Table 1.
Efficacy results in registrational trials for 2nd and 3rd generation TKIs and KRAS-inhibitors in clinical practice.
| Oncogene | TKI | Registrational Trial | N° of Patients | Control Arm | Primary EP | Efficacy Results | CNS Activity in Patients with Evaluable Lesions |
|---|---|---|---|---|---|---|---|
| EGFR exon 19 deletions and exon 20 L858R | Afatinib | Phase IIB LUX-Lung-7 [14,61] | 319 | Gefitinib | PFS | Median PFS 11.0 vs. 10.9 months (HR 0.74; 95% CI, 0.57–0.95; p = 0.0178) |
NA |
| Dacomitinib | Phase III ARCHER 1050 [15,16] | 452 | Gefitinib | PFS | Median PFS 14.7 vs. 9.2 months (HR 0.59; 95% CI, 0.47–0.74; p < 0.0001) |
- | |
| Osimertinib | Phase III FLAURA [20,21,62] | 556 | Gefitinib or Erlotinib | PFS | Median PFS 18.9 vs. 10.2 months (HR 0.46; 95% CI, 0.37–0.57; p < 0.001) |
icORR 91% vs. 68% icDoR 15.2 vs. 18.8 months |
|
| ALK | Ceritinib | Phase III ASCEND-4 [63] | 376 | PBC | PFS | Median PFS 16.6 vs. 8.1 months (HR 0.55; 95% CI, 0.42–0.73; p < 0.00001) |
icORR 72.7% vs. 27.3% icDoR 16.6 months vs. NE |
| Alectinib | Phase III ALEX [34,35] | 303 | Crizotinib | PFS | Median PFS 34.8 vs. 10.9 months (HR 0.43; 95% CI 0.32–0.58, p = 0.0001) |
icORR 81% vs. 50% icDoR 17.3 vs. 5.5 months |
|
| Brigatinib | Phase III ALTA 1L [36] | 275 | Crizotinib | PFS | Median PFS 24.0 vs. 11.1 months (HR 0.48, 95% CI 0.35–0.66, log-rank p < 0.0001) |
icORR 78% vs. 26% icDoR 27.9 vs. 9.2 months |
|
| Lorlatinib | Phase III CROWN [37,38,64] | 296 | Crizotinib | PFS | Median PFS NR vs. 9.3 months (HR 0.28; 95% CI 0.19–0.41, p < 0.001) |
icORR 83% vs. 23% icDoR NR vs. 10.2 months |
|
| ROS1 | Entrectinib | Phase I-II ALKA-372-001, STARTRK-1, and STARTRK-2 [43,44] | 161 | - | ORR DoR |
ORR 67.1% (95% CI 59.3–74.3) Median DoR 15.7 months (95% CI 13.9–28.6) |
icORR 79.2% icDoR 12.9 months |
| MET Exon 14 skipping | Tepotinib | Phase II VISION trial [50,65] | 111, 1L T+ (cohort C + A) |
- | ORR | ORR 56.8% (95% CI, 47.0–66.1) | icORR 55% icDoR 9.5 months |
| 97, ≥2L (cohort C + A) |
ORR 49.5% (95% CI, 39.2–59.8) | ||||||
| Capmatinib | Phase II GEOMETRY-mono-1 trial [49,66,67,68] |
28 Treatment-naïve (cohort 5b) |
- | ORR | ORR 67.9% (95% CI, 47.6–84.1) | iORR 67.9% | |
| 32 Treatment-naïve (expansion cohort 7) |
ORR 65.6% (95% CI, 46.8–81.4) | ||||||
| 69 pretreated 2/3L (cohort 4) |
ORR 40.6% (95% CI, 28.9–53.1) | iORR 40.6% | |||||
| 31 pretreated 2L (expansion cohort 6) |
ORR 51.6% (95% CI, 33.1–69.8) | ||||||
| KRAS G12C | Sotorasib | Phase II CodeBreaK 100 [69] | 174 | - | ORR | ORR 40.7% (95% CI, 33.3–48.4) | icORR NR icDoR NR |
| Phase III CodeBreak 200 [45] | 345 | Docetaxel | PFS | Median PFS 5.6 vs. 4.5 months (HR 0.66; 95% CI 0.51–0.86, p = 0.0017) |
icORR 33% | ||
| Adagrasib | Phase I/II KRYSTAL-1 [47,70] | 116 | - | ORR | ORR 42.9% (95% CI, 34.5–52.6) | icORR 42% icDoR 12.7 months |
|
| RET | Selpercatinib | Phase I/II LIBRETTO-001 [54,71] | 69 Treatment-naïve | - | ORR | ORR 84% (95% CI, 73–92) | icORR 82% icDoR 9.4 months |
| 247 PPP | ORR 61% (95% CI, 55–67) | ||||||
| Pralsetinib | Phase I/II ARROW [55] | 75 Treatment-naïve | - | ORR | ORR 72% (95% CI, 60–82) | icORR 78% | |
| 136 PPP | ORR 59% (95% CI, 50–67) | ||||||
| BRAF V600E |
Dabrafenib/ Trametinib |
Phase II BRF113928 [56] |
36 Treatment-naïve (Cohort C) | - | ORR | ORR 63.9% (95% CI, 46.2–79.2) | NA |
| 57 Pretreated (Cohort B) |
- | ORR 68.4% (95% CI, 54.8–80.1) | |||||
| NTRK | Larotrectinib | Phase I/II NAVIGATE [58] | 20 NSCLC | - | ORR | ORR 73% (95% CI, 45–92) | icORR 63% |
| Entrectinib | Phase I/II STARTRK-1; STARTRK-2; ALKA-372–001 [59,60] | 22 NSCLC | - | ORR | ORR 63.6% (95% CI, 40.7–82.8) | icORR 67% |
CI: confidence interval; CNS: central nervous system; DoR: duration of response; EP: end point; HR: hazard ratio; icDCR: intracranial disease control rate; icDoR: intracranial duration of response; icORR: intracranial ORR; NA: not available; NE: not estimable; NR: not reached; NSCLC: non-small cell lung cancer; OR: odds ratio; ORR: objective response rate; OS: overall survival; PPP: platinum-pretreated patients; PFS: progression-free survival; T+: MET ex14 skipping positive in tissue biopsy; TKI: tyrosine kinase inhibitor; TTF: time-to-treatment failure.