Table.

ALK inhibitors, targets, mutational activity profiles, and toxicities

Drug	Targets	Sensitive ALK mutations	Resistant ALK mutations	Most common grade 1–2 side effects	Most common grade 3–4 side effects	References
Crizotinib	ALK MET ROS1	L1198F	1151T ins L1152R C1156Y F1174L L1196M L1198F G1202R S1206Y G1269A	Visual changes Orthostatic hypotension, Elevated creatinine, Peripheral edema Nausea Diarrhea Fatigue Constipation		[18][29]
Ceritinib	ALK IGF-R1 InsR ROS1	L1196M G1269A I1171T S1206Y L1152R F1174L V1180L	G1202R F1174C C1156Y .	Constipation Abdominal pain Decreased appetite	Diarrhea Vomiting Dehydration Elevated LFTs Low Phosphorous Elevated Lipase Fatigue	[16][18]
Alectinib	ALK LTK GAK	L1196M C1156Y F1174L G1269A S1206Y L1152R 1151T-ins	G1202 V1180L I1171T	Dysgeusia Elevated AST Elevated ALT Elevated bilirubin Elevated creatinine Rash Constipation Fatigue Myalgia Edema Elevated CPK Nausea Photosensitivity	Neutropenia Elevated creatinine Elevated CPK	[20]
Brigatinib	ALK ROS1 EGFR (including T790m)*	G1202R L1196M C1156Y G1202R G1269A S1206Y 1151T-ins F1174C I1171T D1203N E1210k F1245C	L1198F	Nausea Fatigue Headache, Diarrhea Vomiting Edema	Elevated ALT Dyspnea Pneumonia Pulmonary embolism Elevated lipase Hypertension Elevated amylase Fatigue Hyponatraemia Hypophosphatemia	[21]
Entrectinib	NTRK, ROS1, ALK	L1196M C1156Y		Paraesthesia Asthenia Nausea Vomiting Myalgia Arthralgia Dysgeusia Diarrhea	Asthenia Muscle weakness Cognitive impairment	[30]
Lorlatinib	ALK ROS1	L1196M G1202R G1269A	L1198F	Hypercholesterolemia Peripheral edema Peripheral neuropathy	Hypercholesterolemia	[31]

^*Preclinical evidence of activity against activating and resistance EGFR mutations but minimal clinical efficacy.

InsR: Insulin receptor.

IGF-R1: Insulin like growth factor.

MET: Proto-oncogene protein c-MET

ALK: Anaplastic lymphoma kinase

EGFR: Epidermal growth factor receptor

ROS1: ROS Proto-Oncogene 1

LTK: Leukocyte Receptor Tyrosine Kinase

GAK: Cyclin G-associated kinase

ALT: Alanine transaminase

AST: Aspartate transaminase

LFTs: Liver function tests

CPK: Creatine phosphokinase

NTRK1: Neutrotrophic tyrosine kinase 1