Table 1.
Main results from phase III trials testing immune checkpoint blockers in hepatocellular carcinoma
| IMbrave15019 | CheckMate 45914 | KEYNOTE-24013 | ||||
| Atezolizumab/bevacizumab (n=336) | Sorafenib (n=165) | Nivolumab (n=371) | Sorafenib (n=372) | Pembrolizumab (n=278) | Placebo (n=135) | |
| Inclusion criteria | Locally advanced or metastatic, no prior systemic therapy, Child-Pugh A, ECOG PS 0–1 | Advanced HCC not amenable to surgery/LRT, no prior systemic therapy, Child-Pugh A, ECOG PS 0–1 | Intermediate or advanced HCC not amenable to LRT; prior sorafenib treatment; Child-Pugh A; ECOG PS 0–1 | |||
| Primary endpoint(s) | Overall survival, progression-free survival | Overall survival* | Overall survival, progression-free survival* | |||
| BCLC A/B/C, n (%) |
8 (2)/52 (15)/276 (82) | 6 (4)/26 (16)/133 (81) | 15 (4)/53 (14)/303 (82) | 18 (5)/63 (17)/291 (78) | 0/56 (20)/222 (80) | 0/29 (22)/106 (79) |
| Overall survival | ||||||
| Median (95% CI), months | NE | 13.2 (10.4 to NE) | 16.4 (13.9 to 18.4) | 14.7 (11.9 to 17.2) | 13.9 (11.6 to 16.0) | 10.6 (8.3 to 13.5) |
| HR (95% CI) | 0.58 (0.42 to 0.79) | 0.85 (0.72 to 1.02) | 0.781 (0.611 to 0.998) | |||
| P value | <0.001 | 0.0752 | 0.0238 | |||
| Progresion-free survival | ||||||
| Median (95% CI), months | 6.8 (5.7 to 8.3) | 4.3 (4.0 to 5.6) | 3.7 (3.1 to 3.9) | 3.8 (3.7 to 4.5) | 3.0 (2.8 to 4.1) | 2.8 (1.6 to 3.0) |
| HR (95% CI) | 0.59 (0.47 to 0.76) | 0.93 (0.79 to 1.10) | 0.718 (0.570 to 0.904) | |||
| P value | <0.001 | NR | 0.0022 | |||
| Radiological response† | ||||||
| CR, n (%) | 18 (6) | 0 | 14 (4) | 5 (1) | 6 (2) | 0 |
| PR, n (%) | 71 (22) | 19 (12) | 43 (12) | 21 (6) | 45 (16) | 6 (4) |
| SD, n (%) | 151 (46) | 69 (43) | 130 (35) | 180 (48) | 122 (44) | 66 (49) |
| PD, n (%) | 64 (20) | 39 (25) | 136 (37) | 105 (28) | 90 (32) | 57 (42) |
| ORR, n (%) | 89 (27) | 19 (12) | 57 (15) | 26 (7) | 51 (18) | 6 (4) |
| DCR, n (%) | 240 (74) | 88 (55) | 203 (55) | 215 (58) | 173 (62) | 72 (53) |
| Duration of response | ||||||
| Median, months | NE | 6.3 (95% CI 4.7 to NE) | 23.3 (range, 3.1–34.5) | 23.4 (range, 1.9–28.7) | 13.8 (range, 1.5–23.6) | NE (2.8–20.4) |
| Treatment duration | ||||||
| Median, months | 7.4/6.9 | 2.8 | 4.2 | 3.7 | 3.5 | 2.8 |
| Treatment-related adverse events | ||||||
| All-grade, n (%) | 276 (84) | 147 (94) | NR | NR | 170 (61) | 65 (49) |
| Grades 3–4, n (%) | 117 (36) | 71 (46) | 81 (22) | 179 (49) | 51 (18) | 10 (7) |
| Grade 5, n (%) | 6 (2) | 1 (<1) | 1 (<1) | 1 (<1) | NR‡ | NR‡ |
| Common adverse events | Hypertension, proteinuria, diarrhoea, fever | Diarrhoea, PPE, anorexia, hypertension | Fatigue, pruritus, rash, AST increase | PPE, diarrhoea, anorexia, fatigue | AST increase, bilirubin increase, fatigue, pruritus | Fatigue, cough, AST increase, diarrhoea, anorexia |
| Quality-of-life assessment | Atezolizumab+bevacizumab delayed time to deterioration | Nivolumab improved QoL and reduced treatment burden | NR | |||
*Failed to meet prespecified threshold of significance for primary endpoints.
†Independent review according to RECIST version 1.1.
‡No grade 5 events occurred in ≥1.0% of patients.
AST, aspartate aminotransferase; CR, complete response; DCR, disease control rate; HCC, hepatocellular carcinoma; LRT, locoregional therapy; NE, not estimable; NR, not reported; ORR, overall response rate; PD, progressive disease; PPE, palmar-plantar erythrodysesthesia; PR, partial response; ECOG PS, Eastern Cooperative Oncology Group Performance Status; SD, stable disease.