Table 2.
Safety and tolerability of PD-1/PD-L1 monotherapy or combination therapy in total HCC patients and HBV+ subgroup.
| Drug | ClinicalTrials.gov number | Target | HBV+ HCC (%) | Safety evaluation in HBV+ HCC | All-grade TRAEs | Grade ≥3 TRAEs | All-grade TRAES (details) | Grade ≥3 TRAEs (details) | References |
|---|---|---|---|---|---|---|---|---|---|
| Nivolumab | NCT01658878 (escalation phase) | PD-1 | 15 (31%) | Comparable symptomatic TRAEs to total HCC; No new safety signals | 40 (83%) | 12 (25%) | *Rash (23%), AST increase (21%), lipase increase (21%), pruritus (19%), amylase increase (19%), ALT increase (15%), diarrhea (10%), decreased appetite (10%) | Lipase increase (13%), AST increase (10%), ALT increase (6%), amylase increase (4%), fatigue (1%), anemia (1%) | (57) |
| Nivolumab | NCT01658878 (expansion phase) | PD-1 | 51 (24%) | Comparable symptomatic TRAEs to total HCC; No reactivation of HBV; No instances of anti-HBs seroconversion; No new safety signals | — | 40 (19%) | Comparable to that observed in the dose-escalation phase | — | (57) |
| Nivolumab | NCT02576509 | PD-1 | 116 (31%) | — | — | 81 (22%) | *Skin (28%), hepatic (17%), endocrine (13%), Gastrointestinal (9%), Hypersensitivity/infusion reaction (8%) | *Hepatic (10%), Skin (2%), Gastrointestinal (2%) | (56) |
| Nivolumab | — | PD-1 | — | — | — | 2 (6%) | — | Bullous lichenoid drug eruption (3%), hepatitis (3%) | (59) |
| Nivolumab | — | PD-1 | 56 (74%) | No observed HBV reactivation | — | 2 (3%) | Liver dysfunction (21%), pruritus (16%), anorexia (16%), nausea (13%), fatigue (8%) | liver dysfunction (1%), diabetes (1%) | (58) |
| Pembrolizumab | NCT02702414 | PD-1 | 22 (21%) | No cases of flares of HBV; Few immune-mediated hepatitis | 76 (73%) | 27 (26%) | *Fatigue (21%), increased AST (13%), pruritus (12%), diarrhea (11%), rash (10%) | Increased AST (7%), fatigue (4%), increased ALT (4%) | (60) |
| Pembrolizumab | NCT02702401 | PD-1 | — | No cases of HBV flare | — | — | — | — | (61) |
| Camrelizumab (SHR-1210) | NCT02989922 | PD-1 | 181 (83%) | High HBV infection rate (84%); Similar safety profile with total HCC | — | 47 (22%) | *RCEP (67%), increased AST (25%), increased ALT (24%), proteinuria (23%), increased Blood bilirubin (17%) | *Increased AST (5%), decreased neutrophil count (3%) | (64) |
| BGB-A317 | NCT02407990 | PD-1 | — | — | 2 (18%) | 0 (0%) | Fatigue (9%), rash (9%) | — | (63) |
| Cemiplimab | NCT02383212 | PD-1 | — | — | — | — | Fatigue (27%), decreased appetite (23%), increased AST (23%), abdominal pain (23%), pruritus (23%), dyspnea (23%) | — | (62) |
| Durvalumab | NCT01693562 | PD-L1 | 9 (23%) | — | 32 (80%) | 8 (20%) | *Fatigue (28%), pruritus (25%), increased AST (23%), decreased appetite (13%), increased ALT (10%), diarrhea (10%), nausea (10%) | *Increased AST (8%), Increased ALT (5%) | (65) |
| Atezolizumab + bevacizumab | NCT02715531 | PD-L1 + VEGF | 51 (50%) | No new safety signals | 84 (82%) | 30 (27%) | Decreased appetite (28%), fatigue (20%), rash (20%), pyrexia (20%) | Hypertension (10%) | (69) |
| Atezolizumab + bevacizumab | NCT03434379 | PD-L1 + VEGF | 164 (49%) | — | 276 (84%) | 117 (36%) | *Hypertension (nearly 30%); diarrhoea, decreased appetite, pyrexia, increased ALT (all > 10%) | *Hypertension (10%) | (70) |
| Pembrolizumab + lenvatinib | NCT03006926 | PD-1 + VEGF | 8 (27%) | No unexpected safety signals | 28 (93%) | 18 (60%) | Decreased appetite (53%), hypertension (53%), diarrhea (43%), fatigue (40%), dysphonia (30%), proteinuria (30%) | *Hypertension (17%), increased AST (17%), WBC count decreased (13.3%), hyponatremia (10%) | (71) |
| Nivolumab + ipilimumab | NCT01658878 | PD-1 + CTLA-4 | — | — | — | 148 (37%) | Pruritus, rash (data not shown) | — | (68) |
| Durvalumab + tremelimumab | NCT02519348 | PD-L1 + CTLA-4 | 11 (28%) | TRAEs: Pruritus (27%), diarrhea (27%), increased ALT (27%), increased AST (27%), increased lipase (18%), rash (18%), increased amylase (18%), pancreatitis (9%) No unexpected safety signals | 26 (65%) | 10 (25%) | Fatigue (28%), pruritus (23%), increased ALT (20%), increased AST (18%), increased lipase (15%) | Increased AST (10%), increased lipase (10%), increased ALT (5%) | (66) |
| Durvalumab + tremelimumab | NCT02821754 | PD-L1 + CTLA-4 | — | — | — | — | — | — | (67) |
Data are expressed as n (%) or event (%). TRAE, treatment-related adverse event; TRSAEs, treatment-related serious adverse event; AST, aspartate aminotransferase; ALT, alanine aminotransferase; RCEP, reactive cutaneous capillary endothelial proliferation; DT, discontinued treatment. *partial AEs with highest incidence are displayed.