Table 1. Pre-clinical and clinical data of approved and investigational ALK inhibitors.
| ALK-inhibitor (pharmaceutical company) | Molecular targets | ALK mutations targeted | Clinical trial (Comparator, line) [publication] | Phase | No. of patients | ORR (%) | Median PFS (months); median OS (months) | Most common grade 1–2 AEs (%) |
|---|---|---|---|---|---|---|---|---|
| Crizotinib (Xalkori®,Pfizer) | ALK, MET, ROS1 | PROFILE1001 | I | 149 | 61% | 9.7 | Edema: 35%; nausea: 35%; visual disturbance: 29%; bradycardia: 24%; vomiting: 24% | |
| PROFILE1005 [Blackhall et al. ESMO 2017] | II | 261 | 60% | 8.1 | Visual disturbance: 59%; nausea: 58%; vomiting: 44%; diarrhea: 41% | |||
| PROFILE1007 (vs. pemetrexed/docetaxel, 2nd line) [Shaw et al. 2013] | III | 347 | 65% vs. 20%, P<0.001 | 7.7 vs. 3.0 (P<0.001); median OS: 20.3 vs.22.8 (P=0.54) | Visual disturbance: 60%; diarrhea: 60%; nausea: 55%; vomiting: 47%; constipation: 42%; increased AST: 38%; edema: 31%; fatigue: 27% | |||
| PROFILE1014 (vs. platinum/pemetrexed, 1st line) [Solomon et al. 2014] | III | 343 | 74% vs. 45%, P<0.001 | 10.9 vs. 7.0 (P<0.001); median OS: not reached in either group | Visual disturbance: 71%; diarrhea: 61%; edema: 49%; vomiting: 46%; constipation: 43%; increased AST: 36% | |||
| Ceritinib (LDK378) (Zycadia®,Pfizer) | ALK, IGF-1R, ROS1 | L1196M, I1171T, G1269A, I1171T, S1206Y, L1152R, F1174L, V1180L | ASCEND-1 [Shaw et al. 2014] [Kim et al. 2016] | I | 130 | 72% in crizotinib-naïve, 56% in crizotinib-pretreated | 18.4 in crizotinib-naïve, 6.9 in crizotinib-pretreated | Nausea: 82%; diarrhea: 75%; vomiting: 65%; fatigue: 47%; increased ALT: 35% |
| ASCEND-2 [Mok et al. 2015] [Crino et al. 2016] | II | 140 (crizotinib-pretreated) | 38.6% | 5.7 | Nausea: 81.4%; diarrhea: 80.0%; vomiting: 62.9% | |||
| ASCEND-3 [Felip et al. ASCO 2015] | II | 124 (crizotinib-naive) | 63.7% | 11.1 | Diarrhea: 82.3%; nausea: 74.2%; vomiting: 66.9% | |||
| ASCEND-4 (vs. platinum/pemetrexed, 1st line) [Soria JC et al. 2017] | III | 376 (crizotinib-naive) | 72.5% vs. 26.7% (P<0.001) | 16.6 vs. 8.1 (P<0.001) | Diarrhea: 85%; nausea: 69%; vomiting: 66% | |||
| ASCEND-5 (vs. docetaxel or pemetrexed, 3rd line) [Shaw et al. 2017] | III | 231 (previously treated with platinum doublet and crizotinib) | 39.1% vs. 6.9% | 5.4 vs. 1.6 (P<0.001) | Diarrhea: 68%; nausea: 58%; vomiting: 44%; increased ALT: 22%; increased AST: 23%; fatigue: 22% | |||
| Alectinib (CH5424802/RO5424802) (Roche) | ALK, LTK, GAK | L1196M, C1156Y, F1174L, G1269A, S1206Y, L1152R, 1151T-ins | AF-001JP [Seto et al. 2013] [Tamura et al. 2014] | I/II | 46 (crizotinib-naive) | 93.5% | 10.3 | Dysgeusia: 30%; increased AST: 28%; increased bilirubin: 28%; increased creatinine: 26%; rash: 26%; constipation: 24%; increased ALT: 22% |
| AF-002JG (dose escalation) [Gadgeel et al. 2014] | I/II | 47 (crizotinib-pretreated) | 55% | N/A | Fatigue: 30%; myalgia: 17%; peripheral oedema: 15% | |||
| NP28673 (NCT01801111) [Ignatius Ou et al. 2016] | II | 138 (crizotinib-pretreated) | 49.2% | 8.9 | Myalgia: 17%; constipation: 15%; fatigue: 14%; asthenia: 11%; increased AST: 10% | |||
| NP28761 (NCT01871805) [Shaw et al. 2016] | II | 87 (crizotinib-pretreated) | 47.8% | 6.3 | Constipation: 36%; fatigue: 30%; peripheral oedema: 22%; myalgia: 22%; increased AST: 21%; increased CPK: 21%; nausea: 20%; diarrhea: 18%; increased ALT: 18% | |||
| ALEX (vs. crizotinib) (NCT02075840) [Peters et al. 2017] | III | 126 (crizotinib-naive) | 81% vs. 50% | 25.7 vs. 10.4 | Nausea: 48%; diarrhea: 45%; vomiting: 38%; ALT increased: 30% | |||
| J-ALEX (vs. crizotinib) (JapicCTI-132316) [Hida et al. 2017] | III | 103 (crizotinib-naive) | 85% vs. 70% | Not reached vs. 10.2 | Constipation: 35%; nasopharyngitis: 20%; blood creatine phosphokinase increase: 17% | |||
| Brigatinib (AP26113) (ARIAD) | ALK, T790M-mutant EGFR, ROS1 | G1202R, C1156Y, L1196M, l1171T, F1174C, F1245C, L1198F, L1152R, L1152p, D1203N, G1269A, S1206Y, 1151T-ins, E1210K, | NCT01449461 [Camidge et al. 2015] | I/II | 79 (crizotinib-pretreated) | 71% | 13.4 | Nausea: 52%; fatigue: 42%; diarrhea: 40% |
| ALTA trial (NCT02094573) [Kim et al. 2017] | II | 222 (crizotinib-refractory) | 45% in 90 mg, 54% in 180 mg | 9.2 in 90 mg, 12.9 in 180 mg | Nausea: 33%/40%; diarrhea: 19%/38%; headache: 28%/27%; cough: 18%/34% | |||
| Lorlatinib (PF-06463922) (Pfizer) | ALK, ROS1, EGFR | G1202R, C1156Y, l1171N/S/T, F1174C, V1180L, L1196M, L1198F, D1203N, E1210K, G1269A | NCT01970865 (dose escalation) | I/II | 32 (crizotinib-pretreated) | 53.1% | 12.9 | Hypercholesterolemia: 69%; peripheral edema: 37% |
| Entrectinib (RXDX-101) | ALK, TrkA, TrkB, TrkC, ROS1 | C1156Y, L1196M | NCT02097810 (dose escalation) | I/II | 4 (crizotinib-naive) | 50% | NR | Paraesthesia: 42%; nausea: 37%; myalgia: 34%; asthenia: 27%; dysgeusia: 27%; vomiting: 21%; arthralgia: 19%; diarrhea: 19% |
| Ensartinib (X-396) | ALK, MET | L1196M, C1156Y | NCT01625234 | I | 8 (crizotinib-naive), 12 (crizotinib-pretreated) | 88% in crizotinib-naïve pts, 83% in crizotinib-pretreated pts | NR | Rash: 31%; nausea: 31%; vomiting: 29%; fatigue: 26%; oedema: 17%; pruritus: 11% |
ALK, anaplastic lymphoma kinase; ORR, overall response rate; PFS, progression-free survival; OS, overall survival.