Table 3. Safety profile of ALK inhibitors.
| Drug | Study | Grade 3–4 toxicities | Most common all-grade adverse event |
|---|---|---|---|
| Crizotinib | Phase I (63) (PROFILE-1001), 149 patients | ALT: 6 pts (4%); AST: 5 pts (3%) | Visual disorders: 96 pts (64%) |
| Phase II (12) (PROFILE-1005), 901 patients | Neutropenia: 72 pts (8%); ALT: 55 pts (6.1%); fatigue: 22 pts (2.5%) | Visual disorders: 571 pts (63.3%) | |
| Phase III (11) (PROFILE-1007), 173 patients | ALT/AST: 27 pts (16%); dyspnea: (7 patients, 4%) |
Visual disorders: 103 pts (60%) | |
| Phase III (13) (PROFILE-1014), 172 patients | ALT/AST: 24 pts (14%) | Visual disorders: 122 pts (71%) | |
| Ceritinib (LDK378), 750 mg/die | Phase I (70) (ASCEND-1), 255 patients | ALT: 73 pts (30%); AST: 25 pts (10%); diarrhea: 15 pts (6%); nausea: 15 pts (6%); lipase: 16 pts (6%); hyperglycaemia: 15 pts (6%) |
Diarrhea: 213 pts (86%) |
| Phase II (71) (ASCEND-2), 140 patients | ALT: 24 pts (17.1%), nausea: 9 pts (6.4%), diarrhea: 9 pts (6.4%), fatigue: 9 pts (6.4%), dyspnea: 8 pts (5.7%), AST: 7 pts (5%) |
Nausea: 114 pts (81.4%) | |
| Phase II (72) (ASCEND-3), 124 patients | Gamma-GT: 23 pts (18.5%); ALT: 19 pts (15.3%); AST: 9 pts (7.3%) |
Diarrhea: 102 pts (82.3%) | |
| Alectinib (CH5424802, RO5424802) | Phase I/II (73) (AF-001JP), phase II portion, 46 patients | Neutropenia: 2 pts (4%); CPK: 2 pts (4%) | Dysgeusia: 14 pts (30%) |
| Phase I/II (74) (AF-002JG), dose escalation, 47 patients | Gamma-GT: 2 pts (4%); neutropenia: 2 pts (4%); hypophosphatemia: 2 pts (4%) | Fatigue: 14 patients (30%) | |
| Phase II (75) (NP28761), 86 patients | CPK: 7 pts (8%); ALT: 5 pts (6%); AST: 4 patients (5%) | Constipation: 31 pts (36%) | |
| Phase II (76) (NP28673), 136 patients | Dyspnea: 4 pts, 3%; ALT: 2 pts (2%); AST: 2 pts (2%) | Constipation: 45 pts (33%) | |
| Brigatinib (AP26113) | Phase I/II (77) (NCT01449461), 137 patients | Lipase: 12 pts (9%); dyspnea: 9 pts (7%); pneumonia: 8 pts (6%); fatigue: 6 pts (4%); hypoxia: 7 pts (5%); amylase: 6 pts (4%) |
Nausea: 71 pts (52%) |
| Lorlatinib (PF-06463922) | Phase I/II (78), dose escalation (NCT01970865), 45 patients | Hypercholesterolemia: 5 pts (11%) | Hypercholesterolemia: 26 pts (59%) |
| Entrectinib (RXDX-101) | Phase I (112) (ALKA-372-001), 38 patients | Asthenia (DLT): 2 pts (5.3%); muscular weakness (DLT): 2 pts (5.3%) | Paresthesia: 16 pts (42%) |
| Phase I/IIa (113) (STARTRK-1), 27 patients | Neutropenia (DLT): 3 pts (11%); fatigue (DLT): 2 pts (7%); cognitive impairment (DLT): 2 pts (7%) | Fatigue: 9 pts (33%) |
ALK, anaplastic lymphoma kinase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; gamma-GT, gamma-glutamyl-transpeptidase; CPK, creatine-phosphokinase; DLT, dose-limiting toxicity.