Table 1.
Baseline characteristics of included articles.
| No. | Reference | NCT number | Phase | Drug name | Treatment regimen | First-line treatment | Tumor type | Involving patients | Treatment related deaths | Treatment related discontinuation | Treatment related grades 3–5 adverse events | Treatment related any adverse events |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PD-1/PD-L1 VS. Chemotherapy | ||||||||||||
| 11 | Huang et al. (18) | NCT03099382 (ESCORT) | III | Camrelizumab (PD-1) | Camrelizumab VS. (Docetaxel, irinotecan) | NO | OSCC | 448 | 10 | 28 | 131 | 413 |
| 22 | Galsky et al. (19) | NCT02807636 (IMvigor130) | III | Atezolizumab (PD-L1) | Atezolizumab VS. GC | YES | UC | 744 | 7 | N/A | 376 | 584 |
| 33 | Kato et al. (20) | NCT02569242 (ATTRACTION-3) | III | Nivolumab (PD-1) | Nivolumab VS. (Paclitaxel or Docetaxel) | NO | OSCC | 417 | 5 | 37 | 171 | 335 |
| 44 | Hellmann et al. (21) | NCT02477826 (CheckMate227) | III | Nivolumab (PD-1) | Nivolumab VS. Platinum doublet Chemotherapy | YES | NSCLC | 961 | 8 | 100 | 281 | 723 |
| Hellmann et al. (22) | 96 | 280 | 711 | |||||||||
| 55 | Mok et al. (23) | NCT02220894 (KEYNOTE-042) | III | Pembrolizumab (PD-1) | Pembrolizumab VS. PC or CP | YES | NSCLC | 1,251 | 27 | 115 | 365 | 952 |
| 66 | Wu et al. (24) | NCT02613507 (CheckMate078) | III | Nivolumab (PD-1) | Nivolumab VS. Docetaxel | NO | NSCLC | 493 | 7 | 27 | 109 | 346 |
| 77 | Cohen et al. (25) | NCT02252042 (KEYNOTE-040) | III | Pembrolizumab (PD-1) | Pembrolizumab VS. (Methotrexate, Docetaxel or Cetuximab) | NO | HNSCC | 480 | 6 | 27 | 118 | 351 |
| 821 | Burtness et al. (26) | NCT02358031 (KEYNOTE-048) | III | Pembrolizumab (PD-1) | Pembrolizumab VS. Cetuximab + Chemotherapy | YES | HNSCC | 587 | 11 | N/A | 250 | 453 |
| 98 | Powles et al. (27) | NCT02302807 (IMvigor211) | III | Atezolizumab (PD-L1) | Atezolizumab VS. Chemotherapy | NO | UC | 902 | 13 | 79 | 293 | 714 |
| 109 | Shitara et al. (28) |
NCT02370498 (KEYNOTE-061) |
III | Pembrolizumab (PD-1) | Pembrolizumab VS. Paclitaxel | NO | GC/GEJC | 570 | 4 | 24 | 138 | 387 |
| 1110 | Barlesi et al. (29) | NCT02395172 (JAVELIN Lung 200) | III | Avelumab (PD-L1) | Avelumab VS. Docetaxel | NO | NSCLC | 758 | 18 | 79 | 219 | 564 |
| 1211 | Bang et al. (30) | NCT02625623 (JAVELINGastric300) | III | Avelumab (PD-L1) | Avelumab VS. Paclitaxel or Irinotecan | NO | GC/GEJC | 361 | 1 | 16 | 73 | 221 |
| 1312 | Hida et al. (31) | NCT02008227 (OAK) | III | Atezolizumab (PD-L1) | Atezolizumab VS. Docetaxel | NO | NSCLC | 101 | 0 | 13 | 54 | 93 |
| Rittmeyer et al. (32) | 1,187 | 1 | N/A | 337 | 886 | |||||||
| 1413 | Bellmunt et al. (33) | NCT02256436 (KEYNOTE-045) | III | Pembrolizumab (PD-1) | Pembrolizumab VS. (Paclitaxel, Docetaxel, or Vinflunine) | NO | UC | 521 | 8 | 43 | 166 | 392 |
| 1514 | Reck et al. (34) | NCT02142738 (KEYNOTE-024) | III | Pembrolizumab (PD-1) | Pembrolizumab VS. Platinum-based Chemotherapy | YES | NSCLC | 304 | 4 | 27 | 121 | 248 |
| 1615 | Ferris et al. (35) | NCT02105636 (CheckMate141) | III | Nivolumab (PD-1) | Nivolumab VS. (Methotrexate, Docetaxel, or Cetuximab) | NO | HNSCC | 347 | 3 | N/A | 73 | 225 |
| 1716 | Herbst et al. (36) | NCT01905657 (KEYNOTE-010) | II/III | Pembrolizumab (PD-1) | Pembrolizumab 2 mg/kg VS. Docetaxel | NO | NSCLC | 648 | 8 | 46 | 152 | 466 |
| Herbst et al. (36) | Pembrolizumab 10 mg/kg VS. Docetaxel | NO | NSCLC | 652 | 8 | 48 | 164 | 477 | ||||
| 1817 | Fehrenbacher et al. (37) | NCT01903993 (POPLAR) | II | Atezolizumab (PD-L1) | Atezolizumab VS. Docetaxel | NO | NSCLC | 277 | 4 | 26 | 72 | 214 |
| 1918 | Borghaei et al. (38) | NCT01673867 (CheckMate057) | III | Nivolumab (PD-1) | Nivolumab VS. Docetaxel | NO | NSCLC | 555 | 2 | 54 | 174 | 435 |
| 2019 | Brahmer et al. (39) | NCT01642004 (CheckMate017) | III | Nivolumab (PD-1) | Nivolumab VS. Docetaxel | NO | NSCLC | 260 | 3 | 17 | 83 | 187 |
| 2120 | Weber et al. (40) | NCT01721746 (CheckMate037) | III | Nivolumab (PD-1) | Nivolumab VS. (Dacarbazine or Paclitaxel + Carboplatin) | NO | Melanoma | 370 | 0 | 14 | 56 | 262 |
| PD-1/PD-L1 + Chemotherapy VS. Chemotherapy | ||||||||||||
| 11 | Schmid et al. (41) | NCT03036488 (KEYNOTE-522) | III | Pembrolizumab (PD-1) | Pembrolizumab + PC VS. PC | YES | TNBC | 1,170 | 4 | 230 | 881 | 1161 |
| 22 | Galsky et al. (19) | NCT02807636 (IMvigor130) | III | Atezolizumab (PD-L1) | Atezolizumab + GC VS. GC | YES | UC | 843 | 13 | N/A | 695 | 807 |
| 3 | Reck et al. (42) | NCT02366143 (IMpower150) | III | Atezolizumab (PD-L1) | Atezolizumab + BCP VS. BCP | YES | NSCLC | 787 | N/A | N/A | 382 | 737 |
| Socinski et al. (43) | 20 | N/A | 427 | 747 | ||||||||
| 43 | West et al. (44) | NCT02367781 (IMpower130) | III | Atezolizumab (PD-L1) | Atezolizumab + nPC VS. nPC | YES | NSCLC | 705 | 9 | N/A | 495 | 670 |
| 54 | Paz-Ares et al. (45) | NCT03043872 (CASPIAN) | III | Durvalumab (PD-L1) | Durvalumab + EP VS. EP | YES | SCLC | 531 | 7 | 28 | 259 | 477 |
| 66 | Paz-Ares et al. (46) | NCT02775435 (KEYNOTE-407) | III | Pembrolizumab (PD-1) | Pembrolizumab + PC or nPC VS. PC or nPC | YES | NSCLC | 558 | 16 | N/A | N/A | N/A |
| 77 | Horn et al. (47) | NCT02763579 (IMpower133) | III | Atezolizumab (PD-L1) | Atezolizumab + EC VS. EC | YES | SCLC | 394 | 6 | N/A | 228 | 369 |
| 88 | Schmid et al. (48) | NCT02425891 (IMpassion130) | III | Atezolizumab (PD-L1) | Atezolizumab + nab-Paclitaxel VS. nab-Paclitaxel | YES | TNBC | 890 | 4 | N/A | 315 | 846 |
| 99 | Langer et al. (49) | NCT02039674 (KEYNOTE-021) | III | Pembrolizumab (PD-1) | Pembrolizumab + CP VS. CP | YES | NSCLC | 121 | 3 | 14 | 39 | 111 |
| PD-1/PD-L1 VS. Placebo | ||||||||||||
| 1 | Zimmer et al. (50) | NCT02523313 (IMMUNED) | III | Nivolumab (PD-1) | Nivolumab VS. Placebo | NO | Melanoma | 107 | 0 | 8 | 18 | 75 |
| 2 | Eggermont et al. (51) | NCT02362594 (KEYNOTE-054) | III | Pembrolizumab (PD-1) | Pembrolizumab VS. Placebo | NO | Melanoma | 1,011 | 2 | N/A | 91 | 731 |
| 3 | Eggermont et al. (52) | 1 | 74 | 92 | 728 | |||||||
| 4 | Kang et al. (53) | NCT02267343 (ATTRACTION-2) | III | Nivolumab (PD-1) | Nivolumab VS. Placebo | NO | GC/GEJC | 491 | 7 | 13 | 41 | 184 |
| 5 | Hui et al. (54) | NCT02125461 (PACIFIC) | III | Durvalumab (PD-L1) | Durvalumab VS. Placebo | NO | NSCLC | 709 | N/A | N/A | N/A | N/A |
| 6 | Antonia et al. (55) | N/A | N/A | |||||||||
| 7 | Antonia et al. (56) | 76 | 447 | |||||||||
| PD-1 VS. PD-1 + CTLA-4 | ||||||||||||
| 1 | Zimmer et al. (50) | NCT02523313 (IMMUNED) | III | Nivolumab (PD-1) | Nivolumab VS. Nivolumab + Ipilimumab | NO | Melanoma | 111 | 0 | 41 | 54 | 100 |
| 2 | Larkin et al. (57) | NCT01844505 (CheckMate067) | III | Nivolumab (PD-1) | Nivolumab VS. Nivolumab + Ipilimumab | YES | Melanoma | 626 | 3 | 170 | 259 | 571 |
| 3 | Hodi et al. (58) | 3 | 165 | 255 | 570 | |||||||
| 4 | Wolchok et al. (59) | 3 | 160 | 251 | 570 | |||||||
| 5 | Larkin et al. (60) | 1 | 138 | 223 | 556 | |||||||
| 6 | Hellmann et al. (21) | NCT02477826 (CheckMate227) | III | Nivolumab (PD-1) | Nivolumab VS. Nivolumab + Ipilimumab | YES | NSCLC | 967 | 10 | 152 | 265 | 698 |
| 7 | Hellmann et al. (22) | 9 | 145 | 254 | 684 | |||||||
| 8 | Antonia et al. (61) | NCT01928394 (CheckMate032) | I/II | Nivolumab (PD-1) | Nivolumab 3 mg/kg VS. Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg | NO | SCLC | 159 | 2 | 13 | 33 | 102 |
| 9 | Antonia et al. (61) | Nivolumab 3 mg/kg VS. Nivolumab 3 mg/kg + ipilimumab1 mg/kg | 152 | 1 | 10 | 24 | 93 | |||||
| PD-1+CTLA-4 VS. CTLA-4 | ||||||||||||
| 1 | Larkin et al. (57) | NCT01844505 (CheckMate067) | III | Nivolumab (PD-1) | Nivolumab + Ipilimumab VS. Ipilimumab | YES | Melanoma | 624 | 3 | 177 | 272 | 568 |
| 2 | Hodi et al. (58) | 3 | 173 | 272 | 567 | |||||||
| 3 | Wolchok et al. (59) | 3 | 172 | 270 | 568 | |||||||
| 4 | Larkin et al. (60) | 1 | 160 | 257 | 567 | |||||||
| 5 | Hodi et al. (62) | NCT01927419 (CheckMate069) | II | Nivolumab (PD-1) | Nivolumab + Ipilimumab VS. Ipilimumab | YES | Melanoma | 140 | 3 | 32 | 61 | 129 |
| PD-1 VS. CTLA-4 | ||||||||||||
| 1 | Larkin et al. (57) |
NCT01844505 (CheckMate067) |
III | Nivolumab (PD-1) |
Nivolumab + Placebo VS. Ipilimumab | YES | Melanoma | 624 | 2 | 87 | 159 | 539 |
| 2 | Hodi et al. (58) | 86 | 157 | 538 | ||||||||
| 3 | Wolchok et al. (59) | 86 | 153 | 538 | ||||||||
| 4 | Larkin et al. (60) | 70 | 136 | 525 | ||||||||
| 5 | Schachter et al. (63) | NCT01866319 (KEYNOTE-006) | III | Pembrolizumab (PD-1) | Pembrolizumab every 2 weeks VS. Ipilimumab | NO | Melanoma | 534 | 1 | 42 | 97 | 419 |
| Schachter et al. (63) | Pembrolizumab every 3 weeks VS. Ipilimumab | 533 | 0 | 53 | 96 | 403 | ||||||
| PD-1/PD-L1 VS. PD-1/PD-L1 + Chemotherapy | ||||||||||||
| 1 | Galsky et al. (19) | NCT02807636 (IMvigor130) | III | Atezolizumab (PD-L1) |
Atezolizumab VS. Atezolizumab + GC | YES | UC | 807 | 12 | N/A | 433 | 645 |
| 2 | Burtness et al. (26) |
NCT02358031 (KEYNOTE-048) |
III | Pembrolizumab (PD-1) |
Pembrolizumab VS. Pembrolizumab + Chemotherapy | YES | HNSCC | 576 | 14 | N/A | 249 | 439 |
| Others | ||||||||||||
| 11 | Reck et al. (42) | NCT02366143 (IMpower150) | III | Atezolizumab (PD-L1) | ACP VS. ABCP | YES | NSCLC | 793 | N/A | N/A | 364 | 727 |
| Reck et al. (42) | Atezolizumab + PC VS. Bevacizumab + PC | 794 | N/A | N/A | 344 | 740 | ||||||
| 23 | Zimmer et al. (50) | NCT02523313 (IMMUNED) | II | Nivolumab (PD-1) | Nivolumab + Ipilimumab VS. Placebo | NO | Melanoma | 106 | 0 | 35 | 42 | 81 |
| 3 | Gutzmer et al. (64) | NCT02908672 (IMspire150) | III | Atezolizumab (PD-L1) | Atezolizumab + VC VS. VC | YES | Melanoma | 511 | N/A | 73 | 390 | 507 |
| 4 | Ascierto et al. (65) | NCT02130466 (KEYNOTE-022) | II | Pembrolizumab (PD-1) | Pembrolizumab + DT VS. DT | NO | Melanoma | 120 | 1 | 39 | 51 | 113 |
| 55 | Motzer et al. (66) | NCT02231749 (CheckMate214) | III | Nivolumab (PD-1) | Nivolumab + Ipilimumab VS. Sunitinib | YES | RCC | 1,082 | 12 | 185 | 599 | 1,034 |
| 6 | Burtness et al. (26) | NCT02358031 (KEYNOTE-048) | III | Pembrolizumab (PD-1) | Pembrolizumab + Chemotherapy VS. Cetuximab + Chemotherapy | YES | HNSCC | 563 | 19 | N/A | 397 | 542 |
| 77 | Sullivan et al. (67) | NCT01656642 | I | Atezolizumab (PD-L1) | Atezolizumab + vemurafenib VS. Atezolizumab + VC | YES | Melanoma | 56 | N/A | 13 | 41 | 56 |
| 88 | Hellmann et al. (21) | NCT02477826 (CheckMate227) | III | Nivolumab (PD-1) | Nivolumab + Ipilimumab VS. Platinum doublet Chemotherapy | YES | NSCLC | 1,146 | 14 | 156 | 394 | 909 |
| 99 | Hellmann et al. (22) | 13 | 151 | 386 | 893 | |||||||
| 1010 | Motzer et al. (68) | NCT02684006 (JAVELIN Renal 101) | III | Avelumab (PD-L1) | Avelumab + Axitinib VS. Sunitinib | YES | RCC | 873 | 4 | 92 | 489 | 837 |
| 1111 | Rini et al. (69) | NCT02420821 (IMmotion151) | III | Atezolizumab (PD-L1) | Atezolizumab + Bevacizumab VS. Sunitinib | YES | RCC | 897 | 6 | 61 | 422 | 840 |
| 1212 | Schachter et al. (63) | NCT01866319 (KEYNOTE-006) | III | Pembrolizumab (PD-1) | Pembrolizumab every 2 weeks VS. Pembrolizumab every 3 weeks | NO | Melanoma | 555 | 1 | 49 | 93 | 442 |
| 1313 | Antonia et al. (61) |
NCT01928394 (CheckMate032) |
I/II | Nivolumab (PD-1) | Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg VS. Nivolumab 3 mg/kg + ipilimumab 1 mg/kg | NO | SCLC | 115 | 3 | 11 | 31 | 91 |
| 1414 | Herbst et al. (36) | NCT01905657 (KEYNOTE-010) | II/III | Pembrolizumab (PD-1) | Pembrolizumab 2 mg/kg VS. Pembrolizumab 10 mg/kg | NO | NSCLC | 682 | 6 | 32 | 98 | 441 |
| 1515 | Motzer et al. (70) | NCT01668784 (CheckMate025) | III | Nivolumab (PD-1) | Nivolumab VS. Everolimus | NO | RCC | 803 | 2 | 83 | 221 | 668 |
PD-1, Programmed Cell Death-1; PD-L1, Programmed Cell Death Ligand 1; CTLA-4, Cytotoxic T lymphocyte associate protein-4; OSCC, Oesophageal Squamous Cell Carcinoma; UC, Urothelial Cancer; NSCLC, Non-Small Cell Lung Cancer; HNSCC, Head and Neck
Squamous Cell Carcinoma; GC/GEJC, Gastric or Gastro-oesophageal Junction Cancer; TNBC, Triple-negative Breast Cancer; SCLC, Small Cell Lung Cancer; HCC, Hepatocellular Carcinoma; RCC, Renal Cell Carcinoma; PC, Paclitaxel + Carboplatin; GC, Gemcitabine + Carboplatin/Cisplatin; BCP, Bevacizumab + Carboplatin + Paclitaxel; EP, Etoposide + Platinum; EC, Etoposide + Carboplatin, CP, Carboplatin + Pemetrexed; nPC, nab-Paclitaxel + Carboplatin; ACP, Atezolizumab + Carboplatin + Paclitaxel; ABCP, Atezolizumab + Bevacizumab + Carboplatin + Paclitaxel; VC, Vemurafenib + Cobimetinib; DT, Dabrafenib + Trametinib.