This randomized clinical trial evaluates clinical outcomes in patients with ERBB2-negative metastatic breast cancer treated with indoximod plus a taxane.
Key Points
Question
Is the combination of indoximod and a taxane superior to a taxane alone in treating patients with ERBB2-negative metastatic breast cancer?
Findings
In this randomized clinical trial of 169 patients with ERBB2-negative metastatic breast cancer, the combination of indoximod and a taxane compared with a single-agent taxane resulted in neither superior clinical outcomes nor significantly greater toxic effects.
Meaning
Indoximod plus a taxane did not have superior efficacy compared with single-agent taxane in patients with metastatic ERBB2-negative breast cancer.
Abstract
Importance
Indoleamine 2,3-dioxygenase 1 (IDO1) causes tumor immune suppression. The IDO1 pathway inhibitor indoximod combined with a taxane in patients with ERBB2-negative metastatic breast cancer was tested in a prospective clinical trial.
Objective
To assess clinical outcomes in patients with ERBB2-negative metastatic breast cancer treated with indoximod plus a taxane.
Design, Setting, and Participants
This phase 2 double-blinded randomized 1:1 placebo-controlled clinical trial enrolled patients at multiple international centers from August 26, 2013, to January 25, 2016. Eligibility criteria included ERBB2-negative metastatic breast cancer, ability to receive taxane therapy, good performance status, normal organ function, no previous immunotherapy use, and no autoimmune disease. The study was discontinued in June 2017 because of lack of efficacy. Data analysis was performed from February 2019 to April 2020.
Interventions
A taxane (paclitaxel [80 mg/m2] weekly 3 weeks on, 1 week off, or docetaxel [75 mg/m2] every 3 weeks) plus placebo or indoximod (1200 mg) orally twice daily as first-line treatment.
Main Outcomes and Measures
The primary end point was progression-free survival (PFS); secondary end points were median overall survival, objective response rate, and toxic effects. A sample size of 154 patients would detect a hazard ratio of 0.64 with 1-sided α = .1 and β = .2 after 95 events. Archival tumor tissue was stained with immunohistochemistry for IDO1 expression as an exploratory analysis.
Results
Of 209 patients enrolled, 169 were randomized and 164 were treated (85 in the indoximod arm; 79 in the placebo arm). The median (range) age was 58 (29-85) years; 166 (98.2%) were female, and 135 (79.9%) were White. The objective response rate was 40% and 37%, respectively (indoximod vs placebo) (P = .74). The median (range) follow-up time was 17.4 (0.1-39.4) months. The median PFS was 6.8 months (95% CI, 4.8-8.9) in the indoximod arm and 9.5 months (95% CI, 7.8-11.2) in the placebo arm (hazard ratio, 1.2; 95% CI, 0.8-1.8). Differences between the experimental and placebo arms in median PFS (6.8 vs 9.5 months) and overall survival (19.5 vs 20.6 months) were not statistically significant. Grade 3 or greater treatment-emergent adverse events occurred in 60% of patients in both arms.
Conclusions and Relevance
This randomized clinical trial found that, among patients with ERBB2-negative metastatic breast cancer, addition of indoximod to a taxane did not improve PFS compared with a taxane alone.
Trial Registration
ClinicalTrials.gov Identifier: NCT01792050
Introduction
Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-metabolizing enzyme that is part of the kynurenine pathway. This pathway leads to the generation of kynurenine and its catabolites from tryptophan and to the depletion of the local supply of tryptophan. Activity of IDO1 permits cancer cell growth primarily by suppressing T-cell activity, as demonstrated by IDO1’s key role in preventing the rejection of allogeneic fetuses in pregnant mice.1 Tryptophan depletion induces cell cycle arrest in the G1 phase of CD8+ and natural killer T cells and increases apoptosis in these cells by inhibiting mammalian target of rapamycin complex 1 (mTORC1).2 These mechanisms also induce the differentiation and activation of the immunosuppressive CD4+ regulatory T cells.3,4 In human cell lines with repressed mTOR activity due to tryptophan depletion, the tryptophan mimetic D-1-methyltryptophan can relieve this mTOR-dependent effect.5 Tryptophan 2,3-dioxygenase (TDO) and IDO1 are broadly activated in human cancers, where they are implicated in tumor immunotolerance.6 In various cancers, IDO1 production is increased by the presence of inflammatory cytokines, including interferon-γ,7,8 and overexpression of IDO1 correlates with poor prognosis9; however, this correlation is unclear in breast cancers.10,11
The arrest of T-lymphocyte proliferation due to tryptophan shortage via IDO1 activity can be partly averted by systemic treatment with an inhibitor of IDO1. In a study by Uyttenhove et al,12 most mice injected with cancer cells that did not express IDO1 rejected the tumor. In contrast, the majority of mice injected with IDO1-expressing cancer cells developed progressive tumors. Furthermore, the mice that received 1-methyl-L-tryptophan rejected IDO1-expressing cells more efficiently than untreated mice and had a significantly slower rate of tumor progression.12 In another study,13 which was based on the indication that taxanes induce T-cell infiltration of tumors, the combination of indoximod and taxane chemotherapy in transgenic breast cancer–bearing mice showed superior antitumor activity to that of either agent alone. Furthermore, lymphodepletion prevented the combination therapy from leading to tumor regression, thereby proving its immune dependency. On the basis of these results, a phase 1 trial was conducted to test indoximod in combination with docetaxel in patients with metastatic solid tumors.14 This trial enrolled and treated 27 patients, of whom 22 were evaluable for response. Four patients (2 with breast cancer, 1 with non–small cell lung cancer, and 1 with thymic tumors) showed partial response.14 In another phase 1 trial,15 which enrolled and treated 48 patients with advanced solid malignant neoplasms, indoximod showed a good toxicity profile and stable disease response over 6 months in 5 patients. In view of these promising results, we conducted this phase 2 study to evaluate the safety and efficacy of indoximod plus taxanes in patients with ERBB2-negative metastatic breast cancer (MBC).
Methods
Clinical Trial Design
This was a phase 2 prospective double-blind multicenter 1:1 randomized placebo-controlled study of patients with ERBB2-negative MBC, conducted in the US and Poland. The study was designed to assess the efficacy, tolerability, and safety of treatment with single-agent taxane therapy—either docetaxel or paclitaxel—in combination with either indoximod or placebo. The patients were randomized in a 1:1 fashion using a permuted block design to receive either indoximod or placebo in combination with a single-agent taxane of the physician’s choice (docetaxel or paclitaxel). The generation of subject codes and randomization was performed by an independent third party (Veristat). We estimated an accrual period of approximately 18 months, a follow-up period of 6 months, and a median progression-free survival (PFS) for the control group of 5 months. Stratification factors included the following: physician’s choice of taxane (docetaxel or paclitaxel), which was to be determined before randomization; hormone receptor status (positive or negative); and the number of metastatic disease sites (1 or >1). The trial protocol is included in Supplement 1. The present study (ClinicalTrials.gov: NCT01792050) was approved by the ethics committee at each participating institution. The Independent Data Safety Monitoring Committee was responsible for the periodic review of the safety data from NewLink Genetics Corporation. Written informed consent was obtained from all patients before enrollment in the study. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Treatment Scheme
Indoximod was administered orally on an empty stomach at a dose of 1200 mg twice daily. This dosing level was based on prior pharmacokinetic and oral bioavailability data. The medication was to be taken on days 1 to 14 of each 21-day cycle (2 weeks on, 1 week off) when given with docetaxel or on days 1 to 21 of each 28-day cycle (3 weeks on, 1 week off) when given with paclitaxel. No specific premedication was required. Docetaxel was administered intravenously at a dose of 75 mg/m2 as a 1-hour infusion after premedication with oral dexamethasone 8 mg (oral) twice daily for 3 days starting on day −1. Paclitaxel was administered weekly at a dose of 80 mg/m2 as a 1-hour intravenous infusion with standard institutional premedication orders using dexamethasone and antihistamines. Docetaxel dose reduction from 75 mg/m2 to 60 mg/m2 was permitted for either febrile neutropenia or a neutrophil count less than 500 cells/mm3 for more than 1 week, neuropathy, or liver dysfunction. Paclitaxel dose reduction of 10 mg/m2 was permitted for neutropenia or thrombocytopenia after a break period and for neuropathy or other grade 2 or 3 nonhematologic adverse events. Use of granulocyte-stimulating growth factor support was permitted if the patient experienced febrile neutropenia or a neutrophil count less than 500 cells/mm3 for more than 7 days, or at the discretion of the treating physician for patient safety. If a dose reduction of indoximod was considered medically necessary, a dose reduction to 800 mg was permitted. If this reduced dose was not tolerated, then discontinuation of the study treatment was required. Patients were asked to document daily indoximod/placebo intake in a medication diary during treatment.
Study Population
Eligible patients were nonpregnant women and men 18 years and older with Eastern Cooperative Oncology Group performance status of 0 or 1; histologically confirmed estrogen receptor (positive or negative)/progesterone receptor (positive or negative) defined as 1% or greater positive staining; ERBB2-negative MBC; measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.116; no prior exposure to chemotherapy in the metastatic setting; estimated life expectancy greater than 4 months; normal organ and bone marrow function; treated and stable central nervous system disease; and the ability to understand and the willingness to sign a written informed consent document. Patients were excluded from the study if they had a history of allergic reactions to compounds similar to docetaxel or tryptophan, an autoimmune disease requiring concurrent use of any systemic immunosuppressants or steroids, HIV infection or other acquired or inherited immunodeficiencies, or more than 1 malignant neoplasm; patients were also excluded if they underwent radiotherapy, treatment with other investigational agents, or experimental active immunotherapy within 3 weeks before study. Sexually active women of childbearing potential had to agree to use contraception for the duration of the study. The patient enrollment flowchart is shown in Figure 1.
Figure 1. Consort Diagram.
End Points and Assessments
The primary objective of the study was to assess median PFS after treatment with docetaxel or paclitaxel in combination with indoximod or placebo for patients with MBC. Secondary objectives were the assessment of median overall survival (OS), objective response rates (ORRs) measured by RECIST 1.1, and the safety profile of a taxane plus indoximod by Common Terminology Criteria for Adverse Events, version 4.03. Secondary objectives also included the analysis of correlative data to determine the mechanism of pathologic variables and clinical benefits.
Immunohistochemistry Analysis
Archival formalin-fixed paraffin-embedded tumor tissue was stained per an optimized protocol for immunohistochemistry staining using a Ventana Discovery XT auto-stainer using IDO1 10.1 antibodies (Millipore) (eMethods in Supplement 2). Aperio Positive Pixel Count Algorithm (Leica Biosystems) was used to generate a transformed continuous numerical score (number of positive pixels divided by the total pixel count in viable whole tissue section multiplied by 1000). A score cutoff of 16.5 or greater for the immunohistochemistry staining of tumor cells (derived as the median score from a cohort of previously stained samples) was used to classify IDO1 expression as high vs low.
Statistical Methods
A modified intention-to-treat analysis for the primary end point was performed, excluding patients who withdrew prior to treatment with no recorded outcome data. Accounting for a dropout rate of up to 10% (evenly distributed between both arms), a 1-sided log-rank test was used to calculate the sample size of 154 patients (77 per study arm), aimed to provide at least 80% power with a 1-sided type I error rate of 0.10, and to detect a hazard ratio (HR) of 0.64 after 95 events. The accrual pattern across time periods was assumed to be uniform. Analyses included all enrolled patients who received 1 or more dose of study drug. Statistical analyses were performed with SAS, version 9.2 (SAS Institute). The PFS and OS were summarized using the Kaplan-Meier method, and CIs for the median and survival rates at different time points were constructed when appropriate. The stratified log-rank test was used to evaluate treatment efficacy and to account for the 3 stratification factors. Additional supportive analyses were performed using Cox proportional hazard models to adjust for stratification variables and covariates. An exploratory analysis was performed to compare PFS between taxane strata. The ORR (complete and partial response) was analyzed using a Fisher exact test between the 2 treatment arms; ORR estimates and 95% Wilson CIs were presented. Linear regression and χ2 techniques were used to study the interaction between IDO1 status and other clinicopathologic variables. Data analysis was performed from February 2019 to April 2020.
Results
Patient Disposition and Baseline Characteristics
Between August 26, 2013, and January 25, 2016, we screened 209 patients for eligibility, of whom 169 were randomized and 164 were treated (85 in the indoximod arm and 79 in the placebo arm). The median (range) age was 58 (29-85) years; 166 (98.2%) were female, and 135 (79.9%) were White. Patients’ baseline characteristics are summarized in Table 1. The study was prematurely discontinued in June 2017 owing to lack of efficacy. Eighty-eight (52.1%) patients were enrolled in the experimental treatment and 81 (47.9%) in the placebo arm. The most common reason for treatment discontinuation was progressive disease. Full patient disposition details are described in Figure 1. Median (range) follow-up was 6 (0.1-31.3) months. Baseline Eastern Cooperative Oncology Group status was 0 in 89 patients (52.7%) and 1 in 80 patients (47.3%). A total of 135 patients (79.8%) had more than 1 disease site. Docetaxel was used in 125 patients (73.9%). The majority of patients (124 patients [69.8%]) had hormone receptor–positive disease. There were no patients with treated/stable brain metastasis who received treatment in the study. Patient characteristics and demographics were generally distributed evenly in each arm.
Table 1. Demographic Characteristics of Patients at Baseline.
| Characteristic | No. (%) | ||
|---|---|---|---|
| Indoximod (n = 88) | Placebo (n = 81) | Overall (n = 169) | |
| Age, median (range), y | 58 (29-76) | 58 (29-85) | 58 (29-85) |
| Female sex | 87 (98.9) | 79 (97.5) | 166 (98.2) |
| Race/ethnicity | |||
| White | 70 (79.5) | 65 (80.2) | 135 (79.9) |
| African American | 14 (15.9) | 11 (13.6) | 25 (14.8) |
| Hispanic | 3 (3.4) | 3 (3.7) | 6 (3.6) |
| Asian | 1 (1.1) | 0 | 1 (0.6) |
| Other | 0 | 2 (2.5) | 2 (1.2) |
| ECOG score | |||
| 0 | 43 (48.9) | 46 (56.8) | 89 (52.7) |
| 1 | 45 (51.1) | 35 (43.1) | 80 (47.3) |
| BMI, median (range)a | 28.48 (18-47) | 29.06 (19-44) | 28.53 (18-47) |
| ER positive | 63 (71.6) | 58 (71.6) | 121 (71.6) |
| PR positive | 47 (53.4) | 46 (56.8) | 93 (55.0) |
| Multiple metastatic sites | 68 (77.3) | 67 (82.7) | 135 (79.9) |
| De novo metastatic | 20 (22.7) | 19 (23.5) | 39 (23.1) |
| Site | |||
| US | 62 (70.1) | 56 (69.1) | 118 (69.8) |
| Poland | 26 (29.5) | 25 (30.9) | 51 (30.2) |
| Choice of taxane | |||
| Docetaxel | 65 (73.9) | 60 (74.1) | 125 (74.0) |
| Paclitaxel | 23 (26.1) | 21 (25.9) | 44 (26.0) |
| Prior hormonal therapy | |||
| 0 | 40 (45.5) | 29 (35.8) | 69 (40.8) |
| 1 | 24 (27.3) | 25 (30.9) | 49 (29.0) |
| 2 | 14 (15.9) | 15 (18.5) | 29 (17.2) |
| ≥3 | 10 (11.3) | 11 (13.6) | 21 (12.4) |
| Unknown | 0 | 1 (1.2) | 1 (0.6) |
| Adjuvant/neoadjuvant chemotherapy | 55 (62.5) | 46 (56.8) | 101 (59.8) |
| Anthracycline containing | 44 (50.0) | 34 (42.0) | 78 (46.2) |
| Taxane containing | 35 (39.8) | 36 (44.4) | 71 (42.0) |
| Unknown | 0 | 1 (1.2) | 1 (0.6) |
Abbreviations: BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; PR, progesterone receptor.
Calculated as weight in kilograms divided by height in meters squared.
Safety
A total of 85 patients (100%) in the indoximod group and 78 (98.7%) in the placebo group had at least 1 treatment-emergent adverse event (TEAE). In both the indoximod and placebo arms, related TEAEs occurred in 58 (68.2%) and 63 (79.7%) patients, respectively; TEAEs grade 3 or greater in severity occurred in 51 (60.0%) and 48 (60.8%) patients, respectively. Four patients (4.7%) in the indoximod arm and 2 (2.5%) in the placebo arm died owing to unrelated TEAEs during the study. A total of 11 (12.9%) and 10 (12.7%) patients in the indoximod and placebo arms, respectively, permanently discontinued the study due to 1 or more TEAEs. The most common TEAEs are reported in Table 2. In the indoximod and placebo arms, anemia (28 [32.9%] and 15 [19%] patients, respectively), fatigue (52 [61.2%] and 36 [45.6%] patients), lymphopenia (18 [21.2%] and 10 [12.7%] patients), hyperglycemia (20 [23.5%] and 7 [8.9%] patients), extremities pain (13 [15.3%] and 8 [10.1%] patients), and cough (17 [20%] and 10 [12.7%] patients) were reported with a higher incidence (≥5% difference in incidence) in the indoximod group; however, these adverse events were easily manageable in the outpatient setting.
Table 2. Most Common (≥15% in Each Treatment Arm) Adverse Events and Laboratory Abnormalities.
| Adverse event | No. (%) | |||
|---|---|---|---|---|
| Indoximod arm (n = 85) | Placebo arm (n = 79) | |||
| Any grade | Grade ≥3 | Any grade | Grade ≥3 | |
| Gastrointestinal | ||||
| Nausea | 40 (47.1) | 2 (2.4) | 38 (48.1) | 2 (2.5) |
| Diarrhea | 30 (35.3) | 1 (1.2) | 31 (39.2) | 6 (7.6) |
| Constipation | 24 (28.2) | 0 | 27 (34.2) | 1 (1.3) |
| Vomiting | 20 (23.5) | 3 (3.5) | 28 (35.4) | 1 (1.3) |
| Decreased appetite | 17 (20.0) | 1 (1.2) | 19 (24.1) | 0 |
| Dysgeusia | 12 (14.1) | 0 | 17 (21.5) | 0 |
| Abdominal pain | 13 (15.3) | 4 (4.7) | 15 (19.0) | 1 (1.3) |
| Laboratory abnormalities | ||||
| Anemia | 28 (32.9) | 7 (8.2) | 15 (19.0) | 3 (3.8) |
| Hyperglycemia | 20 (23.5) | 3 (3.5) | 7 (8.9) | 0 |
| Neutropenia | 14 (16.5) | 8 (9.4) | 15 (19.0) | 14 (17.7) |
| Lymphopenia | 18 (21.2) | 3 (3.5) | 10 (12.7) | 3 (3.8) |
| Musculoskeletal | ||||
| Arthralgia | 17 (20.0) | 0 | 16 (20.3) | 0 |
| Bone pain | 19 (22.4) | 2 (2.4) | 14 (17.7) | 3 (3.8) |
| Extremity pain | 13 (15.3) | 1 (1.2) | 8 (10.1) | 0 |
| Back pain | 8 (9.4) | 2 (2.4) | 13 (16.5) | 2 (2.5) |
| Myalgia | 7 (8.2) | 0 | 12 (15.2) | 1 (1.3) |
| Neurologic | ||||
| Headache | 19 (22.4) | 1 (1.2) | 24 (30.4) | 2 (2.5) |
| Peripheral neuropathy | 19 (22.4) | 0 | 19 (24.1) | 0 |
| Dizziness | 11 (12.9) | 0 | 19 (24.1) | 0 |
| Insomnia | 13 (15.3) | 0 | 11 (13.9) | 0 |
| Constitutional | ||||
| Fatigue | 52 (61.2) | 6 (7.1) | 36 (45.6) | 4 (5.1) |
| Asthenia | 9 (10.6) | 2 (2.4) | 14 (17.7) | 4 (5.1) |
| Respiratory: cough | 17 (20.0) | 0 | 10 (12.7) | 0 |
| Dermatologic: alopecia | 38 (44.7) | 0 | 51 (64.6) | 0 |
| General: peripheral edema | 26 (30.6) | 1 (1.2) | 23 (29.1) | 1 (1.3) |
| Infection: urinary tract infection | 5 (5.9) | 1 (1.2) | 12 (15.2) | 2 (2.5) |
Efficacy
Survival analyses were conducted on 164 patients; survival data were unavailable on 5 of 169 patients randomized. The PFS was calculated from the day of treatment start until documented progression of disease on radiology scans or death, whichever occurred first. The median PFS was 6.8 months (95% CI, 4.8-8.9) in the indoximod arm, and 9.5 months (95% CI, 7.8-11.2) in the placebo arm (HR, 1.2; 95% CI, 0.8-1.8). The median OS was 19.5 months (95% CI, 14.5-24.4) in the indoximod group and 20.6 months (95% CI, 18.6-22.5) in the placebo group (HR, 1.0; 95% CI, 0.6-1.6; Figure 2). In the indoximod arm, the median PFS was 8.2 months (95% CI, 6.7-9.8) among hormone receptor–positive patients, and 3.2 months (95% CI, 1.9-4.5) among the hormone receptor–negative subset. In comparing the different strata, the median PFS was 8.5 months (95% CI, 6.7-10.4) when indoximod was combined with docetaxel and 3.6 months (95% CI, 2.1-5.0) when indoximod was combined with paclitaxel.
Figure 2. Outcomes in the Entire Study Population and Within the IDO1-Analyzed Population.
A, Progression-free survival in the modified intention-to-treat (mITT) population; B, Overall survival in the mITT population; C, Progression-free survival in the indoleamine 2,3-dioxygenase 1 (IDO1)-low population; D, Progression-free survival in the IDO-high population. HR indicates hazard ratio.
Three patients (3.5%) in the indoximod arm and 2 (2.5%) in the placebo arm achieved a complete response. Thirty-one patients (36.5%) achieved a partial response in the indoximod arm, and 27 (34.2%) achieved partial response in the placebo group. The ORR did not significantly differ between arms.
IDO1 Expression
We performed an exploratory analysis of IDO1 staining samples with outcomes (52 samples [30, IDO1 high; 22, IDO1 low]) to evaluate whether high IDO1 expression was predictive of response to indoximod (Table 3). Our analysis did not demonstrate a benefit for indoximod vs placebo in either IDO1 group (Figure 2). In all the stained samples, patients with high IDO1 expressing tumors (n = 30 [57.7%]) had longer median PFS and OS than patients with low IDO1 expressing tumors (9.9 vs 5.5 months); however, these differences were not statistically significant. Greater numbers of estrogen receptor–negative tumors were in the IDO1 low compared with IDO1 high group for the analysis, which may have affected survival outcomes in this group (eFigure in Supplement 2). However, no correlation was found between hormone receptor status and IDO1 levels.
Table 3. Demographic Characteristics of Patients With IDO1 Analysis at Baseline.
| Characteristic | No. (%) | ||
|---|---|---|---|
| IDO1 low (n = 22) | IDO1 high (n = 30) | Overall (n = 52) | |
| Age, median (range), y | 58.0 (29-73) | 58.5 (31-76) | 58.0 (29-76) |
| Female sex | 22 (100) | 30 (100) | 52 (100) |
| Race/ethnicity | |||
| White | 15 (68.2) | 27 (90.0) | 42 (80.8) |
| African American | 6 (27.3) | 2 (6.7) | 8 (15.4) |
| Hispanic | 1 (3.8) | 1 (3.3) | 2 (3.8) |
| ECOG score | |||
| 0 | 14 (63.6) | 15 (50.0) | 29 (55.8) |
| 1 | 8 (36.4) | 15 (50.0) | 23 (44.2) |
| BMI, median (range)a | 29.76 (20-47) | 26.50 (19-47) | 29.02 (19-47) |
| ER positive | 13 (59.1) | 23 (76.7) | 36 (69.2) |
| PR positive | 8 (36.4) | 14 (46.7) | 22 (42.3) |
| Multiple metastatic sites | 17 (77.3) | 26 (86.7) | 43 (82.7) |
| De novo metastatic | 5 (22.7) | 10 (33.3) | 15 (28.8) |
| Site | |||
| US | 18 (81.8) | 21 (70.0) | 39 (75.0) |
| Poland | 4 (18.2) | 9 (30.0) | 13 (25.0) |
| Choice of taxane | |||
| Docetaxel | 17 (77.3) | 23 (76.7) | 40 (76.9) |
| Paclitaxel | 5 (22.7) | 7 (23.3) | 12 (23.1) |
| Prior hormonal therapy | |||
| 0 | 10 (45.5) | 12 (40.0) | 22 (42.3) |
| 1 | 5 (22.7) | 10 (33.3) | 15 (28.8) |
| 2 | 2 (9.1) | 1 (3.3) | 3 (5.8) |
| ≥3 | 5 (22.7) | 6 (20.0) | 11 (21.1) |
| Unknown | 0 | 1 (3.3) | 1 (1.9) |
| Adjuvant or neoadjuvant chemotherapy | 13 (59.1) | 16 (53.3) | 29 (55.8) |
| Anthracycline based | 7 (31.8) | 16 (53.3) | 23 (44.2) |
| Taxane based | 10 (45.5) | 11 (36.7) | 21 (40.4) |
| Unknown | 0 | 1 (3.3) | 1 (1.9) |
Abbreviations: BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; IDO1, indoleamine 2,3-dioxygenase 1; ER, estrogen receptor; PR, progesterone receptor.
Calculated as weight in kilograms divided by height in meters squared.
Discussion
This is the first known report of a phase 2 study that assesses the efficacy of an IDO1 pathway inhibitor in combination with taxane chemotherapy in patients with MBC. The data did not show any clinical benefit with the addition of indoximod to taxane chemotherapy in patients with ERBB2-negative MBC. The toxicity profile of indoximod plus a taxane showed a slight increase in selected low-grade adverse events (in particular hyperglycemia) in keeping with the safety profile of indoximod monotherapy. Overall, the combination was manageable, with few discontinuations due to TEAEs. The exploratory IDO1 biomarker analysis was not predictive for indoximod benefit. There was a trend toward inferior outcomes in IDO1-low patients, but this may be due to an imbalance in patients with adverse prognosis within the analyzed patients as opposed to the IDO1 status itself.
The mechanism of action of indoximod is distinct from other direct inhibitors of the IDO1 enzyme. Indoximod was selected for clinical development by the National Cancer Institute as a lead compound because of its superior preclinical antitumor activity compared with other similar agents. More potent direct inhibitors of IDO1 activity were subsequently developed and have entered clinical trials. Studies using indoximod and other IDO1 inhibitors have yet to result in any new indications across a number of different tumor types and immunotherapy combinations. The phase 3 study ECHO-301/KEYNOTE-252,17 which combined the IDO1 inhibitor epacadostat with pembrolizumab in metastatic melanoma, failed to demonstrate a clinical benefit compared with placebo plus pembrolizumab. The ECHO-203 study,18 which combined epacadostat with the anti–programmed cell death ligand 1 antibody durvalumab, did not show ORRs in unselected patients with advanced pancreatic cancer. Given the extensive evidence supporting the role of IDO1 in tumor-mediated immunosuppression, this result was unexpected. Clinical trials are currently ongoing19,20 in which the IDO1 inhibitor linrodostat in combination with nivolumab is being tested as first-line therapy in hepatocellular carcinoma and in combination with platinum-based neoadjuvant chemotherapy and nivolumab in muscle-invasive bladder cancer. Improper selection of patients most suitable for IDO1 inhibitor treatment might have contributed to these negative results.
In a phase 2 study21 that compared epacadostat vs tamoxifen in treating patients with recurrent epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer, there was no significant difference in efficacy between the 2 arms. In this study, IDO1 expression was observed in 94% of archival samples, but only low levels of expression were detected in the majority of IDO1-positive patients. Other possible explanations for the lack of response in previous studies include translational limitations of available preclinical models, other compensatory immune-escape mechanisms, and incomplete inhibition of the tryptophan metabolism pathway with first-generation IDO1 inhibitors. Tryptophan 2,3-dioxygenase has been implicated in the development of multiple tumors, including breast cancers. Increased levels of kynurenine have been observed in cancer cell lines with high TDO activity, suggesting a TDO-dependent alternative mechanism of immune invasion.22,23 In a study by Smith et al,24 IDO1-deficient mice had increased levels of kynurenine in the lungs, indicating a potential induction of alternative pathways for kynurenine production, such as IDO2 or TDO2. There are efforts to investigate agents with broader potent activity against both IDO1 and TDO within tumors. Newer drugs targeting both IDO1 and TDO, such as RG70099, are currently in development. These drugs reduced kynurenine plasma levels by approximately 90% in preclinical in vivo models. This dual blockade may overcome the failures of the first-generation IDO1 inhibitors.25 Better outcomes could be achieved by using these more potent agents in conjunction with better tools (ie, tissue biomarkers or functional imaging) in selected patients with high IDO1 and/or TDO tumor activity.
Limitations
Our study had several limitations. This was a small phase 2 trial intended to initially explore the efficacy of indoximod. The selection of different taxane schedules, to accommodate local treatment preferences, may have affected the PFS calculations for the 2 arms because of the lower PFS observed with weekly administered paclitaxel. However, because the allocation was balanced across the arms, it is unlikely to have affected the ultimate conclusions. Also, not all patients had available archival tissue, and the study was not able to acquire fresh pretreatment or on-treatment biopsies.
Conclusions
In this randomized clinical trial, there was no difference in median PFS between the groups receiving taxane plus indoximod or taxane plus placebo. Additional biomarker research is needed to indicate which patients would benefit more from IDO1 inhibitors or IDO1/TDO combinations. Expression of IDO1 should be investigated further as a biomarker in future prospective studies of IDO1 inhibitors.
Trial Protocol
eMethods.
eFigure. A. OS in IDO low population. B. OS in IDO high population.
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eMethods.
eFigure. A. OS in IDO low population. B. OS in IDO high population.
Data Sharing Statement