Table 1.
Studies investigating immune checkpoint blockade for UM treatment.
| Author/Trial [Reference] |
Design | Number of Evaluated (Enrolled) Patients | Intervention | Dosage | ORR | PR | CR | PFS (Median) | OS (Median) | Severe AEs > grade 3 |
|---|---|---|---|---|---|---|---|---|---|---|
| Anti-CTLA-4 antibodies | ||||||||||
| Ipilimumab | ||||||||||
| Rozeman 2019 SECIRA-UM [104] | Open-label, 3-armed, single center phase Ib/II trial |
3 | Ipilimumab + RFA |
0.3 mg/kg | 0 | 0 | 0 | 2 mo. | n.r. | 1/3 (33%) * |
| 19 | Ipilimumab + RFA |
3 mg/kg | 0 | 0 | 0 | 2 mo. | 9.7 mo. | 6/19 (32%) * | ||
| 19 | Ipilimumab + RFA |
10 mg/kg | 0 | 0 | 0 | 2 mo. | 14.2 mo. | 10/19 (52%) * | ||
| Shaw 2012 [105] | EAP | 18 | Ipilimumab | 3 mg/kg | n.r. | n.r. | n.r. | 14.5 wks. (range 6 – 64) |
n.r. | not clearly reported |
| Kelderman 2013/ WIN-O [106] |
EAP | 22 | Ipilimumab | 3 mg/kg | 1/22 (4.5%) | 1/22 (4.5%) | 0 | 2.9 mo. (95% CI 2.3–5.3) |
5.2 mo. (95% CI 4.9–9.6) |
3/22 (13.6%) |
| Maio 2013 [107] | EAP | 82 (83) | Ipilimumab | 3 mg/kg | 4/82 (4.8%) | 4/82 (4.8%) | 0 | 3.6 mo. (95% CI 2.8–4.4) |
6.0 mo. (95% CI 4.3–7.7) |
5/82 (6%) |
| Zimmer 2015 [108] | Observational, prospective, open-label, uncontrolled, multicenter phase II trial | 53 | Ipilimumab | 3 mg/kg | 0 | 0 | 0 | 2.8 mo. (95% CI 2.5–2.9) |
6.8 mo. (95% CI 3.7–8.1) |
19/53 (36%) * |
| Jung 2017 [109] | NPP | 10 | Ipilimumab | 3 mg/kg | n.r. | n.r. | n.r. | 2.8 mo. | not reached | 0 |
| Piulats 2014/ GEM1 [110] |
Observational, prospective, open-label, single-arm phase II trial | 31 (32) | Ipilimumab | 10 mg/kg | 2/31 (6.5%) | 2/31 (6.5%) | 0 | n.r. | 9.8 mo. | 5/31 (16%) |
| Danielli 2012/ I-OMEAP [111] |
EAP | 13 | Ipilimumab | 10 mg/kg | 0 | 0 | 0 | n.r. | 36 wks. (range 2–172+) | 3/13 (23%) |
| Fountain 2019/ NCT01585194 [112] |
Interventional, prospective, open-label, phase I/II trial | 10 | Ipilimumab (adjuvant setting) |
3 mg/kg (n = 3) 10 mg/kg (n = 7) |
n.r. | n.r. | n.r. | n.r. | n.r. | 1/10 (10%) |
| Luke 2013 [113] | Uncontrolled, multicenter, retrospective analysis | 39 | Ipilimumab | 3 mg/kg (n = 34) 10 mg/kg (n = 5) |
2/39 (5.1%) | 1 (late) (2.6%) | 1/39 (2.6%) | n.r. | 9.6 mo. (95% CI 6.3–13.4) | 7/39 (17.9%) |
| Itchins 2017 [114] | Uncontrolled, single-center, retrospective cohort analysis | 37 | sequential TAC (fotemustine) + ICB (ipi, nivo or pembro) + systemic chemotherapy |
100 mg/m² (fotemustine), 3 mg/kg (ipi/nivo) 2 mg/kg (pembro) |
ICB first-line: 1/14 (7.1%) ICB second-line: 2/12 (16.7%) |
Ipi: 1/22 (4.5%) Pembro: 2/15 (13%) Nivo: 1/4 (25%) |
0 | 9 mo. (95% CI 6.2–13.2) |
17.0 mo. (95% CI 12–26) | not clearly reported |
| Tremelimumab | ||||||||||
| Joshua 2015 [116] | Observational, prospective, open-label, multicenter phase II study |
11 | Tremelimumab | 15 mg/kg | 0 | 0 | 0 | 2.9 mo. (95% CI 2.8–3.0) |
12.8 mo. (95% CI 3.8–19.7) |
not clearly reported |
| Anti-PD-1 antibodies | ||||||||||
| Nivolumab | ||||||||||
| Schadendorf 2017/ CheckMate172 [117] | Single-arm, open-label, multicenter, phase II trial |
34 (75) | Nivolumab | 3 mg/kg | 2/34 (5.8%) at 12 wks. |
2/34 (5.8%) | 0 | n.r. | 11 mo. (95% CI 7–15) | not clearly reported |
| van der Kooij 2017 [118] | uncontrolled, multicenter, retrospective analysis | 17 | Nivolumab Pembrolizumab |
3 mg/kg (nivo) 2 mg/kg (pembro) |
0 | 0 | 0 | 2.3 mo. | 9.6 mo. | 0 |
| Tian 2016 [119] | uncontrolled retrospective analysis | 8 (9) | Nivolumab Pembrolizumab |
n.r. | 2/8 (25%) | 2/8 (25%) | 0 | n.r. | not clearly reported | n.r. |
| Namikawa 2019 [120] | uncontrolled, single-center, retrospective analysis | 14 | Nivolumab | 2 mg/kg (n = 13) 3 mg/kg (n = 1) |
1/12 (7.1%) | 1/12 (7.1%) | 0 | 10 wks. (range 4–105) |
60 wks. (range 5–105) |
1/12 (7.1%) grade 4 hyper-glycemia |
| Pembrolizumab | ||||||||||
| Kottschade 2016 [121] | EAP | 8 (10) | Pembrolizumab | 2 mg/kg | 3/8 (37.5%) | 2/8 (25%) | 1/8(12.5%) | 18 wks. (range 3.14–49.3) |
n.r. | 1/10 (10%) |
| Karydis 2016 [122] | EAP | 25 | Pembrolizumab | 2 mg/kg | 2/25 (8%) | 2/25 (8%) | 0 | 91 days | not reached | 0 |
| Johnson 2019/ NCT02359851 [123] | single-arm, multicenter, open-label, phase II trial | 5 | Pembrolizumab | n.r. | 1/10 (20%) | 0 | 1/5 (20%) | 11.0 mo. | not reached | 1/5 (20%) |
| Bol 2019 [115] | Retrospective, population-based study | 43 | Pembrolizumab | n.r. | 3/43 (7%) | 3/43 (7%) | 0 | 4.8 mo. | 10.3 mo. | n.r. |
| 24 | Ipilimumab | n.r. | 0 | 0 | 0 | 3.0 mo. | 9.9 mo. | |||
| 19 | Ipilimumab + Nivolumab | n.r. | 4/19 (21.1%) | 4/19 (21.1%) | 0 | 3.7 mo. | 18.9 mo. | |||
| Algazi 2016 [124] | uncontrolled, multicenter, retrospective analysis | 38 | Pembrolizumab | 2 mg/kg (n = 27), 10 mg/kg (n = 9), unknown (n = 2) | 2/56 (3.4%) | 1/38 (2.6%) | 0 | 2.6 mo. (95% CI 2.4–2.8) |
7.7 mo. (95% CI 0.7–14.6) |
0 |
| 16 | Nivolumab | 1 mg/kg (n = 4), 2 mg/kg (n = 1), 3 mg/kg (n = 10), 10 mg/kg (n = 1) |
1/16 (6.3%) | 0 | ||||||
| 2 | Atezolizumab | 10 mg/kg (n = 1), 15 mg/kg (n = 1) |
0 | 0 | ||||||
| Piperno-Neumann 2016 [125] | uncontrolled, single-center, retrospective analysis | 21 | Pembrolizumab Nivolumab |
n.r. | 0 | 0 | 0 | 3 mo. | n.r. | n.r. |
| Rossi 2019 [126] | Single-arm, prospective study | 17 | Pembrolizumab | 2 mg/kg | 2/17 (11.7%) | 2/17 (11.7%) | 0 | 3.8 mo. (95% CI 2.9–9.7) |
not reached | 0 |
| Combined ICB: anti-CTLA-4 + anti-PD-1 antibodies | ||||||||||
| Shoushtari 2016 [127] | EAP | 6 | Nivolumab + ipilimumab; nivolumab or pembrolizumab (maintenance) |
1 mg/kg (nivo) + 3 mg/kg (ipi); 3 mg/kg (nivo, maintenance), 2 mg/kg (pembro, maintenance) |
0 | 0 | 0 | 2.8 months (95% CI 1.2–4.6) |
n.r. | n.r. |
| Piulats 2018/ GEM1402 NCT02626962 [128] |
single-arm, open-label, multicenter, phase II trial | 50 (52) | Nivolumab + ipilimumab; nivolumab (maintenance) |
1 mg/kg (nivo) + 3 mg/kg (ipi); 3 mg/kg (nivo, maintenance) |
6/50 (12%) | 6/50 (12%) |
0 | 3.3 mo. | 12.7 mo. | not clearly reported |
| Heppt 2017 [129] | uncontrolled, multicenter, retrospective analysis | 12 (15) | Nivolumab/ pembrolizumab + ipilimumab | 3 mg/kg (ipi) + 1 mg/kg (nivo), 3 mg/kg (nivo, maintentance) (n = 7) 1 mg/kg (ipi) + 3 mg/kg (nivo), 3 mg/kg (nivo, maintentance) (n = 2) 1 mg/kg (ipi) + 2 mg/kg (pembro), 2 mg/kg (pembro, maintentance) (n = 6) |
2/12 (16.7%) | 2/12 (16.7%) | 0 | 2.8 mo. | not reached | 4/15 (26.7%) * |
| 53 (54) | Pembrolizumab monotherapy | 2 mg/kg | 3/53 (5.7%) | 3/53 (5.7%) | 0 | 3.1 mo. | 14 mo. | 4/54 (7.4%) * | ||
| 32 | Nivolumab monotherapy | 3 mg/kg | 1/32 (3.1%) | 1/32 (3.1%) | 0 | 2.8 mo. | 10 mo. | 4/32 (12.5%) * | ||
| Heppt 2019 [130] | uncontrolled, multicenter retrospective analysis | 59 | Nivolumab + ipilimumab | 3 mg/kg (ipi) + 1 mg/kg (nivo), 3 mg/kg (nivo, maintenance) |
10/64 (15.6%) | 8/64 (12.5%) | 2/64 (3.1%) | 3.0 mo. (95% CI 2.4–3.6) | 16.1 months (95% CI 12.9–19.3) | 1/64 (1.6%) |
| 5 | Pembrolizumab + ipilimumab | 1 mg/kg (ipi) + 2 mg/kg (pembro), 2 mg/kg (pembro, maintenance) |
||||||||
| Karivedu 2019 [131] | uncontrolled, single-center, retrospective analysis/case series | 8 | TACE + nivolumab + ipilimumab, TACE + nivolumab (maintenance) | 3 mg/kg (ipi) + 1 mg/kg (nivo), 240 mg (nivo, maintenance) |
2/8 (25%) | 2/8 (25%) | 0 | n.r. | 14 mo. | 4/8 (50%) colitis; severity not clearly reported |
All studies investigated ICB in patients with metastatic melanoma; exception: Fountain 2019/ NCT01585194 (adjuvant ICB in patients with a high risk for developing metastases). *: Authors did not distinguish between grade 3 and 4 when reporting the severity of AEs. Abbreviations: CI = confidence interval; DCR = disease control rate; EAP = expanded access program; ICB = immune checkpoint blockade; ipi = ipilimumab; mo. = months; nivo = nivolumab; NPP = named patient program; n.r. = not reported; pembro = pembrolizumab; RFA = radiofrequency ablation; TAC = transarterial chemotherapy; TACE = transarterial chemoembolization; wks. = weeks.