Table 2.

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	G1202R^a	L1196M
				G1269A/S	G1202R^b
					S1206C/Y
					E1210K
					G1269A/S
Reported resistance mutations to the TKI	I1151Tins	I1151Tins	I1171T/N/S	G1202R^{^a}	L1198F + C1156Y^c	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 ALK^G1202R 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).