Pharmacologic properties of ALK inhibitors approved by the FDA or in clinical testing
ALK TKI | Crizotinib (PF-02341066) | Ceritinib (LDK378) | Alectinib (RO/CH5424802) | Brigatinib (AP26113) | Lorlatinib (PF-06463922) | Entrectinib (RXDX-101) | Ensartinib (X-396) |
---|---|---|---|---|---|---|---|
Manufacturer | Pfizer | Novartis | Genentech | Ariad | Pfizer | Ignyta | Xcovery |
Targets other than ALK | ROS1 | ROS1 | GAK | ROS1 | ROS1 | NTRK1 | ROS1 |
MET | IGF1R | LTK | NTRK2 | MET | |||
IR | RET | NTRK3 | AXL | ||||
ROS1 | |||||||
Resistance mutations known to be targeted by TKI | L1198F | I1171T/N | L1152P/R | I1151Tins | I1151Tins | C1156Y/T | C1156Y/T |
L1196M | C1156Y/T | L1152P/R | L1152P/R | L1196M | L1196M | ||
S1206C/Y | F1174C/L/V | C1156Y/T | C1156Y/T | ||||
G1269A/S | L1196M | F1174C/L/V | I1171T/N/S | ||||
S1206C/Y | L1196M | F1174C/L/V | |||||
G1269A/S | G1202Ra | L1196M | |||||
G1269A/S | G1202Rb | ||||||
S1206C/Y | |||||||
E1210K | |||||||
G1269A/S | |||||||
Reported resistance mutations to the TKI | I1151Tins | I1151Tins | I1171T/N/S | G1202Ra | L1198F + C1156Yc | G1202R | N.D. |
L1152P/R | L1152P/R | V1180L | E1210K + S1206C | ||||
C1156Y/T | C1156Y/T | G1202R | E1210K + D1203N | ||||
I1171T/N/S | F1174C/L/V | ||||||
F1174C/L/V | G1202R | ||||||
V1180L | |||||||
L1196M | |||||||
G1202R | |||||||
S1206C/Y | |||||||
E1210K | |||||||
G1269A/S | |||||||
Regulatory approval | Approved for 1L and beyond | Approved for crizotinib-pretreated | Approved for crizotinib-pretreated; breakthrough therapy designation for 1L | Breakthrough therapy designation for crizotinib-pretreated | N/A | N/A | N/A |
Phase of testing | Phase III complete | III | III | III | III | II | III |
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).