Background
Number of initiated clinical trials (n) | |||
---|---|---|---|
Compound/Phase |
Combination
|
Monotherapy
|
Total
|
epacadostat |
54
|
5
|
59
|
I or I/II | 28 | 31 | 31 |
II | 19 | 21 | 21 |
III | 7 | 0 | 7 |
BMS-986205 |
18
|
0
|
18
|
I or I/II | 7 | 0 | 7 |
II | 7 | 0 | 7 |
III | 4 | 0 | 4 |
indoximod |
12
|
2
|
14
|
I or I/II | 8 | 2 | 10 |
II | 4 | 0 | 4 |
navoximod |
1
|
2
| |
I | 1 | 1 | 2 |
KHK-2455 |
2
|
0
|
2
|
I | 2 | 0 | 2 |
PF-06840003 |
0
|
1
|
1
|
I | 0 | 1 | 1 |
LY-3381916 |
1
|
0
|
1
|
I | 1 | 0 | 1 |
DN1406131 |
0
|
1
|
1
|
I | 0 | 1 | 1 |
Total |
88
|
10
|
98
|
IDO1 inhibitors under clinical development
Cancer type | Number of initiated trials | Most advanced phase of trial |
---|---|---|
Lung cancer | 16 | III |
Head and neck cancer | 12 | III |
Gynecological tumorsb | 12 | II |
Melanoma | 11 | III |
Urothelial carcinomac | 11 | III |
Brain tumorsd | 8 | II |
Othere | 34 | III |
The development path of epacadostat
Assay | Enzyme source/cell | IC50 (nM) | Ref | ||
---|---|---|---|---|---|
Enzymatic | His-tagged human IDO1 | 71.8 | [79] | ||
Cellular | CT26 colon carcinoma cells | 76 | [65] | ||
Pan02 pancreatic adenocarcinoma cells | 27 | [65] | |||
293/MSR-human IDO1 a | 15.0 | [79] | |||
293/MSR-mouse IDO1 a | 52.4 | [79] | |||
293/MSR-mouse IDO2 a | > 5000 | [79] | |||
293/MSR-human TDO a | > 10,000 | [79] | |||
Human dendritic cells | 12.7 | [79] | |||
Hela human cervical carcinoma cells | 7.1 | [79] | |||
SKOV-3 ovarian cancer cell | 15.3 | [84] | |||
Type of inhibition | Ref | Ki | Ref | Binding sites | Ref |
Competitive b | [85] | 1 µM b | [85] | Heme iron c | [86] |
Mouse model | Tumor growth reduction | Impact on immune function | Ref |
---|---|---|---|
CT26 colon carcinoma | 34 % a at 30 mg/kg BID 57 % a at 100 mg/kg BID | Activity of tumor infiltrating lymphocytes increased | [65] |
PAN02 pancreatic adenocarcinoma | 37 % a at 25 mg/kg BID 57 % a at 100 mg/kg BID | - | [79] |
CT26 colon carcinoma | 47.5 % b at 100 mg/kg BID | - | [87] |
Lewis lung carcinoma | 51 % c at 80 mg/kg daily | Intratumoural ratio of CD4 effector T cells to Tregs elevated | [88] |
B16F10 melanoma | 50 % c at 80 mg/kg daily | Intratumoural ratio of CD4 effector T cells to Tregs elevated | [88] |
Lewis lung carcinoma | 68 % d at 60 mg/kg daily | Intratumoural ratio of CD4 effector T cells to Tregs elevated | [89] |
CT26 colon carcinoma | 23.4 % b at 100 mg/kg BID | - | [90] |
RIL-175 hepatocellular carcinoma | Significant tumor reduction when combined with anti-PD-1, not significant at 300 mg/kg as single agent | - | [83] |
MMTV-Neu breast cancer | Tumor growth inhibition enhanced when combined with lapatinib and BMS777607 (MerTK inhibitor), not significant reduction at 20 mg/kg as single agent | - | [81] |
B16F10 melanoma | Significant tumor reduction when combined with agonistic CD40 antibody, not significant reduction at 100 mg/kg as single agent | Percentage of CD8+ CD107a+ effector T cells in tumor increased | [82] |
B16SIY melanoma | Complete responders found when combined with αCTLA-4 (3/16) and αPD-L1 (2/15) e | Frequency of tumor-reactive T cells in tumor-draining lymph nodes and spleen not substantially increased | [80] |
Treatment | Identifier/Trial name | Phase | Patients | Key results | Ref |
---|---|---|---|---|---|
Epacadostat | NCT01195311 | I | 52 | 1. MTD not established with dosing up to 700 mg BID 2. Near maximal changes observed at doses of ≥ 100 mg BID with > 80–90 % IDO1 inhibition achieved 3. Stable disease lasting ≥ 16 weeks observed in 7 patients 4. 300 mg BID selected as the recommended phase II monotherapy dose 5. PD modelling established | |
Epacadostat | NCT01685255 | I/II | 42 | 1. Trial terminated due to slow accrual and lack of evidence of superiority 2. No significant difference in efficacy observed compared to tamoxifen in biochemical-only relapse ovarian cancer 3. IDO1 expression observed in 94 % of archival tumor samples | [94] |
Epacadostat + ipilimumab | NCT01604889 | I/II | 50 | 1. Doses ≤ 50 mg BID generally well tolerated when combined with ipilimumab 2. IDO1 inhibition achieved with epacadostat doses ≥ 25 mg BID | [95]a |
Epacadostat + pembrolizumab | NCT02178722 ECHO-202/ KEYNOTE-037 | I/II | 62 | 1. 100 mg BID plus pembrolizumab recommended for phase II evaluation 2. 12 (55 %) of 22 patients with melanoma achieved objective response | [76]b |
Epacadostat + nivolumab | NCT02327078 ECHO-204 | I/II | 50 | 1. 100 mg BID plus nivolumab recommended for phase III evaluation 2. 31 (62 %) of 50 patients with melanoma achieved objective disease | [77]c |
Epacadostat + pembrolizumab | NCT02752074 ECHO-301/KEYNOTE-252 | III | 706 | 1. No significant difference in PFS found between the treatment groups (median 4.7 months for epacadostat plus pembrolizumab vs. 4.9 months for pembrolizumab alone; [HR] 1.00; one-sided p = 0.52) 2. No significant difference in PFS found between the treatment groups in IDO1-positive patient | [78] |
Future directions
Which biomarker should be used for IDO1 selective inhibitor therapy?
Whether plasma KYN concentration is an efficient pharmacodynamic marker?
Tumor type | No. of patients | Source | TRP | KYN | KYN/TRP ratio | Ref |
---|---|---|---|---|---|---|
CRC | 66 | serum | ↓ | − | ↑ | [39] |
Melanoma | 87 | serum | ↓ | − | ↑ | [40] |
Lung | 123 | serum | ↓ | ↑ | ↑ | [41] |
Lung | 36 | serum | ↓ | − | ↑ | [43] |
Ovarian carcinoma | 20 | serum | ↓ | − | ↑ | [44] |
Gynecologic cancersb | 109 | serum | − | ↑ | ↑ | [45] |
CRC | 69 | serum | ? | ↑ | ? | [116] |
Lung | 33 | serum | ? | ? | ↑ | [46] |
ATL | 96 | serum | − | ↑ | ↑ | [42] |
Glioblastoma | 10 | serum | ↓ | ↓c | − | [47] |
Cervical cancer | 27 | tumor | ↓ | ↑ | ↑ | [117] |