, 137, 184)(78, 124–130)(74, 78, 131)(132–134)(135, 136)
  • Abbreviations: TKI, tyrosine kinase inhibitor; IGF1R, insulin-like growth factor 1 receptor; IR, insulin receptor; GAK, cyclin G–associated kinase; LTK, leukocyte receptor tyrosine kinase; RET, rearranged during transfection; TRK, tropomyosin receptor kinase; N.D., not determined; 1L, first-line; N/A, not applicable.

  • aBrigatinib has been reported to have some activity against the ALKG1202R mutation (128–130), but G1202R has also been detected in biopsy specimens from patients with ALK-rearranged NSCLC who relapsed on brigatinib (78), suggesting that its potency may be compromised against this mutation.

  • bG1202R is a highly refractory mutation resistant to all first- and second-generation inhibitors, but targeted by lorlatinib (74, 78).

  • cL1198F has been found to confer resistance to lorlatinib in the context of another mutation, C1156Y (74).