Major achievements in clinical outcomes for patients with druggable genetic alterations
| Gene/Mutation | Drug | Study | Number of patients | Response rate | PFS | OS | Reference | Brief description of the study |
|---|---|---|---|---|---|---|---|---|
| EGFR ex19del and L858R | Osimertinib | NCT02296125 (FLAURA) | 279, treatment-naive | 80% | 18.9 months | 38.6 months | [11] | Phase III, osimertinib vs. 1st-generation TKI |
| Osimertinib + chemotherapy | NCT04035486 (FLAURA2) | 279, treatment-naive | 83% | 29.4 months | Not reached | [14] | Phase III, osimertinib plus chemotherapy vs. osimertinib alone | |
| Erlotinib + ramucirumab | NCT02411448 (RELAY) | 224, treatment-naive | 76% | 19.4 months | Not reached | [15] | Phase III, erlotinib plus ramucirumab vs. erlotinib alone | |
| EGFR exon 20 insertions | Amivantamab | NCT02609776 (CHRYSALIS) | 81, previously treated | 40% | 8.3 months | 22.8 months | [16] | Phase I |
| ERBB2 (HER2) mutations | Trastuzumab deruxtecan (T-DXd) | NCT04644237 (DESTINY-Lung02) | 152, previously treated | 49% (5.4 mg/kg); 56% (6.4 mg/kg)* | 9.9 months (5.4 mg/kg); 15.4 months (6.4 mg/kg)* | 19.5 months (5.4 mg/kg); not reached (6.4 mg/kg)* | [17]* | Phase II, comparison of two drug doses |
| BRAF V600 mutations | Dabrafenib + trametinib | NCT01336634 | 36, treatment-naive | 64% | 10.9 months | 17.3 months | [18] | Phase II |
| Encorafenib + binimetinib | NCT03915951 | 59, treatment-naive | 75% | Not reached | Not reached | [19] | Phase II | |
| KRAS G12C | Sotorasib | NCT04303780 (CodeBreak 200) | 141, previously treated by chemotherapy and ICI | 28% | 5.6 months | 10.6 months | [20] | Phase III, sotorasib vs. docetaxel |
| Adagrasib | NCT03785249 (KRYSTAL-1) | 112, previously treated by chemotherapy and ICI | 43% | 6.5 months | 12.6 months | [21] | Phase I−II | |
| MET exon 14 skipping mutations | Capmatinib | NCT02414139 (GEOMETRY) | 28, treatment-naive | 68% | 12.4 months | 20.8 months | [22] | Phase II |
| Tepotinib | NCT02864992 (VISION) | 164, treatment-naive | 57% | 12.6 months | 21.3 months | [23] | Phase II | |
| ALK fusions | Alectinib | NCT02075840 (ALEX) | 152, treatment-naive | 83% | 34.8 months | Not reached | [24] | Phase III, alectinib vs. crizotinib |
| Lorlatinib | NCT03052608 (CROWN) | 149, treatment-naive | 76% | Not reached (above 3 years) | Not reached | [25] | Phase III, lorlatinib vs. crizotinib | |
| ROS1 fusions | Crizotinib | NCT00585195 (PROFILE 1001) | 53, previously treated and treatment-naive | 72% | 19.3 months | 51.4 months | [26] | Phase I |
| Entrectinib | NCT02097810 (STARTRK-1), NCT02568267 (STARTRK-2), EudraCT, 2012-000148-88 (ALKA-372-001) | 168, previously treated (without TKI) and treatment-naive | 68% | 15.7 months | 47.8 months | [27] | Phase I−II | |
| Repotrectinib | NCT03093116 (TRIDENT-1) | 71, treatment-naive | 79% | 35.7 months | Not reached | [28] | Phase I−II | |
| RET fusions | Pralsetinib | NCT04222972 (ARROW) | 75, treatment-naive | 72% | 13.0 months | Not reached | [29] | Phase I−II |
| Selpercatinib | NCT04194944 (LIBRETTO-431) | 129, treatment-naive | 84% | 24.8 months | Not reached | [30] | Phase III, selpercatinib vs. pembrolizumab plus chemotherapy | |
| NTRK fusions | Entrectinib | NCT02097810 (STARTRK-1), NCT02568267 (STARTRK-2), EudraCT, 2012-000148-88 (ALKA-372-001) | 51, previously treated and treatment-naive | 63% | 28.0 months | 41.5 months | [31] | Phase I−II |
| Larotrectinib | NCT02576431 and NCT02122913 | 20, previously treated | 73% | 35.4 months | 40.7 months | [32] | Phase I−II |
* Significantly higher incidence of severe adverse event at higher dose of the drug. PFS: progression-free survival; OS: overall survival; ICI: immune checkpoint inhibitor; TKI: tyrosine kinase inhibitor