Table 3.
ALK inhibitor characteristics: dosing, toxicity, IC50, and additional molecular targets
| Drug | Standard Dose | Toxicities | ALK IC50 | Additional Targets |
|---|---|---|---|---|
| Crizotinib [39–41, 87] | 250 mg twice daily (with or without food) | Visual effects (60%), nausea (45%), diarrhea (40%), edema (25%), constipation (25%), decreased appetite (18%), fatigue (15%) | 24 nM | MET, ROS1, VEGFR2, PDGFRβ, IRK, Lck, Tie2, TrkA, TrkB, RON, Axl |
| Ceritinib [55, 57, 81] | 750 mg (five 150-mg capsules) daily (without food) | Nausea (82%; 5% Gr 3–4), diarrhea (75%; 7% Gr 3–4), vomiting (65%; 5% Gr 3–4), fatigue (47%; 5% Gr 3–4), ↑ ALT (35%; 21% Gr 3–4), constipation (32%), abdominal pain (30%), decreased appetite (29%), ↑ AST (25%; 11% Gr 3–4) | 200 pM | IGF1-R, INSR, STK22D |
| Alectinib [56, 59, 88] | 600 mg twice daily | Fatigue (30%), myalgia (17%), edema (15%), ↑ CPK (15%), nausea (15%), ↑ ALT (13%), photosensitivity (13%), constipation (11%) | 3 nM | LTK, GAK |
| Brigatinib (AP26113) [85, 89] | Standard dose not yet established (30–300 mg daily) | nausea (45%), diarrhea (36%), fatigue (36%), cough (26%), headache (26%), Early-onset pulmonary events, observed ≤7 d after starting treatment, included dyspnea, hypoxia, or new pulmonary opacities on chest computed tomography suggestive of pneumonia or pneumonitis (9%) | 0.37 nM | FLT3, ROS1, IGF1E, INSR |
| Entrectinib (RXDX-101) [86, 90, 91] | Standard dose not yet established (800 mg/m2 used in ALK rearranged NSCLC) | paraesthesia (42%) nausea (37%), myalgia (34%), asthenia (27%), dysgeusia (27%), vomiting (21%), arthralgia (19%) and diarrhoea (19%) | 12 nM | ROS1, Pan-TRK |
| Loratinib (PF-06463922) [92–94] | Standard dose not yet established (10–200 mg daily) | hypercholesterolemia (48%), peripheral oedema (23%) and peripheral neuropathy (21%) | 1.3 nM | ROS1, pan-TRK, LTK, FER, FRK, PTK1, PTK2B, FES |
| Belizatinib (TSR-011) [95] | No standard dose (30 to 480 mg total per daily, administered 1,2, or 3 times daily) | fatigue (26.1%), diarrhea (21.7%), QTc prolongation (21.7%), headache (17.4%), decreased appetite (15.2%), urinary tract infection (15.2%), vomiting (15.2%), anemia (13%), asthenia (13%), constipation 13%), dysgeusia (10.9%) | 0.7 nM | Pan-TRK |