Table 1 |.
Summary of ALK inhibitors approved by the FDA or in clinical testing
| ALK TKI | TKI generation | Status | Trial namea (phase) | Comparator | n | Median PFSb, months (HR, 95% CI) | ORR, % (95% CI) | IC-ORRc, % (95% CI) | ALK mutations refractory to TKI | References |
|---|---|---|---|---|---|---|---|---|---|---|
| Crizotinib | 1G | Approved for 1L and beyond | PROFILE 1014 (phase 3) | Chemotherapy (platinum-based doublet) | 343 | 10.9 versus 7.0 (0.45, 0.35–0.60) |
74% (67–81%) versus 45% (37–53%) |
N/A | L1196M G1202R I1171T/N/S G1269A/S S1206Y I1151Tins L1152P/R C1156Y/T F1174C/L/V V1180L S1206C/Y E1210K |
4,5,43,60 |
| Ceritinib | 2G | Approved for 1L and beyond | ASCEND-4 (phase 3) | Chemotherapy (platinum-based doublet) | 376 | 16.6 versus 8.1 (0.55, 0.42–0.73) |
73% (66–79%) versus 27% (21–34%) |
73% (50–89%) versus 27% (11–50%) |
G1202R/del I1151Tins L1152P/R C1156Y/T F1174C/L/V D1203K G1269A |
6,45 |
| Alectinib | 2G | Approved for 1L and beyond | ALEX (phase 3) | Crizotinib | 303 | 25.7 versus 10.4 (0.50, 0.3–0.70) |
83% (76–89%) versus 76% (68–82%) (INV) |
81% (58–95%) versus 50% (28–72%) (INV) |
G1202R/del V1180L I1171T/N/S L1196M |
7,45,49-51 |
| Brigatinib | 2G | Approved for 1L and beyond | ALTA-1L (phase 3) | Crizotinib | 275 | 24.0 versus 11.1 (0.48, 0.35–0.66) |
74% (66–82%) versus 62% (54–70%) |
78% (52–94%) versus 26% (10–48%) |
G1202R/del E1210K |
8,45-47,90 |
| Ensartinib | 2G | Phase 3 | eXalt3 (phase 3) | Crizotinib | 290 | 25.8 versus 12.7 (0.51, 0.35–0.72) |
74% (66–81%) versus 67% (58–74%) |
64% versus 21% |
G1269A G1202R/del E1210K | 48,90 |
| Lorlatinib | 3G | Approved for 1L and beyond | CROWN (phase 3) | Crizotinib | 296 | NR versus 9.3 (0.27, 0.18–0.39) |
76% (68–83%) versus 58% (49–66%) |
82% (57–96%) versus 23% (5–54%) |
C1156Y + L1198F I1171N + L1198F G1202R + F1174L G1202R + L1196M D1203N + L1196M G1202R + S1206Y G1202R + C1156Y G1202R + G1269A C1156Y + G1269A I1171N/T + D1203N G1202R + G1269A G1202R + L1204V + G1269A G1202R + S1206F + G1269A D1203N + E1210K + G1269A |
9,36,52-54,65,68 |
| TPX-0131 | 4G | Phases 1–2 | FORGE-1 (NCT04849273) |
None | N/A | N/A | N/A | N/A | N/A | 97 |
| NVL-655 | 4G | Phases 1–2 | ALKOVE-1 (NCT05384626) |
None | N/A | N/A | N/A | N/A | N/A | 98 |
a
Seminal global randomized phase 3 trials are listed for the FDA-approved agents and for ensartinib, which is approved as first-line treatment in China.
b
Median PFS according to blinded independent review committee assessment is shown.
c
Intracranial response rates in patients with baseline measurable brain metastases are shown, according to blinded independent review committee assessment unless indicated otherwise. CI, confidence interval; HR, hazard ratio; IC-ORR, intracranial ORR; INV, per-investigator assessment; NR, not reached; N/A, not available.