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Phase 2 trial of the IDO pathway inhibitor indoximod plus gemcitabine / nab-paclitaxel for the treatment of patients with metastatic pancreas cancer
Abstract
4015 Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that is exploited by tumors to prevent and evade anti-tumor immunity. Inhibitors of the IDO pathway, such as indoximod, are an increasingly validated class of potential cancer therapeutics. The combination of gemcitabine (G) and nab-paclitaxel (N) is a current SOC for metastatic pancreas cancer (MPC). Pre-clinical models have demonstrated synergy between indoximod and chemotherapy. Methods: Single arm study with indoximod (1200mg BID continuous) plus G / N (1000mg/m2 / 125mg/m2 q week x3 per 4-week cycle). Patients had treatment naïve MPC or 1st line therapy after previous resection and adjuvant therapy. Treatment continued until disease progression or toxicity. Primary endpoint was an improvement in median overall survival (mOS) from a historical 8.5 months for G / N to 12.1 months (hazard ratio (HR) of 0.70). Secondary endpoints included overall response rate (ORR) by site review RECIST 1.1. An expansion cohort enrolled patients undergoing pre and on-treatment (end Cycle 2) tumor biopsies. Results: A total of 135 patients initiated treatment in Phase 2 including 36 in the biopsy group. 104 were efficacy evaluable (EE) per the pre-specified definition of completing one cycle of therapy with one on-treatment imaging study. The ORR in the EE was 46.2% (48/104) with 1% CR (1/104) and 45.2% PR (47/104). The mOS in the EE was 10.9 months. Combination was generally well tolerated with fatigue, nausea, and anemia being the most commonly observed adverse events. Immunologic data by immunohistochemistry from biopsy samples (n = 11) indicate responders have increased intra-tumoral CD8 density after 2 cycles of therapy compared to non-responders (p = 0.030). Conclusions: EE patients had a mOS of 10.9 months and ORR of 46.2%; responding patients had an increased intra-tumoral CD8 density. The study did not meet the pre-specified primary goal of a 30% reduction in HR. However, the combination demonstrated activity with a promising ORR and immunologic correlation with response. These data support the continued development of combination indoximod immuno-chemotherapy for MPC. Clinical trial information: NCT02077881.
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Studies of IDO pathway blockade with radiation, chemotherapy, and tumor vaccines suggest improvement relative to those treatments alone.
“Studies of IDO pathway blockade with radiation, chemotherapy and tumor vaccines suggest an improvement relative to those treatments alone (53,54).”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [54]
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Broadening the Impact of Immunotherapy to Pancreatic Cancer: Challenges and Opportunities
Balachandran, V. P., Beatty, G. L., & Dougan, S. K. (2019) · Gastroenterology · doi:10.1053/j.gastro.2018.12.038 · Cited by 444
Self-citationLabadie, B. W., Bao, R., & Luke, J. J. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-2882 · Cited by 413
“Studies of IDO pathway blockade with radiation, chemotherapy, and tumor vaccines suggest an improvement relative to those treatments alone (53, 54).”
BackgroundIndoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy
Fujiwara, Y., Kato, S., Nesline, M., Conroy, J. M., DePietro, P., Pabla, S., & Kurzrock, R. (2022) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2022.102461 · Cited by 315
Trial watch: IDO inhibitors in cancer therapy
Naour, J. L., Galluzzi, L., Zitvogel, L., Kroemer, G., & Vacchelli, E. (2020) · OncoImmunology · doi:10.1080/2162402x.2020.1777625 · Cited by 192
Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer
Fox, E. E., Oliver, T., Rowe, M. M., Thomas, S., Zakharia, Y., Gilman, P. B., Muller, A. J., & Prendergast, G. C. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00370 · Cited by 126
“In a single-arm study of metastatic PDAC (NCT02077881), 104 of 135 patients enrolled to receive a standard of care regimen of gemcidabine or nab-paclitaxel plus indoximod were judged evaluable for efficacy by a prespecified definition (58).”
The footprint of kynurenine pathway in every cancer: a new target for chemotherapy
Ala, M. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.173921 · Cited by 109
Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion
DeVito, N. C., Plebanek, M. P., Theivanthiran, B., & Hanks, B. A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02876 · Cited by 105
Targeting indoleamine-2,3-dioxygenase in cancer: Scientific rationale and clinical evidence
Ricciuti, B., Leonardi, G. C., Puccetti, P., Fallarino, F., Bianconi, V., Sahebkar, A., Baglivo, S., Chiari, R., & Pirro, M. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.12.004 · Cited by 97
“Median overall survival (mOS) was 10.9 months (Bahary et al., 2018) [NCT02077881].”
BackgroundInfluentialZakharia, Y., McWilliams, R. R., Rixe, O., Drabick, J. J., Shaheen, M. F., Grossmann, K. F., Kolhe, R. B., Pacholczyk, R., Sadek, R., Tennant, L., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-002057 · Cited by 100
“In other studies, indoximod shows encouraging clinical safety and activity signals in different types of cancers, utilizing different combinations with chemotherapy, 23–26 chemoradiotherapy, 27 vaccines 28 and immune checkpoint therapy.”
Self-citationRecent advances in clinical trials targeting the kynurenine pathway
Pires, A. S., Sundaram, G., Heng, B., Krishnamurthy, S., Brew, B. J., & Guillemin, G. J. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.108055 · Cited by 86
Facts and Hopes in Immunotherapy of Pancreatic Cancer
Bockorny, B., Grossman, J. E., & Hidalgo, M. M. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-3452 · Cited by 87
Indoleamine 2,3-Dioxygenase (IDO) Inhibition as a Strategy to Augment Cancer Immunotherapy
Yentz, S. E., & Smith, D. C. (2018) · BioDrugs · doi:10.1007/s40259-018-0291-4 · Cited by 70
Role of tryptophan metabolism in cancers and therapeutic implications
Liu, X., & Zhai, X. (2021) · Biochimie · doi:10.1016/j.biochi.2021.01.005 · Cited by 73
Stone, T. W., & Williams, R. O. (2023) · Cancers · doi:10.3390/cancers15112895 · Cited by 67
Indoleamine Dioxygenase Inhibitors: Clinical Rationale and Current Development
Zhu, M. M. T., Dancsok, A. R., & Nielsen, T. O. (2019) · Current Oncology Reports · doi:10.1007/s11912-019-0750-1 · Cited by 55
“Although biochemically the biopsies showed an increase in intra-tumoral CD8+ T-cell density after two cycles of therapy in responders compared to non-responders, clinically the trial did not meet its primary endpoint [96].”
BackgroundResultPeng, X., Zhao, Z., Liu, L., Bai, L., Tong, R., Yang, H., & Zhong, L. (2022) · Drug Design Development and Therapy · doi:10.2147/dddt.s373780 · Cited by 48
“No indoximod-related serious AEs occurred.(50,51) The median OS was 10.”
BackgroundMoreno, A. C. R., Porchia, B. F. M. M., Pagni, R. L., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01914 · Cited by 42
“The IDO inhibitors 1MT (enantiomers and racemic mixture) were chosen to compose our therapeutic approach based on their preclinical and clinical data as adjuvants of antitumor therapies (20, 22, 23, 27).”
BackgroundMethodUpdate of early phase clinical trials in cancer immunotherapy
Lee, D. H. (2021) · BMB Reports · doi:10.5483/bmbrep.2021.54.1.242 · Cited by 37
Kong, X., Lü, P., Liu, C., Guo, Y., Yang, Y., Peng, Y., Wang, F., Zhang, B., Dou, X., Shi, H., et al. (2021) · Molecular Medicine Reports · doi:10.3892/mmr.2021.12001 · Cited by 30
“Phase II clinical trials of the effect of Indoximod, an IDO inhibitor on melanoma (NCT02073123) (53), pancreatic cancer (NCT02077881) (54) and castrated prostate cancer (NCT01560923) (55) are underway with promising results.”
BackgroundMolecular Mechanisms and Potential Therapeutic Reversal of Pancreatic Cancer-Induced Immune Evasion
Gan, L.-L., Hii, L., Wong, S. F., Leong, C., & Mai, C. (2020) · Cancers · doi:10.3390/cancers12071872 · Cited by 28
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Resistance Exercise Modulates Kynurenine Pathway in Pancreatic Cancer Patients
Pal, A., Zimmer, P., Clauss, D., Schmidt, M. E., Ulrich, C. M., Wiskemann, J., & Steindorf, K. (2020) · International Journal of Sports Medicine · doi:10.1055/a-1186-1009 · Cited by 24
“Another study conducted by Bahary et al, showed that IDO pathway inhibitors increased intra-tumoral CD8 density after 2 cycles of therapy compared to non-responders in metastatic pancreatic cancer patients [24].”
ResultNew Developments in T Cell Immunometabolism and Implications for Cancer Immunotherapy
Oberholtzer, N. P., Quinn, K. M., Chakraborty, P., & Mehrotra, S. (2022) · Cells · doi:10.3390/cells11040708 · Cited by 19
“Increased intra-tumoral CD8 density was observed [245] Completed (2020)”
BackgroundThe Role of Immune Checkpoint Inhibitors in Metastatic Pancreatic Cancer: Current State and Outlook
Tran, L. C., Özdemir, B. C., & Berger, M. D. (2023) · Pharmaceuticals · doi:10.3390/ph16101411 · Cited by 18
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“9 months in PDA patients, comparable with chemotherapy alone [135].”
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Future of immunotherapy in pancreas cancer and the trials, tribulations and successes thus far
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THE RISE, FALL, AND FUTURE PROMISE OF IDO1 INHIBITORS FOR IMMUNO-ONCOLOGY
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Metadata
- Authors
- Bahary, N., Wang-Gillam, A., Haraldsdottir, S., Somer, B. G., Lee, J. S., O'Rourke, M. A., Nayak-Kapoor, A., Beatty, G. L., Liu, M., Delman, D., Rossi, G. R., Kennedy, E. P., Vahanian, N. N., Link, C. J., & Garrido-Laguna, I.
- Affiliations
- University of Pittsburgh Medical Center (US)
- Washington University School of Medicine in St. Louis, St. Louis, MO;
- Stanford University, Stanford, CA;
- West Cancer Center (US)
- Valley Health System (US)
- Center for Integrative Oncology and Survivorship, Greenville, SC;
- Augusta University (US)
- Hospital of the University of Pennsylvania (US)
- University of Pennsylvania (US)
- NewLink Genetics (United States) (US)
- University of Utah Huntsman Cancer Institute, Salt Lake City, UT;
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2018-05-20
- Volume
- 36
- Issue
- 15_suppl
- Pages
- 4015-4015
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2891572283
- Cited by
- 39
- References
- 0
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 4 · 2022: 6 · 2021: 10 · 2020: 7 · 2019: 3 · 2018: 6
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- indoximod, metastatic pancreatic cancer, gemcitabine, nab-paclitaxel, combination chemotherapy, immune checkpoint inhibitors, CD8+ T cells, tumor-infiltrating lymphocytes, tumor immune microenvironment, overall survival, first-line therapy, treatment-naive patients, adverse events
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