Major clinical trials of HER2-directed therapy in gastric cancer
| Anti-HER2 regimen | Key trial | Phase | Design | Outcomes | ||
|---|---|---|---|---|---|---|
| Perioperative therapy | ||||||
| mAb | Trastuzumab | NEOHX16 | II | Trastuzumab + XELOX | R0 resection rate: 78%; pCR: 8% | 2021 |
| HER-FLOT17 | II | Trastuzumab + FLOT | R0 resection rate: 93%; pCR: 21.5% | 2021 | ||
| PETRARCA18 | II | Trastuzumab + pertuzumab + FLOT FLOT | pCR: 35% vs. 12% | 2020 | ||
| INNOVATION | II | CT Trastuzumab + CT Trastuzumab + pertuzumab + CT | mpRR: 23.3% vs. 37.0% vs. 26.4% R0 resection rate: 83.9% vs. 90.3% vs. 85.9% | 2019 | ||
| ADCs | T-DXd | EPOC2003 | II | T-DXd | Ongoing | NCT05034887 |
| First line | ||||||
| mAb | Trastuzumab | ToGA3,* | III | Trastuzumab + CT CT | ORR: 47% vs. 35%; mOS: 13.8 vs. 11.1 m; mPFS 6.7 vs. 5.5 m | 2010 |
| KEYNOTE8116,7 | III | Pembrolizumab + trastuzumab + CT Trastuzumab + CT | ORR: 74.4% vs. 51.9%; pCR 11.3% vs. 3.1%; mOS: 20.0 vs. 16.8 m; mPFS 10.0 vs. 8.1 m | 2023 | ||
| Margetuximab | MAHOGANY8 | II/III | Margetuximab + retifanlimab | Cohort A (HER2 3+, PD-L1+) ORR: 53%; DCR: 73% | 2022 | |
| Pertuzumab | JACOB4 | III | Pertuzumab + trastuzumab + CT Trastuzumab + CT | ORR: 56.7% vs. 48.3%; mOS: 17.5 vs. 14.2 m; mPFS 8.5 vs. 7.0 m | 2018 | |
| BsAb | Zanidatamab (ZW25) | BGB-A317-ZW25-101 | Ib/II | ZW25 + tislelizumab + CT | ORR 75.8%, DCR 100% mPFS 10.9 m | NCT04276493 |
| HERIZON-GEA-01 | III | ZW25 + CT ± tislelizumab Trastuzumab + CT | Ongoing | 2022 | ||
| KN026 | KN026-20320 | II | KN026 + KN046 | ORR: 77.8%; DCR: 92.6% | 2023 | |
| TKIs | Lapatinib | LOGiC5 | III | Lapatinib + XELOX XELOX | ORR: 53% vs. 39%; mOS: 12.2 vs. 10.5 m; mPFS: 6.0 vs. 5.4 m | 2016 |
| Second line | ||||||
| mAb | Trastuzumab | T-ACT9 | II | Paclitaxel + trastuzumab Paclitaxel | ORR: 31.6% vs. 33.3%; mOS: 10.0 vs. 10.2 m; mPFS: 3.2 vs. 3.7 m | 2020 |
| HER-RAM10 | Ib/II | Trastuzumab + ramucirumab + paclitaxel | ORR: 54%; DCR: 96%; mOS: 13.6 m; mPFS: 7.1 m | 2023 | ||
| ADCs | T-DXd | Destiny-Gastric0214,* | II | T-DXd | ORR: 41.8%; mOS: 12.1 m; mPFS: 5.6 m | 2023 |
| Destiny-Gastric04 | III | T-DXd Taxane + ramucirumab | ongoing | NCT04704934 | ||
| RC-48 | RC48-C00815,* | II | RC-48 | ORR: 24.8%; mOS: 7.9 m; mPFS: 4.1 m | 2021 | |
| T-DM1 | GATSBY12 | II/III | T-DM1 Paclitaxel/docetaxel | ORR: 20.6% vs. 19.6%; mOS: 7.9 vs. 8.6 m; mPFS: 2.7 vs. 2.9 m | 2017 | |
| BsAb | KN026 | KN026-202 | II | KN026 | Cohort 1 (HER2 +): ORR: 56%; mPFS: 8.3 m; mOS: 16.3 m | NCT03925974 |
| TKIs | Lapatinib | TyTAN11 | III | Lapatinib + paclitaxel Paclitaxel | ORR: 27% vs. 9%; mOS: 11.0 vs. 8.9 m; mPFS: 5.4 vs. 4.4 m | 2014 |
| Tucatinib | MOUNTAINEER02 | II/III | Trastuzumab + tucatinib + ramucirumab + CT | Ongoing | NCT04499924 | |
| Third line and beyond | ||||||
| mAb | Margetuximab | CP-MGAH22-0521 | Ib/II | Margetuximab + pembrolizumab | HER2 3+, PD-1+ cohort; ORR: 44% | 2020 |
| ADCs | T-DXd | Destiny-Gastric0113 | II | T-DXd Paclitaxel/irinotecan | ORR: 51% vs. 14%; mOS: 12.5 vs. 8.4 m; mPFS: 5.6 vs. 3.5 m | 2020 |
ADC, antibody drug conjugate; BsAb, bi-specific antibody; CT, chemotherapy; DCR, disease control rate; FLOT, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel; m, months; mAb, monoclonal antibody; mPFS, median progression free survival; mOS, median overall survival; mpRR, major pathological response rate; ORR, objective response rate; pCR, pathological complete response; TKIs, tyrosine kinase inhibitor; XELOX, oxaliplatin, capecitabine. *Associated treatment recommended by clinical guidelines.