1. IDO Inhibitors in Cancer Immunotherapy
Geoffrey T. Gibney, MD Co-leader, Melanoma Disease Group Georgetown Lombardi Comprehensive Cancer Center Medstar Georgetown University Hospital Washington, DC
This activity is supported by an educational grant from Incyte Corporation

2. Disclosures
Geoffrey T. Gibney, MD, has disclosed that he has received consulting fees from Genentech and Novartis and fees for non-CME/CE services from Merck.
This slide lists the disclosure information of the faculty involved in the development of these slides.

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4. Tumor Immune Phenotypes
Inflamed Tumor
Noninflamed Tumor
IDO
DC, dendritic cell.
A current focus in oncology is to identify tumor types based on their immune signatures, which guides the use of immunotherapies.[1] Tumors that are inflamed show signs of immune infiltrate, generally T-cells that are recruited to the microenvironment. Negative regulators also present themselves after this immune infiltration has occurred and tend to be checkpoints such as PD-1, as well as other regulatory cells like T-regs and other cells that may dampen the immune response against the tumor. Patients with an inflamed tumor phenotype have shown promising results with immunotherapies.
By contrast, noninflamed tumors have poor T-cell trafficking from the periphery vasculature into the tumor microenvironment, which may be related to suppression by surrounding cells, including macrophages and fibroblasts. In this group, less benefit has been seen in clinical trials of immunotherapies.
Reference:
1. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:
Reprinted by permission from Macmillan Publishers Ltd: Nature Immunology. Gajewski TF, et al. 2013;14: , ©2013.
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5. IDO1: Indoleamine 2,3-Dioxygenase 1
An important regulatory molecule in the inflamed tumor phenotype is IDO1. This enzyme is present in tumor cells, dendritic cells, macrophages, and B lymphocytes.[1,2] Its primary action is the conversion of tryptophan to kynurenine within these cells[2]; the depletion of tryptophan plus the accumulation of kynurenine help to suppress T-cell responses.
References:
1. Godin-Ethier J, Hanafi LA, Duvignaud JB, et al. IDO expression by human B lymphocytes in response to T lymphocyte stimuli and TLR engagement is biologically inactive. Mol Immunol. 2011;49:
2. Zhai L, Spranger S, Binder DC, et al. Molecular pathways: targeting IDO1 and other tryptophan dioxygenases for cancer immunotherapy. Clin Cancer Res, 2015;21:
Image reprinted from Clin Cancer Res, 2015;21: , Zhai L, et al, Molecular pathways: targeting IDO1 and other tryptophan dioxygenases for cancer immunotherapy, with permission from AACR.
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6. IDO1 Inhibitors in Clinical Development
Name
Class
Phase
Data Published or Presented
Indoximod (NLG2101, D-1MT)*[1,2]
Selective IDO1 inhibitor
I-II
Yes[3]
Epacadostat (INCB024360)*[4,5]
I-III
Yes[6]
GDC0919 (NLG919, RG6078)[7] I
Yes[8]
IDO5 peptide[9]
IDO peptide vaccine*
Yes[10]
IDO1 inhibition has been identified as a potential approach to making tumors more receptive to immunotherapy, and it appears to enhance antitumor immune responses. Drug classes in development include selective IDO1 inhibitors and IDO peptide vaccines, both of which are designed to inhibit or deplete immune cells with high IDO1 expression.
At least 3 IDO inhibitors are in clinical development: indoximod, epacadostat, and GDC An IDO peptide vaccine has also been studied.
*Stimulates immune response against IDO1-expressing cells.
1. NCT NCT Soliman HH, et al. Oncotarget. 2014;5: NCT NCT Gangadhar TC, et al. ESMO Abstract 1110PD. 7. NCT Nayak A, et al. J Immunother Cancer. 2014;2(suppl 3):P NCT Iversen TZ, et al. Basic Clin Pharmacol Toxicol. 2015;116:19-24.
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7. Phase I Trial: IDO1 Inhibitor Monotherapy With Indoximod
3 + 3 dose-escalation study of indoximod in pts with advanced solid tumors, life expectancy > 4 mos (N = 48)
Dosed orally at 10 levels (200 mg, 300 mg, 400 mg, 600 mg, 800 mg daily; or 600 mg, 800 mg, 1200 mg, 1600 mg, 2000 mg BID) on 28-day continuous cycle
Treatment continued until disease progression, toxicity, withdrawal
Safety assessed every 2 wks
Most frequent AEs were anemia, fatigue, anorexia, dyspnea, cough, and nausea, predominantly grade 1 or 2
DLTs observed: hypophysitis (n = 3)
Doses up to 2000 mg BID well tolerated (MTD not reached)
No CR, no PR, 5 SD (10%) for at least 6 mos
AE, adverse event; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; SD, stable disease.
Indoximod is a selective IDO1 inhibitor. Soliman and colleagues[1] conducted a phase I dose-escalation trial of indoximod that enrolled patients with advanced solid tumors that were largely treatment refractory after multiple lines of therapy (N = 48). The population was predominantly patients with sarcoma, non‑small‑cell lung cancer (NSCLC), or colorectal cancer. Dose levels ranged from mg/day or mg BID on a 28-day continuous cycle. Treatment was continued until disease progression, toxicity leading to intolerance, or study withdrawal.
The best response was stable disease for at least 6 months occurring in 10% of patients. Adverse events occurred in one half of the patients, predominantly grade 1/2; the most common included anemia, fatigue, and nausea. There were 3 cases of dose-limiting toxicities in patients previously treated with immune checkpoint inhibitors, all hypophysitis, none leading to withdrawal. A maximum tolerated dose was not reached at 2000 mg BID.
Reference:
1. Soliman HH, Minton SE, Han HS, et al. A phase I study of indoximod in patients with advanced malignancies. Oncotarget. 2016;7:
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Soliman HH, et al. Oncotarget. 2016;7:

8. Phase I Trial: IDO1 Inhibitor Monotherapy With Epacadostat
3 + 3 dose-escalation study in pts with advanced malignancies (N = 52)
Dosed orally in 28-day cycles (50 mg daily; 50 mg, 100 mg, 300 mg, mg, 500 mg, 600 mg, 700 mg BID)
Treatment continued until disease progression, toxicity
PK/PD assessed on Days 1, 15
Most frequent grade 3/4 AEs were fatigue (11.5%), abdominal pain (9.6%), and hypokalemia (9.6%)
2 DLTs observed: radiation pneumonitis (n = 1) and fatigue (n = 1)
Doses up to 700 mg BID well tolerated
No CR, no PR, 8 SD (15.4%) at ≥ 16 wks
AE, adverse event; DLT, dose-limiting toxicity; PK/PD, pharmacokinetics/ pharmacodynamics; SD, stable disease.
Beatty and colleagues[1] conducted a phase I dose-escalation study of the IDO1 inhibitor epacadostat in 52 patients with advanced malignancies. Patients received doses from 50 mg/day to 700 mg BID until progression or toxicity. Although no objective responses were noted, 8 patients achieved stable disease lasting 16 weeks or longer using doses above 112 mg/day. Even the highest tested dose levels were well tolerated. Most frequent grade 3/4 adverse events were fatigue (11.5%), abdominal pain (9.6%), and hypokalemia (9.6%).
Reference:
1. Beatty GL, O’Dwyer PJ, Clark J, et al. Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO1) INCB in patients (pts) with advanced malignancies. Program and abstracts of the 2013 American Society of Clinical Oncology annual meeting; May 31 - June 4, 2013; Chicago, Illinois. Abstract 3025.
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Beatty GL, et al. ASCO Abstract 3205.

9. Phase I Vaccination Trial: IDO1 Inhibitor Monotherapy With IDO5 Peptide Vaccine
Phase I study of an IDO5 peptide vaccine given monthly in 15 pts with HLA-A2–positive non-small-cell lung cancer
Median OS = 25.9 months; differences in baseline characteristics may have influenced results
One pt with IDO5 peptide vaccine had PR and 6 others achieved SD for more than 8.5 months
Treatment well tolerated; no reported grade 3/4 events
Iversen and colleagues[1] conducted a phase I study of an IDO5 peptide vaccine given monthly in 15 patients with HLA-A2–positive NSCLC. Results showed a median OS of 25.9 months, which was significantly longer than the median in a separate cohort of HLA-A2–negative patients treated with standard therapies, although differences in baseline characteristics could have influenced these results. One patient had a PR and 6 others achieved stable disease for more than 8.5 months with the IDO5 peptide vaccine. The treatment was well tolerated, with no reported grade 3/4 adverse events.
Reference:
1. Iversen TZ, Engell-Noerregaard L, Ellebaek E, et al. Long-lasting disease stabilization in the absence of toxicity in metastatic lung cancer patients vaccinated with an epitope derived from indoleamine 2,3 dioxygenase. Clin Cancer Res. 2014;20:
Iversen TZ, et al. Clin Cancer Res. 2014;20:

10. IDO1 Inhibitor Combination Strategies
Plus
IDO1 inhibitor
Chemotherapy
Vaccine/
immune stimulus
Immune
checkpoint
inhibitor
Based on clinical trial findings with both the selective IDO1 inhibitor as well as the IDO vaccine, combinations of the IDO1 inhibitor with other antitumor agents are now being investigated. These include chemotherapies, vaccines, and other immune stimuli, as well as immune checkpoint inhibitors.
This discussion will focus primarily on combinations of IDO1 inhibitors with immune checkpoint inhibitors, based on preclinical data and promising emerging clinical data.
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11. Upregulation of IDO1 Can Occur Concurrently With Other Immunosuppressive Mechanisms
PD-L1
FoxP3
CD8
Pt 1
Pt 2
IDO1 upregulation typically does not occur in isolation—other immunosuppressive mechanisms may be present. In this example of tumor biopsies from a patient with metastatic melanoma, IDO positivity in the inflamed tumor microenvironment coexists with upregulation of PD-L1 expression and FoxP3-positive regulatory T-cells.[1,2] This indicates that there may be concurrent immunosuppressive mechanisms present that would require combination therapy strategies for clinical benefit, and inhibiting IDO1 in isolation may not be sufficient to achieve an antitumor response.
References:
1. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:
2. Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5:200ra116.
Image from Spranger S, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5:200ra116. Reprinted with permission from AAAS. Readers may view, browse, and/or download material for temporary copying purposes only, provided these uses are for noncommercial personal purposes. Except as provided by law, this material may not be further reproduced, distributed, transmitted, modified, adapted, performed, displayed, published, or sold in whole or in part, without prior written permission from the publisher.
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12. Preclinical Data With Combination IDO1 and Immune Checkpoint Inhibition
No treatment
Anti–CTLA-4
IDO inhibitor
Anti–CTLA-4 + IDO inhibitor
No treatment
Anti–PD-L1
IDO inhibitor
Anti–PD-L1 + IDO inhibitor
500
500
400
400
300
300
Tumor Size (mm²)
Tumor Size (mm²)
200
200
Combining the 2 approaches is supported by preclinical data. In a melanoma mouse model with an intact immune system, mice were treated with IDO inhibitor alone, checkpoint therapy alone, or a combination of both, starting 7 days after the tumor inoculation.[1]
Results showed the best control of tumor growth when the IDO1 inhibitor was combined with either an anti–CTLA-4 agent or an anti–PD-L1 agent. Both combination strategies induced a greater capacity of the tumor-infiltrating CD8-positive T-cells to secrete IL-2 and proliferate, meaning that they were more active and potentially more capable of an antitumor response. This was complemented by the observation of 2.0-fold to 3.5-fold increases in splenic tumor antigen–specific T-cells with both combination therapy strategies vs IDO monotherapy or no treatment at all, suggesting that this was a systemic antitumor effect.
Reference:
1. Spranger S, Koblish HK, Horton B, et al. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer. 2014;2:3.
100
100 7 14 21 26 7 14 21 24
Days After
Tumor Inoculation
Days After
Tumor Inoculation
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Spranger S, et al. J Immunother Cancer. 2014;2:3.

13. IDO1 Inhibitor/Vaccine Plus Immune Checkpoint Inhibitors: Select Clinical Trials
Regimen
Phase
Pt Population
Status
ClinicalTrials.gov
Epacadostat + ipilimumab
I/II
Melanoma
Active, not recruiting, data available[1]
NCT
IDO vaccine + ipilimumab I
Completed, data available
NCT
Indoximod + ipilimumab, nivolumab, or pembrolizumab
Recruiting, data available[2]
NCT
Epacadostat + pembrolizumab
Multiple malignancies
Recruiting, data available[3]
NCT
III
Recruiting
NCT
Epacadostat + nivolumab
NCT
Epacadostat + atezolizumab
NSCLC
NCT
Epacadostat + durvalumab
NCT
GDC atezolizumab
NCT
Based on these and other data, the combination of an IDO1 inhibitor plus an immune checkpoint agent is being evaluated in multiple clinical trials. These include various combinations of either an IDO1 inhibitor or IDO vaccine, plus either anti–CTLA-4 or anti–PD-1/PD-L1 therapy. Four of these studies have data available for this discussion: epacadostat plus ipilimumab,[1] IDO vaccine plus ipilimumab,[2] indoximod plus ipilimumab, nivolumab, or pembrolizumab,[3] and epacadostat plus pembrolizumab.[4]
References:
1. Gibney GT, et al. Updated results from a phase 1/2 study of epacadostat (INCB024360) in combination with ipilimumab in patients with metastatic melanoma. Program and abstracts of the 2015 European Society of Medical Oncology; September 25-29, 2015; Vienna Austria. Abstract 511.
2. Kennedy E, Rossi GR, Vahanian NN, et al. Phase 1/2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus ipilimumab for the treatment of unresectable stage 3 or 4 melanoma. Program and abstracts of the 2014 American Society of Clinical Oncology; May 30 - June 3, 2014; Chicago, Illinois. Abstract TPS9117.
3. ClinicalTrials.gov. Peptide vaccination in combination with either ipilimumab or vemurafenib for the treatment of patients with unresectable stage III or IV malignant melanoma: a phase I study (first in man). Available at: Accessed November 8, 2016.
4. Gangadhar TC, Hamid, O, Smith DC, et al. Preliminary results from a phase 1/2 study of epacadostat (INCB024360) in combination with pembrolizumab in patients with selected advanced cancers. Program and abstracts of the 2015 Society for Immunotherapy of Cancer; November 4-8, 2015; National Harbor, Maryland. Abstract 142.
1. Gibney GT, et al. ESMO Abstract Kennedy E, et al. ASCO Abstract TPS Gangadhar TC, et al. J Immunother Cancer. 2015;3(suppl 2):O7.
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14. Phase I/II Study of Epacadostat Plus Ipilimumab in Melanoma: Design
Pts (N = 42) with unresectable or metastatic melanoma, life expectancy ≥ 3 mos, ECOG PS 0 or 1
Initial phase I dose-escalation study of 300-mg BID epacadostat plus 4 doses of ipilimumab (3 mg/kg IV Q3W)
Clinically significant ALT elevations in 5/7 pts; all recovered
Design amended to lower dose of epacadostat (25 mg BID, 50 mg BID continuous; 50 mg BID intermittent; 75 mg total daily) plus ipilimumab (3 mg/kg IV Q3W x 4)
ALT, alanine aminotransferase; ECOG, Eastern Cooperative Oncology Group; PS, performance status.
My colleagues and I conducted a phase I/II study of epacadostat plus ipilimumab in 42 patients with unresectable or metastatic melanoma.[1] The patients had a life expectancy of at least 3 months, a performance status of 0 or 1, and could be either treatment naive or refractory. Treatment was started with epacadostat 300 mg BID combined with 4 doses of ipilimumab using standard dosing of 3 mg/kg IV every 3 weeks, in 4 doses.
Clinically significant increases in alanine aminotransferase (ALT) were noted in 5 of the initial 7 patients treated at 300 mg BID, and treatment was discontinued in these patients; all recovered with the administration of corticosteroids. Based on these findings, the study design was amended to start epacadostat at a lower dose of 25 mg BID, 50 mg BID (continuous or intermittent), or 75 mg/day (50 mg in the morning, 25 mg in the evening).
Reference:
1. Gibney GT, et al. Updated results from a phase 1/2 study of epacadostat (INCB024360) in combination with ipilimumab in patients with metastatic melanoma. Program and abstracts of the 2015 European Society of Medical Oncology; September 25-29, 2015; Vienna Austria. Abstract 511.
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Gibney GT, et al. ESMO Abstract 511.

15. Epacadostat Plus Ipilimumab in Melanoma: Baseline Characteristics
Pt Characteristic
25 mg BID (n = 8)
50 mg BID Continuous (n = 18)
50 mg BID Intermittent (n = 9)
75 mg Total Daily Dose (n = 7)
Age, median yrs (range)
67 (34-81)
57 (25-78)
69 (49-77)
62 (35-81)
Male, %
75.0
50.0
66.7
42.9
ECOG PS 0/1, %
62.5/37.5
88.9/11.1
66.7/33.3
85.7/14.3
Mutated BRAF, %
25.0
44.4
22.2
14.3
Prior radiotherapy, %
M classification, % 1a 1b 1c
12.5
27.8
11.1
ECOG, Eastern Cooperative Oncology Group; PS, performance status.
The median age ranged from years in the 4 treatment arms, with a slight predominance of males. Less than one half of the patients had BRAF mutant melanoma. The majority of patients had distant metastatic disease (M1a-c), with M1c accounting for approximately one half of the population.
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Gibney GT, et al. ESMO Abstract 511.

16. Epacadostat Plus Ipilimumab in Melanoma: Prior Regimens
25 mg BID (n = 8)
50 mg BID Continuous (n = 18)
50 mg BID Intermittent (n = 9)
75 mg Total Daily Dose (n = 7)
Prior regimens, %
None
1-2
≥ 3
100
55.6
27.8
16.7
66.7
33.3
71.4
28.6
Regimen types,%
Immunotherapy
Checkpoint inhibitor
IL-2
Other
BRAF inhibitor
Chemotherapy
0 0 0
11.1
22.2
14.3
ECOG, Eastern Cooperative Oncology Group; PS, performance status.
Patients in the 25 mg BID group had received no previous treatment regimens. The percentage of patients with previous radiation therapy ranged from 22% to 50% in the other groups. Previous immunotherapy exposure was most frequent in the 50 mg BID continuous and intermittent groups, which included previous checkpoint inhibitors. Other previous agents included BRAF-targeted therapy, chemotherapy, and selective tyrosine kinase inhibitors.
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Gibney GT, et al. ESMO Abstract 511.

17. Epacadostat Plus Ipilimumab in Melanoma: Safety
AE (all grades), %
25 mg (n = 8)
50 mg Continuous (n = 18)
50 mg Intermittent (n = 9)
75 mg (n = 7)
Total (N = 42)*
Rash
62.5
55.6
11.1
85.7
52.4
Pruritus
25.0
33.3
42.9
38.1
Diarrhea
37.5
22.2
ALT increased
16.7
28.6
21.4
AST increased
14.3
Hypothyroidism
11.9
Colitis
5.6
9.5
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DLT, dose-limiting toxicity.
Compared with epacadostat 700 mg BID, the lower starting doses of epacadostat used in the expansion cohorts were much better tolerated. ALT and aspartate aminotransferase (AST) elevations were seen in 21% and 17% of patients respectively, but grade 3/4 AST and ALT elevations were seen in only 9.5% and 7.1% of patients respectively. The other most common adverse events included rash, pruritus, diarrhea, hypothyroidism, and colitis. These are overlapping toxicities that are commonly seen with ipilimumab monotherapy.
The investigators concluded that epacadostat up to 50 mg BID plus ipilimumab 3 mg/kg was generally well tolerated.
*Other AEs (total): adrenal insufficiency (7.1%), vitiligo (7.1%), acute renal failure (4.8%), hypophysitis (4.8%), hypopituitarism (2.4%), idiopathic thrombocytopenic purpura (2.4%), pneumonitis (2.4%).
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Gibney GT, et al. ESMO Abstract 511.

18. Epacadostat Plus Ipilimumab in Melanoma: Efficacy
Pts, %
Immunotherapy Naive
25 mg (n = 8)
50 mg Cont (n = 12)
50 mg Inter (n = 6)
75 mg (n = 6)
Total (n = 32)
ORR CR PR
37.5
16.7
8.3
33.3
28.1
9.4
18.8 SD
25.0
DCR
62.5
41.7
50.0
66.7
53.1 PD
31.3
Unknown
12.5
15.6
Cont, continuous; DCR, disease control rate; Inter, intermittent; SD, stable disease.
In the immunotherapy-naive patients, the ORR was 28% (by Response Evaluation Criteria in Solid Tumors [RECIST]). There were no objective responses in patients previously treated with immunotherapy. Overall disease control rates were 53.1% for the immunotherapy-naive arm vs 30.0% for the immunotherapy-treated arm. In the immunotherapy-naive patients, the median PFS was 5.3 months, which compares reasonably well to historical data seen with ipilimumab monotherapy.[1,2] In those earlier ipilimumab studies, the ORR was 11% to 19%, and median PFS times ranged from months.
References:
1. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:
2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.
1. Gibney GT, et al. ESMO Abstract Postow MA, et al. N Engl J Med. 2015;372: Larkin J, et al. N Engl J Med. 2015;373:23-34.
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19. Phase I Study of IDO Vaccine Plus Ipilimumab in Melanoma
Pts with stage III/IV melanoma, ECOG PS ≤ 2 (N = 10); pts (n = 9) systemically therapy naive (1 pt IFN)
Dosed with ipilimumab (3 mg/kg IV Q3W x 4) plus vaccinated with IDO 21-mer peptide in Montanide (SC, weekly x 4, then biweekly x 3)
Endpoints: safety, vaccine response, clinical response
Blood drawn 5x (baseline, Wks 3, 7, 12, 20-24, 28-36)
PET/CT performed 4x (baseline, Wks 12, 20-24, 28-36)
ECOG, Eastern Cooperative Oncology Group; PS, performance status.
Bjoern and colleagues[1] conducted a phase I study of an IDO vaccine plus ipilimumab in 10 patients with stage III/IV melanoma and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Most patients were naive to systemic therapy, although 1 had received interferon in the adjuvant setting prior to enrollment.
Treatment consisted of ipilimumab at the standard dosing of 3 mg/kg IV every 3 weeks for 4 doses, in addition to the IDO vaccine. The vaccine was a 21-mer peptide in Montanide, administered SC weekly for 4 doses, and then biweekly for 3 doses. Of note, this was a slightly different approach than was evaluated in the phase I monotherapy study discussed earlier.
Of most importance, the IDO vaccine was a 21 amino acid peptide with multiple MHC class I predicted epitopes compared with a 9 amino acid peptide restricted to a specific MHC class I HLA-A2 presentation in the phase I monotherapy study.
Endpoints included safety, vaccine response, and clinical response. Blood was drawn at 5 different time points, including baseline and Weeks For restaging, PET/CT scans were performed at baseline and at Weeks 12, 20-24, and
Reference:
1. Bjoern J, Iversen TZ, Nitschke NJ, et al. Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2,3-dioxygenase in combination with ipilimumab. Cytotherapy. 2016;18:
Slide credit: clinicaloptions.com
Bjoern J, et al. Cytotherapy. 2016;18:

20. IDO Vaccine Plus Ipilimumab in Melanoma: Outcomes
No grade 3/4 AEs; 1 grade 5 colitis event observed after pt declined hospital readmission/infliximab in the corticosteroid-refractory setting
Local vaccine injection-site reactions, rash, pruritus, and diarrhea were most common (grade 1/2)
5 SD; 1 pt with unconfirmed PR, then progression in nontarget lesions
AE, adverse event; SD, stable disease.
Common adverse events included injection-site reactions, as well as common toxicities associated with ipilimumab, including rash, pruritus, and diarrhea.
No grade 3/4 adverse events were attributed to treatment, but 1 patient had a grade 5 event (died of treatment-related colitis). The investigators commented that this patient had declined readmission to the hospital after experiencing corticosteroid-refractory colitis and therefore did not receive further management, including infliximab.
Efficacy data showed 1 patient achieved an unconfirmed PR and then progressed, with a total of 5 achieving stable disease as their best response.
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Bjoern J, et al. Cytotherapy. 2016;18:

21. Phase Ib/II: Indoximod Plus Ipilimumab, Nivolumab, or Pembrolizumab
Phase Ib study in pts with melanoma (N = 9): (3 pts at 600 mg BID, 6 pts at 1200 mg BID) plus ipilimumab (3 mg/kg Q3W x 4)
Outcomes:
No DLTs; indoximod plus ipilimumab well tolerated; most common AEs fatigue, pruritus, diarrhea, rash, abdominal pain, headache
1 CR
Phase II study in pts with melanoma (N = 96 planned): indoximod (1200 mg BID) plus immune checkpoint inhibitor (4 cycles of ipilimumab, repeat cycles of nivolumab, repeat cycles of pembrolizumab)
On disease progression, provider can switch to another checkpoint inhibitor while continuing indoximod
AE, adverse event; DLT, dose-limiting toxicity.
Zakharia and colleagues[1] conducted a phase Ib/II study of IDO1 inhibition with indoximod plus the anti–CTLA-4 antibody ipilimumab or anti–PD-1 therapy with nivolumab or pembrolizumab. In the phase Ib portion, 9 patients with treatment-naive metastatic melanoma received ipilimumab at 3 mg/kg plus indoximod 600 mg BID (3 patients) or 1200 mg BID (6 patients).
No dose-limiting toxicities were seen. Overall, indoximod plus ipilimumab was well tolerated; common adverse events were fatigue, rash, diarrhea, abdominal pain, and headache. One patient had a CR, but further details on objective responses and stable disease were not reported.
These data supported the ongoing phase II portion of the study in patients with unresectable stage III/IV melanoma (planned N = 96).[2] Indoximod is being dosed at 1200 mg BID combined with standard dosing of one of 3 immune checkpoint inhibitors: ipilimumab, nivolumab, or pembrolizumab. In this study, when patients progress on one checkpoint inhibitor plus indoximod, they may continue with the other class of checkpoint inhibitor, still combined with indoximod.
References:
1. Zakharia Y, Drabick JJ, Khleif S, et al. Updates on phase1b/2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus checkpoint inhibitors for the treatment of unresectable stage 3 or 4 melanoma. Program and abstracts of the 2016 American Society of Clinical Oncology; June 3-7, 2016; Chicago, Illinois. Abstract 3075.
2. Zakharia Y, Drabick J, Khleif S, et al. Phase II trial of the indoleamine 2, 3-dioxygenase pathway (IDO) inhibitor indoximod plus immune checkpoint inhibitors for the treatment of unresectable stage 3 or 4 melanoma. Program and abstracts of the American Association for Cancer Research; April 16-20, 2016; New Orleans, Louisiana. Abstract CT087.
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Zakharia Y, et al. ASCO Abstract 3075.

22. Change in Tumor Volume (%)
Indoximod Plus Ipilimumab, Nivolumab, or Pembrolizumab: Phase II Preliminary Results
200
2735%
150
100 50
Change in Tumor Volume (%)
CR, complete response; Pts, patients; ORR, overall response rate.
The preliminary results of the phase II portion were also presented at ASCO 2016.[1] In total, 40 patients have been enrolled so far with 22 patients receiving pembrolizumab, 14 patients receiving ipilimumab, and 4 patients receiving nivolumab.
Of the 28 patients to date who have received indoximod plus a checkpoint inhibitor, the ORR was 36%, with a CR rate of 11%. The response rate in patients treated with indoximod plus pembrolizumab was 53% with a CR rate of 13%. This is an exciting result because historical data for pembrolizumab monotherapy shows an ORR of 33% for all melanoma patients and 45% for treatment-naive melanoma patients.[2]
The potential efficacy of checkpoint inhibition combined with indoximod was also demonstrated by the tumor response plot that showed reductions in tumor burden in multiple patients between cycles 3 and 6. Patients with longer follow-up showed continued responses with this combination therapy.
Reference:
1. Zakharia Y, Drabick JJ, Khleif S, et al. Updates on phase1b/2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus checkpoint inhibitors for the treatment of unresectable stage 3 or 4 melanoma. Program and abstracts of the 2016 American Society of Clinical Oncology; June 3-7, 2016; Chicago, Illinois. Abstract 3075.
2. Ribas A, Hamid O, Daud A, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315:
-50
-100 C0 C3 C4 C5 C6 C7 C8 C9
C10
C11
Treatment Cycles
Slide credit: clinicaloptions.com
Zakharia Y, et al. ASCO Abstract 3075.

23. Phase Ib/II Epacadostat Plus Pembrolizumab: Study Design
Dose-escalation/dose-expansion study in pts with advanced cancers, life expectancy > 12 wks, ECOG PS 0/1, checkpoint inhibitor naive (N = 54)
Dose-escalation phase of epacadostat (25 mg, 50 mg, mg, 300 mg BID) plus pembrolizumab (2 mg/kg Q3W)
Dose-expansion phase of epacadostat (50 mg, 100 mg, mg BID) plus pembrolizumab (200 mg Q3W)
Responses assessed Q9W per RECIST 1.1
ECOG PS, Eastern Cooperative Oncology Group; PS, performance status.
The combination of epacadostat plus pembrolizumab has also been evaluated in a phase Ib/II dose-escalation/dose-expansion study presented by Gangadhar and colleagues.[1,2] Patients had advanced cancers, had a life expectancy of longer than 12 weeks, had an ECOG performance status of 0/1, and were naive to checkpoint inhibitor therapy. In total, 62 patients have been enrolled so far.
The dose-escalation portion of epacadostat started at 25 mg BID and reached 300 mg BID, in combination with pembrolizumab 2 mg/kg every 3 weeks. Running parallel, the dose-expansion portion included epacadostat at 3 different dose levels ( mg BID) in combination with pembrolizumab at 200 mg every 3 weeks. Responses were assessed every 9 weeks (RECIST 1.1 criteria).
References:
1. Gangadhar TC, Hamid, O, Smith DC, et al. Preliminary results from a phase 1/2 study of epacadostat (INCB024360) in combination with pembrolizumab in patients with selected advanced cancers. Program and abstracts of the 2015 Society for Immunotherapy of Cancer; November 4-8, 2015; National Harbor, Maryland. Abstract 142.
2. Gangadhar TC, Hamid O, Smith DC, et al. Epacadostat plus pembrolizumab in patients with advanced melanoma and select solid tumors: updated phase 1 results from ECHO-202/KEYNOTE-037 Program and abstracts of the 2016 European Society of Medical Oncology; October 7-11, 2016; Copenhagen, Denmark. Abstract 1110PD.
Slide credit: clinicaloptions.com
Gangadhar TC, et al. SITC Abstract 142.

24. Phase Ib/II Study of Epacadostat Plus Pembrolizumab: Baseline Characteristics
Total (N = 56)
25 mg (n = 4)
50 mg (n = 19)
100 mg (n = 18)
300 mg (n = 15)
Tumor type, %
Melanoma
RCC
NSCLC
TCC EA
TNBC
SCCHN 36 20 18 9 5 4 50 25 68 21 22 6 39 17 11 6) 7 40 13
Median age, yrs (range)
59 (30-88)
47 (30-63)
60 (37-81)
61.5 (39-88)
59 (30-84)
Male, % 55 53 66
ECOG PS, % 1 57 43
100 74 26 56 44 27 73
EA, endometrial adenocarcinoma; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; PS, performance status; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; TCC, transitional cell carcinoma; TNBC, triple-negative breast cancer.
The majority of patients in this study had metastatic melanoma (n = 36). The next most common tumor types were renal cell carcinoma and NSCLC. In the dose-escalation groups, the median age ranged from years. Most patients were male, and more than one half of the patients had a performance status of 0.
Slide credit: clinicaloptions.com
Gangadhar TC, et al. SITC Abstract 142. 24

25. Phase Ib/II Study of Epacadostat Plus Pembrolizumab: Treatment-Related AEs
AE, % (all grades ≥ 10%, phase I pts)
All Grades (N = 62)
Grades 3 or 4 (N = 62)
Any grade
Rash
Fatigue
Pruritus
Arthralgia
Diarrhea
Nausea
Pyrexia
Vomiting 81 29 23 19 18 16 11 8 2
AE, adverse event; AST, aspartate aminotransferase; CNS, central nervous system; DLT, dose-limiting toxicity.
Dose-limiting toxicities included rash in 2 patients, increased AST in 1 patient, and a central nervous system disorder in 1 patient. Of note, 1 patient discontinued therapy due to grade 3 AST elevation. Overall, only 8% of patients experienced a treatment-related adverse event that led to treatment discontinuation in the phase I portion. No treatment-related deaths were reported. The most common events were rash and fatigue. There did not appear to be a substantial increase in grade 3 adverse events with epacadostat plus pembrolizumab compared with historical data for pembrolizumab alone, suggesting that this combination was relatively well tolerated.
Other grade 3/4 AEs > 2%: increased lipase (5%), increased amylase (3%)
Treatment-related AEs led to discontinuation in 5 patients (8%): grade 3 arthralgia,
grade 3 AST increased/grade 2 ALT increased, grade 3 lipase increased, grade 3 aseptic meningitis, and grade 2 nervous system disorder
No treatment-related deaths
Slide credit: clinicaloptions.com
Gangadhar TC, et al. ESMO Abstract 1110PD.

26. Phase Ib/II Study of Epacadostat Plus Pembrolizumab: Efficacy
Melanoma (n = 19)
RCC (n = 11)
NSCLC (n = 12)
TCC (n = 5)
EA (n = 7)
TNBC (n = 3)
SCCHN (n = 2)
ORR, % CR PR 58 26 32 18 60 28 14 50
SD, % 16 45 17 67
DCR, % 74 63 59
100
DCR, disease control rate; EA, endometrial adenocarcinoma; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; SD, stable disease; TCC, transitional cell carcinoma; TNBC, triple-negative breast cancer.
Most of the available data from this study are for the melanoma cohort. In 19 evaluable treatment-naive patients from the phase I portion, the ORR was 58% (CR: 26%). This compares favorably with the historical data for pembrolizumab, as mentioned earlier.
These data suggest enhanced activity with the combination of epacadostat plus pembrolizumab in melanoma.
With the caveat that the nonmelanoma cohorts had fewer evaluable patients, there was also suggestion of enhanced activity in the 12 evaluable patients with NSCLC where an ORR of 42% was observed, which is higher than reported previously with pembrolizumab monotherapy in unselected NSCLC patients.
These early data are encouraging and hopefully will lead to future studies involving this combination. A randomized phase III study of epacadostat plus pembrolizumab in metastatic melanoma is currently accruing patients.[1]
Reference:
1. ClinicalTrials.gov. A phase 3 randomized, double-blind, placebo-controlled study of pembrolizumab (MK-3475) in combination with epacadostat or placebo in subjects with unresectable or metastatic melanoma (Keynote-252 / ECHO-301). Available at: Accessed November 8, 2016.
Slide credit: clinicaloptions.com
Gangadhar TC, et al. ESMO Abstract 1110PD.

27. Biomarkers: PBMCs
Phase I study in melanoma pts (N = 10) treated with IDO vaccination plus ipilimumab showed increased reactivity of PBMCs to IDO vaccine after 8 and 12 wks of treatment but no association with efficacy[1]
Phase I/II study in melanoma pts (N = 24) treated with IDO inhibitor epacadostat plus ipilimumab showed dose-dependent IDO1 inhibition in PBMCs[2]
100
25 mg BID
50 mg BID
300 mg BID 80 60
PBMC, peripheral blood mononuclear cell.
The clinical development of combinations of IDO inhibitors plus immune checkpoint therapy will be greatly helped by the identification of biomarkers identifying patients for whom this strategy will be most beneficial. Although more data are needed, some biomarker development is under way.
In the phase I study of the IDO vaccine plus ipilimumab, there was increased reactivity of peripheral blood mononuclear cells when patients were treated with the IDO vaccine at the 8- and 12-week time points.[1] This suggests that the effects of the vaccine can be monitored. However, in this study, there was no clear association with efficacy.
In the study with epacadostat in combination with ipilimumab, patients’ peripheral blood was examined to determine how well IDO1 inhibition was achieved in peripheral blood mononuclear cells.[2] As seen in the slide, results showed a dose-dependent increase in IDO1 inhibition, as measured by the ability to induce IDO1 inhibition and levels of tryptophan and kynurenine.
In both studies, the data suggest that peripheral IDO1 inhibition can be monitored, but results may not directly correlate to what is seen in the tumor microenvironment.
References:
1. Bjoern J, Iversen TZ, Nitschke NJ, et al. Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2,3-dioxygenase in combination with ipilimumab. Cytotherapy. 2016;18:
2. Gibney GT, Hamid O, Gangadhar TC, et al. Preliminary results from a phase 1/2 study of INCB combined with ipilimumab (ipi) in patients (pts) with melanoma. Program and abstracts of the 2014 American Society of Clinical Oncology; May 30 - June 3, 2014; Chicago, Illinois. Abstract 3010.
IDO1 Inhibition (%) 40 20 1 2 3 4 5 6
Hrs
1. Bjoern J, et al. Cytotherapy. 2016;18: Gibney GT, et al. ASCO Abstract 3010.
Slide credit: clinicaloptions.com

28. Other Biomarkers Melanoma Cohort[1] NSCLC Cohort[1] 100 100 50 50
PD-L1 positive
PD-L1 negative
PD-L1 unknown
100
PD-L1 positive
PD-L1 negative
PD-L1 unknown 50 50
Best Change From
Baseline (%)
-50
-50
-100
-100
IHC, immunohistochemistry; NSCLC, non-small cell lung cancer.
The phase Ib/II study of epacadostat plus pembrolizumab gathered data on the association between PD-L1 tumor responses and objective responses in patients with cancer.[1,2] These waterfall plots demonstrate the benefit in melanoma patients who were PD-L1 positive (by IHC staining of baseline tumor). The left figure shows that multiple patients with PD-L1–positive tumors (yellow bars) had tumor reduction, but there were 2 patients with PD-L1–negative disease demonstrating objective responses (orange bars).
The right figure shows patients with NSCLC. In this small group, 1 patient with a PD-L1–negative tumor, 2 patients with PD-1–positive tumors, and 2 patients with unknown PD-L1 status tumors had objective responses with greater than 30% tumor reduction. Therefore, it is unclear whether PD-L1 status will be an important biomarker for IDO1 plus checkpoint inhibitor therapy, and further data are needed.
Of note, IHC for IDO1 status within the tumor microenvironment has been studied, and the antibody has been standardized in clinical samples.[3] However, no data are yet available to support a relationship between IDO1 status and clinical activity with this class of agents.
References:
1. Gangadhar TC, Hamid, O, Smith DC, et al. Preliminary results from a phase 1/2 study of epacadostat (INCB024360) in combination with pembrolizumab in patients with selected advanced cancers. Program and abstracts of the 2015 Society for Immunotherapy of Cancer; November 4-8, 2015; National Harbor, Maryland. Abstract 142.
2. Gangadhar TC, Hamid O, Smith DC, et al. Epacadostat plus pembrolizumab in patients with advanced melanoma and select solid tumors: updated phase 1 results from ECHO-202/KEYNOTE-037 Program and abstracts of the 2016 European Society of Medical Oncology; October 7-11, 2016; Copenhagen, Denmark. Abstract 1110PD.
3. Hiscox A, Gustafson H, Couto J, et al. Development of an IHC-based detection method for studying indoleamine 2,3-dioxygenase 1 (IDO1) expression in human cancers. Program and abstracts of the 2014 American Society of Clinical Oncology; May 30 - June 3, 2014; Chicago, Illinois. Abstract 3043.
Pts
Pts
Phase Ib/II study of epacadostat plus pembrolizumab found unclear association between PD-L1 tumor status and tumor burden reduction[1]
IHC for IDO1 has been standardized in clinical samples, but data not available on association with clinical activity[2]
1. Gangadhar TC, et al. ESMO Abstract 1110PD. 2. Hiscox A, et al. ASCO Abstract 3043.

29. Conclusions
IDO1 selective inhibitors and IDO vaccine are well tolerated but demonstrate modest clinical activity as monotherapy in pts with advanced malignancies[1,2]
Preclinical data indicate synergistic potential for combined IDO1 inhibition plus immunotherapies (and chemotherapy)[3]
No early signs of increased serious toxicity with IDO1 inhibition plus immune checkpoint therapy[4]
IDO1 inhibition plus anti–PD-1 therapy shows promising early clinical activity, especially in advanced melanoma patients; phase III study ongoing[5]
Further biomarker development is needed for combination IDO1 inhibition therapeutic strategies
In conclusion, IDO1-selective inhibitors and IDO vaccine strategies are well tolerated but, to date, have demonstrated only modest clinical activity as monotherapy in patients with advanced malignancies.[1,2] The preclinical data discussed here indicate that there may be synergy between IDO1 inhibition and immunotherapies.[3]
In these studies, there were no early signs of increased serious toxicity with the combination of IDO1 inhibition plus immune checkpoint therapy[4] outside of higher doses of epacadostat plus ipilimumab, but this will need to continue being evaluated from ongoing studies. IDO1 inhibition plus anti–PD‑1 therapy has demonstrated promising early clinical activity in patients with advanced melanoma, which led to the phase III KEYNOTE-252 study that is comparing pembrolizumab plus epacadostat vs pembrolizumab plus placebo in patients with unresectable or metastatic melanoma (planned N = 600).[5]
Further biomarker development is clearly needed to guide patient selection for combination IDO1 inhibition therapeutic strategies.
References:
1. Beatty GL, O’Dwyer PJ, Clark J, et al. Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO1) INCB in patients (pts) with advanced malignancies. Program and abstracts of the 2013 American Society of Clinical Oncology annual meeting; May 31 - June 4, 2013; Chicago, Illinois. Abstract 3025.
2. Bjoern J, Iversen TZ, Nitschke NJ, et al. Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2,3-dioxygenase in combination with ipilimumab. Cytotherapy. 2016;18:
3. Spranger S, Koblish HK, Horton B, et al. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer. 2014;2:3.
4. Gibney GT, et al. Updated Results From a phase 1/2 study of epacadostat (INCB024360) in combination with ipilimumab in patients with metastatic melanoma. Program and abstracts of the 2015 European Society of Medical Oncology; September 25-29, 2015; Vienna Austria. Abstract 511.
5. ClinicalTrials.gov. A phase 3 randomized, double-blind, placebo-controlled study of pembrolizumab (MK-3475) in combination with epacadostat or placebo in subjects with unresectable or metastatic melanoma (Keynote-252 / ECHO-301). Available at: Accessed November 8, 2016.
1. Beatty GL, et al. ASCO Abstract Bjoern J, et al. Cytotherapy. 2016;18: Spranger S, et al. J Immunother Cancer. 2014;2:3. 4. Gibney GT, et al. ESMO Abstract ClinicalTrials.gov. NCT
Slide credit: clinicaloptions.com

30. Go Online for More CCO Coverage of Cancer Immunotherapy!
Capsule Summaries of all the key data Additional CME-certified slidesets, modules, and videos on Immunotherapy with expert faculty commentary on key studies
clinicaloptions.com/oncology