Table 1.
Summary of all randomized trials included in the systematic review.
| Author | Year | Study name Digital object identifier |
Phase | Cancer type | Treatment line | Race | Treatment regimen in control arm | VEGFi | EGFR-TKI with VEGFi | EGFR-TKI without VEGFi | Odds ratio | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| EGFR TKI part | N | Any grade | Grade 1–2 | Grade ≥3 | N | Any grade | Grade 1–2 | Grade ≥3 | Any grade | Grade ≥3 | ||||||||
| Spigel DR | 2011 | LUN160 doi: 10.1200/JCO.2010.30.7678 (35). |
Phase 2 | NSCLC | 2nd or 3rd | White 86.7% African American 12.7% |
Erlotinib | Sorafenib | 111 | NA | NA | NA | 55 | NA | NA | NA | – | – |
| Herbst RS | 2011 | BeTa doi: 10.1016/S0140–6736 (11)60545-X (21). |
Phase 3 | NSCLC | 2nd | White 81.9% Black 8.5% Asian 6.4% |
Erlotinib | Bevacizumab | 313 | NA | NA | 2 | 313 | NA | NA | 2 | – | 1.00 |
| Scagliotti GV | 2012 |
NCT00457392 doi: 10.1200/JCO.2011.39.2993 (36). |
Phase 3 | NSCLC | 2nd or later | White 85.9% Asian 10.7% Black plus other 3.3% |
Erlotinib | Sunitinib | 480 | NA | NA | NA | 480 | NA | NA | NA | – | – |
| Groen HJM | 2013 |
NCT00265317 doi: 10.1093/annonc/mdt212 (37). |
Phase 2 | NSCLC | 2nd | Caucasian 96.2% Asian 2.3% |
Erlotinib | Sunitinib | 64 | NA | NA | NA | 64 | NA | NA | NA | – | – |
| Neal JW | 2016 | ECOG-ACRIN 1512 doi: 10.1016/S1470–2045 (16)30561–7 (38). |
Phase 2 | NSCLC | 2nd or 3rd | White 74.1% Asian 2.3% |
Erlotinib | Cabozantinib | 39 | 1 (2.56%) | 0 | 1 (2.56%) | 40 | 1 (2.50%) | 1 (2.50%) | 0 | 1.026 | – |
| Wang Y | 2017 | doi: 10.1016/j.biopha.2017.02.097 (39). | Phase 3 | NSCLC EGFR mut+ 42.1%, EGFR wild 35.0%, Unkown 22.9% |
2nd | Chinese | Erlotinib | Bevacizumab and panitumumab | 150 | NA | NA | NA | 147 | NA | NA | NA | – | – |
| Kato T | 2018 | JO25567: Update safety results doi: 10.1007/s40264–017-0596–0 (40). |
Phase 2 | EGFR-mutated NSCLC | 1st | Japanese | Erlotinib | Bevacizumab | 75 | 2 (2.67%) | 2 (2.67%) | 0 | 77 | 3 (3.90%) | 3 (3.90%) | 0 | 0.676 | 0 |
| Spigel DR | 2018 | doi: 10.1002/cncr.31290 (41). | Phase 2 | NSCLC | 2nd or 3rd | American | Erlotinib | Pazopanib | 126 | NA | NA | NA | 64 | NA | NA | NA | – | – |
| Kitagawa C | 2019 | UMIN000013586 doi: 10.21873/invivo.11498 (42). |
Phase 2 | EGFR-mutated NSCLC | 1st | Japanese | Gefitinib | Bevacizumab | 6 | 1 (16.67%) | 1 (16.67%) | 0 | 10 | 0 | 0 | 0 | – | – |
| Saito H | 2019 | NEJ026 doi: 10.1016/S1470–2045 (19)30035-X (24). |
Phase 3 | EGFR-mutated NSCLC | 1st | Japanese | Erlotinib | Bevacizumab | 112 | 0 | 0 | 0 | 114 | 5 | 5 (4.39%) | 0 | – | – |
| Stinchcombe TE | 2019 |
NCT01532089 doi: 10.1001/jamaoncol.2019.1847 (43). |
Phase 2 | EGFR-mutated NSCLC | 1st | White 85.2%, Asian 3.4% | Erlotinib | Bevacizumab | 43 | 0 NA | NA | NA | 45 | 0 NA | NA | NA | ||
| Nakagawa K | 2019 | RELAY study doi: 10.1016/S1470–2045 (19)30634–5 (23). |
Phase 3 | EGFR-mutated NSCLC | 1st | Asian 77% White 22.2% Other 0.6% |
Erlotinib | Ramucirumab | 221 | 4 (1.80%) | 3 (1.36%) | 1 (0.45%) | 225 | 6 (2.67%) | 4 (1.78%) | 2 (0.89%) | 0.673 | 0.507 |
| Nishio M | 2020 | RELAY study East Asian subset doi: 10.1111/cas.14655 (33). |
Phase 3 | EGFR-mutated NSCLC | 1st | Asian | Erlotinib | Ramucirumab | 164 | 3 (1.83%) | 2 (1.22%) | 1 (0.61%) | 170 | 6 (3.53%) | 3 (1.76%) | 3 (1.76%) | 0.509 | 0.342 |
| Aix SP | 2021 | RELAY study Europe/United States subset doi: 10.1016/j.ctarc.2021.100378 (34). |
Phase 3 | EGFR-mutated NSCLC | 1st | Caucasian 88.5% Asian 8.9% |
Erlotinib | Ramucirumab | 57 | 1 (1.75%) | 1 (1.75%) | 0 | 55 | 0 | 0 | 0 | – | – |
| Akamatsu H | 2021 | WJOG8715L doi: 10.1001/jamaoncol.2020.6758 (44). |
Phase 2 | EGFR T790M-mutated NSCLC | 2nd or later | Japanese | Osimertinib | Bevacizumab | 40 | 4 (10.00%) | 4 (10.00%) | 0 | 41 | 5 (12.20%) | 5 (12.20%) | 0 | 0.80 | |
| Zhao H | 2021 | ACTIVE study (CTONG1706) doi: 10.1016/j.jtho.2021.05.006 (45). |
Phase 3 | EGFR-mutated NSCLC | 1st | Chinese | Gefitinib | Apatinib | 157 | 1 (0.64%) | 0 | 1 (0.64%) | 154 | 2 (1.30%) | 1 (0.65%) | 1 (0.65%) | 0.487 | 0.981 |
| Zhou Q | 2021 | ARTEMIS-CTONG1509 doi: 10.1016/j.ccell.2021.07.005 (46). |
Phase 3 | EGFR-mutated NSCLC | 1st | Chinese | Erlotinib | Bevacizumab | 157 | 1 (0.64%) | 0 | 1 (0.64%) | 153 | 1 (0.65%) | 1 (0.65%) | 0 | 0.974 | |
| Soo RA | 2022 | ETOP 10–16 BOOSTER trial doi: 10.1016/j.annonc.2021.11.010 (47). |
Phase 2 | EGFR T790M-mutated NSCLC | 2nd | Asian 41.0% Non-Asian 59.0% |
Osimertinib | Bevacizumab | 76 | NA | NA | NA | 77 | NA | NA | NA | ||
| Kenmotsu H | 2022 | WJOG9717L doi: 10.1016/j.jtho.2022.05.006 (30). |
Phase 2 | EGFR-mutated NSCLC | 1st | Japanese | Osimertinib | Bevacizumab | 61 | 2 (3.28%) | 1 (1.64%) | 1 (1.64%) | 60 | 11 (18.33%) | 10 (16.67%) | 1 (1.67%) | 0.151 | 0.983 |
| Piccirill MC | 2022 | BEVERLY doi: 10.1016/j.jtho.2022.05.008 (48). |
Phase 3 | EGFR-mutated NSCLC | 1st | Italian | Erlotinib | Bevacizumab | 80 | 0 | NA | NA | 79 | 0 | NA | NA | ||
| Ninomiya T | 2023 | AfaBev-CS doi: 10.1016/j.lungcan.2023.107349 (49). |
Phase 2 | EGFR-mutated NSCLC | 1st | Japanese | Afatinib | Bevacizumab | 49 | 1 (2.04%) | 1 (2.04%) | 0 | 50 | 3 (6.00%) | 2 (4.00%) | 1 (2.00%) | 0.326 | NA |
| Lee Y | 2023 |
NCT03126799 doi: 10.1002/cncr.34553 (50). |
Phase 2 | EGFR-mutated NSCLC + | 1st | Korean | Erlotinib | Bevacizumab | 64 | 2 (3.13%) | 0 | 2 (3.13%) | 63 | 2 (3.17%) | 1 (1.59%) | 1 (1.59%) | 0.984 | 2.00 |
| Nakahara Y | 2023 | OSIRAM-1 doi: 10.1016/j.annonc.2023.10.071 (51). |
Phase 2 | EGFR-mutated NSCLC + | 1st | Japanese | Osimertinib | Ramucirumab | 59 | 5 (8.5%) | 4 (6.7%) | 1 (1.7%) | 62 | 10 (16.1%) | 9 (14.5%) | 1 (1.6%) | 0.481 | 1.05 |
| Wang J | 2023 |
NCT04425187 doi: 10.1016/j.annonc.2023.09.2365 (52). |
Phase 2 | EGFR L858R-mutated NSCLC + | 1st | Chinese | Gefitinib | Bevacizumab | 41 | NA | NA | NA | 39 | NA | NA | NA | ||
| Le X | 2023 | RAMOSE doi: 10.1016/j.annonc.2023.10.072 (53). |
Phase 2 | EGFR-mutated NSCLC + | 1st | White 64.9%, Asian 24.5%, Black 3.6% | Osimertinib | Ramucirumab | 93 | NA | NA | NA | 46 | NA | NA | NA | ||
| ICI part | N | Any grade | Grade 1–2 | Grade ≥ 3 | N | Any grade | Grade 1–2 | Grade ≥ 3 | Any grade | Grade ≥ 3 | ||||||||
| Reck M | 2020 | IMpower 150 doi: 10.1200/JCO.19.03158 (54). |
Phase 3 | Lung adenocarcinoma | 1st | White 82.1% Asian 12.8% Black 1.9% other 3.3% |
Atezolizumab, carboplatin, and paclitaxel | Bevacizumab | 393 | 13 (3.31%) | 7 (1.78%) | 6 (1.53%) | 400 | 23 (5.75%) | 13 (3.25%) | 10 (2.50%) | 0.561 | 0.605 |
| Shiraishi Y | 2023 | WJOG11218L (APPLE study) doi: 10.1001/jamaoncol.2023.5258 (55). |
Phase 3 | Lung adenocarcinoma | 1st | Japanese | Atezolizumab, carboplatin, and pemetrexed | Bevacizumab | 205 | 21 (10.24%) | 12 (5.85%) | 9 (4.39%) | 205 | 19 (9.27%) | 13 (6.34%) | 6 (2.93%) | 1.117 | 1.523 |
| Lu S | 2023 | ORIENT-31 doi: 10.1016/S2213–2600 (23)00135–2 (29). |
Phase 3 | EGFR-mutated NSCLC | 2nd | Chinese | Sintilimab plus chemotherapy | IBI305, which is bevacizumab-biosimilar | 158 | 8 (5.06%) | 7 (4.43%) | 1 (0.63%) | 156 | 11 (7.05%) | 5 (3.21%) | 6 (3.85%) | 0.703 | 0.159 |
| Zhang W | 2023 |
NCT03910127 Doi: 10.1016/j.lungcan.2023.107353 (56). |
Phase 2 | Driver-negative NSCLC | 2nd or later | Chinese | TQB2450 (PD-L1) | Anlotinib (10 or 12 mg) | 68 | NA | NA | NA | 33 | NA | NA | NA | NA | NA |
NA means "not available".
"-" means blank data, because value is not calculated.