Table 1.
Summary of FDA-approved ALK inhibitors
| ALK TKI | Phase | Trial | Treatment | TKI dose | PFS (months) (95% CI) | ORR% (95% CI) | Ref. |
| 1st generation | |||||||
| Crizotinib | I | PROFILE 1001 | Single arm; crizotinib naive | Crizotinib 250 mg BID | 9.7 (7.7-12.8) | 60.8 (52.3-68.9) | Camidge et al., 2012[14] |
| II | PROFILE 1005 | Single arm; recurrent disease after ≥ 1 chemotherapy | Crizotinib 250 mg BID | 8.1 (6.8-9.7) | 60.0 (53.6-65.9) | Kim et al., 2012[15] | |
| III | PROFILE 1007 | Vs. chemotherapy (pemetrexed or docetaxel); second line after one prior platinum-based regimen | Crizotinib 250 mg BID | 7.7 (6.0-8.8) vs. 3.0 (2.6-4.3) | 65 (58-72) vs. 19.5 (14-26) | Shaw et al., 2013[9] | |
| III | PROFILE 1014 | Vs. chemotherapy (pemetrexed and cisplatin or pemetrexed and carboplatin); first line | Crizotinib 250 mg BID | 10.9 (8.3-13.9) vs. 7.0 (6.8-8.2) | 74 (67-81) vs. 45 (37-53) | Solomon et al., 2014[13] | |
| III | PROFILE 1029 | Vs. chemotherapy (pemetrexed and cisplatin or pemetrexed and carboplatin); first line | Crizotinib 250 mg BID | 11.1 (8.3-12.6) vs. 6.8 (5.7-7.0) | 87.5 (79.6-93.2) vs. 45.6 (35.8-55.7) | Wu et al., 2018[16] | |
| 2nd generation | |||||||
| Ceretinib | I | ASCEND-1 | Single arm; refractory disease despite standard therapy | Ceretinib 750 mg daily | 18.4 (11.1 - NE) in ALKi naive vs. 6.9 (5.6-8.7) in ALKi pretreated | 72 (61-82) in ALKi naive vs. 56 (49-64) in ALKi pretreated | Kim et al., 2016[17] |
| II | ASCEND-2 | Single arm; recurrent disease after ≥ 1 chemotherapy who progressed ≤ 30 days from last treatment with crizotinib | Ceretinib 750 mg daily | 5.7 (5.4-7.6) | 38.6 (30.5-47.2) | Crinò et al., 2016[18] | |
| II | ASCEND-3 | Single arm; ALK inhibitor naive | Ceretinib 750 mg daily | 11.1 (9.3 - NE) | 63.7 (54.6-72.2) | Felip et al., 2015[19] | |
| III | ASCEND-4 | Vs. chemotherapy (pemetrexed and cisplatin or pemetrexed and carboplatin); first line | Ceretinib 750 mg daily | 16.6 (12.6-27.2) vs. 8.1 (5.8-11.1) | Soria et al., 2017[20] | ||
| III | ASCEND-5 | Vs. chemotherapy (pemetrexed or docetaxel); progression after chemotherapy and crizotinib | Ceretinib 750 mg daily | 5.4 (4.1-6.9) vs. 1.6 (1.4-2.8) | 39.1 (30.2-48.7) vs. 6.9 (3.0-13.1) | Shaw et al., 2017[21] | |
| I/II | ASCEND-6 | Single arm; progression on crizotinib | Ceretinib 750 mg daily | 5.7 (5.4-7.5) | 40.8 (31.2-50.9) | Zhang et al., 2016[22] | |
| I | ASCEND-8 | Vs. ceretinib 450 mg daily and ceretinib 600 mg daily | Ceretinib 750 mg daily | 450 mg: NE (11.2 - NE) vs. 600 mg: 20.7 (15.8 - NE) vs. 750 mg: 15.4 (8.3 - NE) | 450 mg: 78.1 (66.9-86.9) vs. 600 mg: 72.5 (58.3-84.1) vs. 750 mg: 75.7 (64.3-84.9) | Cho et al., 2017[23] | |
| Alectinib | I/II | AF-001JP | Single arm; ALK inhibitor naive | Alectinib 300 mg BID | 93.5 (82.1-98.6) | Seto et al., 2013[24] | |
| II | NP28761 | Single arm; progression on crizotinib | Alectinib 600 mg BID | 47.8 (35.6-60.2) | Gandhi et al., 2015[25] | ||
| II | NP28673 | Single arm; progression on crizotinib | Alectinib 600 mg BID | 49.2 (40.0-58.4) | Ou et al., 2015[26] | ||
| III | ALEX | Vs. crizotinib; first line | Alectinib 600 mg BID | 82.9 (76.0-88.5) vs. 75.5 (67.8-82.1) | Peters et al., 2017[27] | ||
| III | ALUR | Vs. chemotherapy (pemetrexed or docetaxel); progression after chemotherapy and crizotinib | Alectinib 600 mg BID | 7.1 (6.3-10.8) vs. 1.6 (1.3-4.1) | Novello et al., 2018[28] | ||
| III | J-ALEX | Vs. crizotinib; first line | Alectinib 300 mg BID | NYR (20.3 - NE) vs. 10.2 (8.2-12.0) | Hida et al., 2017[29] | ||
| III | ALESIA | Vs. crizotinib; first line | Alectinib 600 mg BID | NE vs. 11.1 | Zhou et al., 2019[30] | ||
| Brigatinib | I/II | ALTA | Vs. brigatinib 90 mg daily; progression after crizotinib | Brigatinib 90 mg daily for 7 days, then 180 mg daily | 9.2 vs. 15.6 | 48 vs. 53 | Hochmair et al., 2017[31] |
| III | ALTA-1L | Vs. crizotinib; first line | Brigatinib 90 mg daily for 7 days, then 180 mg daily | 71 (62-78) vs. 60 (51-68) | Camidge et al., 2018[32] | ||
| II | J-ALTA | Single arm; progression on alectinib and/or crizotinib | Brigatinib 90 mg daily for 7 days, then 180 mg daily | 7.3 (3.7-12.9) | 34 (21-49) | Yoshida et al., 2023[33] | |
| II | ALTA-2 | Single arm; progression on alectinib or ceretinib | Brigatinib 90 mg daily for 7 days, then 180 mg daily | 3.8 (3.5-5.8) | 26.2 (18.0-35.8) | Kim et al., 2021[34] | |
| III | ALTA-3 | Vs. alectinib; progression on crizotinib | Brigatinib 90 mg daily for 7 days, then 180 mg daily | 19.3 (15.7 - not reached) vs. 19.2 (12.9 - not reached) | 52 (43-61) vs. 61 (52-70) | Yang et al., 2023[35] | |
| 3rd generation | |||||||
| Lorlatinib | III | CROWN | Vs. crizotinib; first line | Lorlatinib 100 mg daily | 78 (70-84) vs. 39% (30-48) | 76 (68-83) vs. 58% (49-66) | Shaw et al., 2020[36] |
FDA: Food and Drug Administration; ALK: anaplastic lymphoma kinase; TKI: tyrosine kinase inhibitor; BID: twice a day; PFS: progression-free survival; 95% CI: 95% confidence interval; ORR: objective response rate; NE: not estimated; ALKi: ALK inhibitor; NYR: not yet reached at the time of data analysis.