First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors
Elizabeth J Davis, Juan Martin-Liberal, Rebecca Kristeleit, Daniel C Cho, Sarah P Blagden, Dominik Berthold, Dana B Cardin, Maria Vieito, Rowan E Miller, Prashanth Hari Dass, Angela Orcurto, Kristen Spencer, John E Janik, Jason Clark, Thomas Condamine, Jennifer Pulini, Xuejun Chen, Janice M Mehnert, Elizabeth J Davis, Juan Martin-Liberal, Rebecca Kristeleit, Daniel C Cho, Sarah P Blagden, Dominik Berthold, Dana B Cardin, Maria Vieito, Rowan E Miller, Prashanth Hari Dass, Angela Orcurto, Kristen Spencer, John E Janik, Jason Clark, Thomas Condamine, Jennifer Pulini, Xuejun Chen, Janice M Mehnert
Abstract
Background: OX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949.
Methods: Phase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7-1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics.
Results: Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1-9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs.
Conclusion: No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors.
Trial registration number: NCT02923349.
Keywords: Clinical Trials as Topic; Immunomodulation; Lymphocytes, Tumor-Infiltrating; T-Lymphocytes; Tumor Microenvironment.
Conflict of interest statement
Competing interests: EJD reports research funding (institution) from Actuate, BMS, FivePrime, Genentech, Incyte, Karyopharm and TopAlliance Biosciences; honoraria from MJH Life Sciences; and advisory role for Deciphera. JM-L reports lecture fees from Astellas, Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche and Sanofi; advisory fees from Bristol-Myers Squibb, Highlight Therapeutics, Novartis, Pierre Fabre, Roche and Sanofi; research grants from Sanofi; travel grants from Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pierre Fabre, Pfizer and Roche. RK reports grants from MSD, Clovis and MSD; advisory role for Basilea, PharmaMar; advisory fees from AstraZeneca, Clovis, Eisai, GSK, Incyte, iTEOS, Pfizer and Roche. DCC reports advisory role for HUYA, Nektar Therapeutics, Pfizer and Werewolf Pharmaceuticals. SPB reports research funding and honoraria from Nucana plc; advisory fees from Amphista and Ellipses; clinical trials funding from Astex, MSD, Redx Pharma, Roche and UCB. DB reports no competing interests. DBC reports advisory role with AbbVie and Rafael Pharmaceuticals; honoraria from OncLive/MJH Life Sciences; research funding (institution) from Advaxis, Array BioPharma, Bristol-Myers Squibb, Celgene, Corcept Therapeutics, EMD Serono, Incyte, Lilly, Rafael Pharmaceuticals and Synta; and travel, accommodations and expenses from AbbVie. MV reports advisory role with Debiopharm and Roche; and travel from Roche. REM reports advisory fees from AZD, Clovis Oncology, Ellipses, GSK, Merck and Shigoni; speakers' fees from AZD, Clovis Oncology, GSK and Roche. PHD and AO report no competing interests. KS reports advisory fees from QED Therapeutics. JEJ, JC and TC report former employment and stock ownership with Incyte. JP and XC report employment and stock ownership with Incyte. JMM reports grants from Amgen, AstraZeneca, Bristol-Myers Squibb, EMD Serono, Immunocore, Incyte, Macrogenics, Merck Sharp & Dohme, Novartis, Polynoma and Sanofi; advisory role with Amgen and Merck Sharp & Dohme; honoraria from EMD Serono and Pfizer; advisory board for Array BioPharma, Bristol-Myers Squibb, Eisai/Merck, EMD Serono, Sanofi/Regeneron and Seagen.
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9628691/bin/jitc-2021-004235f01.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9628691/bin/jitc-2021-004235f02.jpg)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9628691/bin/jitc-2021-004235f03.jpg)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9628691/bin/jitc-2021-004235f04.jpg)
References
- Frauwirth KA, Thompson CB. Activation and inhibition of lymphocytes by costimulation. J Clin Invest 2002;109:295–9. 10.1172/JCI0214941
- Paluch C, Santos AM, Anzilotti C, et al. . Immune checkpoints as therapeutic targets in autoimmunity. Front Immunol 2018;9:2306. 10.3389/fimmu.2018.02306
- Guram K, Kim SS, Wu V, et al. . A threshold model for T-cell activation in the era of checkpoint blockade immunotherapy. Front Immunol 2019;10:491. 10.3389/fimmu.2019.00491
- Granier C, De Guillebon E, Blanc C, et al. . Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. ESMO Open 2017;2:e000213. 10.1136/esmoopen-2017-000213
- Golay J, Andrea AE. Combined anti-cancer strategies based on anti-checkpoint inhibitor antibodies. Antibodies 2020;9:17. 10.3390/antib9020017
- Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39:1–10. 10.1016/j.immuni.2013.07.012
- Ellmark P, Mangsbo SM, Furebring C, et al. . Tumor-directed immunotherapy can generate tumor-specific T cell responses through localized co-stimulation. Cancer Immunol Immunother 2017;66:1–7. 10.1007/s00262-016-1909-3
- Han X, Vesely MD. Stimulating T cells against cancer with agonist immunostimulatory monoclonal antibodies. Int Rev Cell Mol Biol 2019;342:1–25. 10.1016/bs.ircmb.2018.07.003
- Weinberg AD, Morris NP, Kovacsovics-Bankowski M, et al. . Science gone translational: the OX40 agonist story. Immunol Rev 2011;244:218–31. 10.1111/j.1600-065X.2011.01069.x
- Rothfelder K, Hagelstein I, Roerden M, et al. . Expression of the immune checkpoint modulator OX40 in acute lymphoblastic leukemia is associated with BCR-ABL positivity. Neoplasia 2018;20:1150–60. 10.1016/j.neo.2018.09.005
- Croft M. The TNF family in T cell differentiation and function--unanswered questions and future directions. Semin Immunol 2014;26:183–90. 10.1016/j.smim.2014.02.005
- Petty JK, He K, Corless CL, et al. . Survival in human colorectal cancer correlates with expression of the T-cell costimulatory molecule OX-40 (CD134). Am J Surg 2002;183:512–8. 10.1016/S0002-9610(02)00831-0
- Curti BD, Kovacsovics-Bankowski M, Morris N, et al. . OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res 2013;73:7189–98. 10.1158/0008-5472.CAN-12-4174
- Weixler B, Cremonesi E, Sorge R, et al. . OX40 expression enhances the prognostic significance of CD8 positive lymphocyte infiltration in colorectal cancer. Oncotarget 2015;6:37588–99. 10.18632/oncotarget.5940
- Montler R, Bell RB, Thalhofer C, et al. . OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer. Clin Transl Immunology 2016;5:e70. 10.1038/cti.2016.16
- Kim J-Y, Lee E, Park K, et al. . Immune signature of metastatic breast cancer: identifying predictive markers of immunotherapy response. Oncotarget 2017;8:47400–11. 10.18632/oncotarget.17653
- Lee D-W, Ryu HS, Jin M-S, et al. . Immune recurrence score using 7 immunoregulatory protein expressions can predict recurrence in stage I-III breast cancer patients. Br J Cancer 2019;121:230–6. 10.1038/s41416-019-0511-9
- Deng J, Zhao S, Zhang X, et al. . OX40 (CD134) and OX40 ligand, important immune checkpoints in cancer. Onco Targets Ther 2019;12:7347–53. 10.2147/OTT.S214211
- Weinberg AD, Rivera MM, Prell R, et al. . Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol 2000;164:2160–9. 10.4049/jimmunol.164.4.2160
- Gough MJ, Ruby CE, Redmond WL, et al. . OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor. Cancer Res 2008;68:5206–15. 10.1158/0008-5472.CAN-07-6484
- Jensen SM, Maston LD, Gough MJ, et al. . Signaling through OX40 enhances antitumor immunity. Semin Oncol 2010;37:524–32. 10.1053/j.seminoncol.2010.09.013
- Stone EL, O’Brien EM. Investigating the effect of anti-CTLA-4 on tumor-infiltrating effector T cells. J Immunol 2017;198(1 Suppl):56.12.
- Gonzalez AM, Manrique ML, Swiech L, et al. . Abstract 4703: INCAGN1949, an anti-OX40 antibody with an optimal agonistic profile and the ability to selectively deplete intratumoral regulatory T cells. Cancer Res 2017;77:4703. 10.1158/1538-7445.AM2017-4703
- Hansen AR, Infante JR, McArthur G, et al. . Abstract CT097: A first-in-human phase I dose escalation study of the OX40 agonist MOXR0916 in patients with refractory solid tumors. Cancer Res 2016;76(14 Suppl):CT097. 10.1158/1538-7445.AM2016-CT097
- Glisson BS, Leidner RS, Ferris RL, et al. . Safety and clinical activity of MEDI0562, a humanized OX40 agonist monoclonal antibody, in adult patients with advanced solid tumors. Clin Cancer Res 2020;26:5358–67. 10.1158/1078-0432.CCR-19-3070
- Gutierrez M, Moreno V, Heinhuis KM, et al. . OX40 agonist BMS-986178 alone or in combination with nivolumab and/or ipilimumab in patients with advanced solid tumors. Clin Cancer Res 2021;27:460–72. 10.1158/1078-0432.CCR-20-1830
- Diab A, Hamid O, Thompson JA, et al. . A phase I, open-label, dose-escalation study of the OX40 agonist ivuxolimab in patients with locally advanced or metastatic cancers. Clin Cancer Res 2022;28:71–83. 10.1158/1078-0432.CCR-21-0845
- Mayes PA, Hance KW, Hoos A. The promise and challenges of immune agonist antibody development in cancer. Nat Rev Drug Discov 2018;17:509–27. 10.1038/nrd.2018.75
- Wang R, Gao C, Raymond M, et al. . An integrative approach to inform optimal administration of OX40 agonist antibodies in patients with advanced solid tumors. Clin Cancer Res 2019;25:6709–20. 10.1158/1078-0432.CCR-19-0526
- Gonzalez AM, Manrique ML, Breous E, et al. . Abstract 3204: INCAGN01949: an anti-OX40 agonist antibody with the potential to enhance tumor-specific T-cell responsiveness, while selectively depleting intratumoral regulatory T cells. Cancer Res 2016;76:3204. 10.1158/1538-7445.AM2016-3204
- Garber K. Immune agonist antibodies face critical test. Nat Rev Drug Discov 2020;19:3–5. 10.1038/d41573-019-00214-5
- Scherwitzl I, Opp S, Hurtado AM, et al. . Sindbis virus with anti-OX40 overcomes the immunosuppressive tumor microenvironment of low-immunogenic tumors. Mol Ther Oncolytics 2020;17:431–47. 10.1016/j.omto.2020.04.012
- Huddleston CA, Weinberg AD, Parker DC. Ox40 (CD134) engagement drives differentiation of CD4+ T cells to effector cells. Eur J Immunol 2006;36:1093–103. 10.1002/eji.200535637
- Infante JR, Hansen AR, Pishvaian MJ, et al. . A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors. J Clin Oncol 2016;34:101. 10.1200/JCO.2016.34.15_suppl.101
- Wang R, Feng Y, Hilt E. Abstract LB-127: From bench to bedside: exploring OX40 receptor modulation in a phase 1/2a study of the OX40 costimulatory agonist BMS-986178 ± nivolumab (NIVO) or ipilimumab (IPI) in patients with advanced solid tumors. Cancer Res 2018;78(13 Suppl):LB–127.
- Moiseyenko A, Muggia F, Condamine T, et al. . Sequential therapy with INCAGN01949 followed by ipilimumab and nivolumab in two patients with advanced ovarian carcinoma. Gynecol Oncol Rep 2020;34:100655. 10.1016/j.gore.2020.100655
- Choi Y, Shi Y, Haymaker CL, et al. . T-cell agonists in cancer immunotherapy. J Immunother Cancer 2020;8:e000966. 10.1136/jitc-2020-000966
Source: PubMed