An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors

Kirsty Taylor, Helen Loo Yau, Ankur Chakravarthy, Ben Wang, Shu Yi Shen, Ilias Ettayebi, Charles A Ishak, Philippe L Bedard, Albiruni Abdul Razak, Aaron R Hansen, Anna Spreafico, Dave Cescon, Marcus O Butler, Amit M Oza, Stephanie Lheureux, Neda Stjepanovic, Brendan Van As, Sarah Boross-Harmer, Lisa Wang, Trevor J Pugh, Pamela S Ohashi, Lillian L Siu, Daniel D De Carvalho, Kirsty Taylor, Helen Loo Yau, Ankur Chakravarthy, Ben Wang, Shu Yi Shen, Ilias Ettayebi, Charles A Ishak, Philippe L Bedard, Albiruni Abdul Razak, Aaron R Hansen, Anna Spreafico, Dave Cescon, Marcus O Butler, Amit M Oza, Stephanie Lheureux, Neda Stjepanovic, Brendan Van As, Sarah Boross-Harmer, Lisa Wang, Trevor J Pugh, Pamela S Ohashi, Lillian L Siu, Daniel D De Carvalho

Abstract

Purpose: To evaluate whether administration of the oral DNA hypomethylating agent CC-486 enhances the poor response rate of immunologically 'cold' solid tumors to immune checkpoint inhibitor durvalumab.

Experimental design: PD-L1/PD-1 inhibitor naïve patients with advanced microsatellite stable colorectal cancer; platinum resistant ovarian cancer; and estrogen receptor positive, HER2 negative breast cancer were enrolled in this single-institution, investigator-initiated trial. Two 28 day regimens, regimen A (CC-486 300 mg QD Days 1-14 (cycles 1-3 only) in combination with durvalumab 1500 mg intravenous day 15) and regimen B (CC-486 100 mg QD days 1-21 (cycle 1 and beyond), vitamin C 500 mg once a day continuously and durvalumab 1500 mg intravenous day 15) were investigated. Patients underwent paired tumor biopsies and serial peripheral blood mononuclear cells (PBMCs) collection for immune-profiling, transcriptomic and epigenomic analyzes.

Results: A total of 28 patients were enrolled, 19 patients treated on regimen A and 9 on regimen B. The combination of CC-486 and durvalumab was tolerable. Regimen B, with a lower dose of CC-486 extended over a longer treatment course, showed less grade 3/4 adverse effects. Global LINE-1 methylation assessment of serial PBMCs and genome-wide DNA methylation profile in paired tumor biopsies demonstrated minimal changes in global methylation in both regimens. The lack of robust tumor DNA demethylation was accompanied by an absence of the expected 'viral mimicry' inflammatory response, and consequently, no clinical responses were observed. The disease control rate was 7.1%. The median progression-free survival was 1.9 months (95% CI 1.5 to 2.3) and median overall survival was 5 months (95% CI 4.5 to 10).

Conclusions: The evaluated treatment schedules of CC-486 in combination with durvalumab did not demonstrate robust pharmacodynamic or clinical activity in selected immunologically cold solid tumors. Lessons learned from this biomarker-rich study should inform continued drug development efforts using these agents.

Trial registration number: NCT02811497.

Keywords: biomarkers, tumor; combined modality therapy; drug therapy, combination; immunotherapy; translational medical research.

Conflict of interest statement

Competing interests: PLB: Consultant for: Bristol-Myers Squibb (compensated), Sanofi (compensated), Pfizer (compensated). Grant/Research support from (Clinical Trials for aarinstitution): Bristol-Myers Squibb, Sanofi, AstraZeneca, Genentech/Roche, Servier, GlaxoSmithKline, Novartis, SignalChem, PTC Therapeutics, Nektar, Merck, Seattle Genetics, Mersana, Immunomedics, Lilly. AAR: Honoraria: Boehringer Ingelheim. Consultant for: Lilly (compensated), Merck (compensated), Boehringer Ingelheim (compensated). Grant/Research support from (Clinical Trials): CASI Pharmaceuticals, Boehringer Ingelheim, Lilly, Novartis, Deciphera, Karyopharm Therapeutics, Pfizer, Genentech/Roche, Boston Biomedical, Bristol-Myers Squibb, MedImmune, Amgen, GlaxoSmithKline, Blueprint Medicines, Merck, Abbvie, Adaptimmune. ARH: Advisory/Consulting/Research for Genentech/Roche, Merck, GSK, Bristol-Myers Squibb, Novartis, Boston Biomedical, Boehringer-Ingelheim, AstraZeneca, Medimmune. AS: Consultant for (Advisory Board): Merck (compensated), Bristol-Myers Squibb (compensated), Novartis (compensated), Oncorus (compensated), Janssen (compensated). Grant/Research support from (Clinical Trials): Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma. DC: Consulting/Advisory: Agendia, AstraZeneca, GSK, Merck, Novartis, Pfizer, Puma, Roche, Dynamo Therapeutics. Grant/Research support from (Clinical Trials): GlaxoSmithKline, Merck, Pfizer. Intellectual Property: Biomarkers for TTK inhibitors (assigned to institution). MOB: Consulting for: Bristol-Myers Squibb, Novartis, Merck, GlaxoSmithKline, EMD Serono, Sanofi, Immunocore. Grant/Research support from (Clinical Trials): Merck, Takara Bio. AMO: Consultant for: AstraZeneca, MERCK, Clovis Oncology, TESARO (all non-compensated). SL: Consultant for: Merck (compensated), AstraZeneca (compensated), GlaxoSmithKline (compensated), Roche (compensated). PO: Consulatnt for: Providence (compensated), Symphogen (compensated), Tessa (compensated), Research support from: EMD Serono. LS: Consultant for: Merck (compensated), Pfizer (compensated), Celgene (compensated), AstraZeneca/Medimmune (compensated), Morphosys (compensated), Roche (compensated), GeneSeeq (compensated), Loxo (compensated), Oncorus (compensated), Symphogen (compensated), Seattle Genetics (compensated), GSK (compensated), Voronoi (compensated), Treadwell Therapeutics (compensated), Arvinas (compensated), Tessa (compensated), Navire (compensated). Grant/Research support from (Clinical Trials for institution): Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks, Avid. Stockholder in: Agios (spouse). DDC: Research support from Pfizer and Nektar therapeutics.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Demethylation levels of LINE-1 elements in PBMCs during CC-486 treatment. Targeted DNA methylation analysis for LINE-1 elements normalized to screening blood sample of (A) estrogen receptor positive HER2 negative breast cancer cohort, (B) microsatellite stable colorectal cancer cohort and (C) platinum-resistant ovarian cancer. Each line represents the serial methylation levels over time for one patient, in each cohort. PBMCs, peripheral blood mononuclear cells.
Figure 2
Figure 2
Transcriptomic and epigenomic analysis of tumor biopsies during CC-486 treatment. Density distributions of average methylation (beta-values) comparing pre-HMA and post-HMA treatment from (A) cancer cell lines treated with azacitidine, as well as, tumor biopsies from patients that received CC-486 (regimen A) and that received CC-486 + vitamin C (regimen B). (B) Heatmap of fold change in expression of all annotated repetitive elements in the tumor biopsies of all cohorts, and CC-486 regimens. (C) CIBERSORT scores from RNA-sequencing of tumor biopsies of all cohorts, and CC-486 regimens. (D) Fold change of CIBERSORT infiltration scores from tumor biopsies of all cohorts, and CC-486 regimens.
Figure 3
Figure 3
Flow cytometry on serial PBMCs samples measuring circulating (A) percentage of monocytes (CD33+HLA-DR+CD14+) (p=0.09; C2D15 vs screening blood). (B) Percentage of CD3+ T cells at baseline, C1D15 and C2D15 following CC-486 and durvalumab treatment (p=0.01, C2D15 vs screening blood; and p<0.01, C2D15 vs C1D15). (C) Fold change expression levels of Ki67 expression in CD8+, CD4+ T cells and Tregs following CC-486 and durvalumab treatment. SB=screening blood, baseline. Cohort C represents the microsatellite stable colorectal cancers; cohort O represents the platinum resistant ovarian cancers; cohort B represents the estrogen receptor positive, HER2 negative breast cancers. PBMCs, peripheral blood mononuclear cells.

References

    1. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39:1–10. 10.1016/j.immuni.2013.07.012
    1. Spranger S. Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. Int Immunol 2016;28:383–91. 10.1093/intimm/dxw014
    1. Hendry S, Salgado R, Gevaert T, et al. . Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the International Immunooncology biomarkers Working group: Part 1: assessing the host immune response, TILs in invasive breast carcinoma and ductal carcinoma in situ, metastatic tumor deposits and areas for further research. Adv Anat Pathol 2017;24:235–51. 10.1097/PAP.0000000000000162
    1. van der Woude LL, Gorris MAJ, Halilovic A, et al. . Migrating into the tumor: a roadmap for T cells. Trends Cancer 2017;3:797–808. 10.1016/j.trecan.2017.09.006
    1. Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. nature reviews drug discovery 2012 11:5. Nature Publishing Group 2019;18:197–218.
    1. Loo Yau H, Ettayebi I, De Carvalho DD. The cancer epigenome: exploiting its vulnerabilities for immunotherapy. Trends Cell Biol 2019;29:31–43. 10.1016/j.tcb.2018.07.006
    1. Jones PA, Ohtani H, Chakravarthy A, et al. . Epigenetic therapy in immune-oncology. Nat Rev Cancer 2019;19:151–61. 10.1038/s41568-019-0109-9
    1. Palii SS, Van Emburgh BO, Sankpal UT, et al. . Dna methylation inhibitor 5-aza-2'-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol Cell Biol 2008;28:752–71. 10.1128/MCB.01799-07
    1. Chiappinelli KB, Strissel PL, Desrichard A, et al. . Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 2015;162:974–86. 10.1016/j.cell.2015.07.011
    1. Brocks D, Schmidt CR, Daskalakis M, et al. . Dnmt and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats. Nat Genet 2017;49:1052–60. 10.1038/ng.3889
    1. Roulois D, Loo Yau H, Singhania R, et al. . DNA-Demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 2015;162:961–73. 10.1016/j.cell.2015.07.056
    1. Burkart C, Arimoto K-ichiro, Tang T, et al. . Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-λ and elevated secretion of CXCL10. EMBO Mol Med 2013;5:1035–50. 10.1002/emmm.201201864
    1. Li H, Chiappinelli KB, Guzzetta AA, et al. . Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 2014;5:587–98. 10.18632/oncotarget.1782
    1. Kim K, Skora AD, Li Z, et al. . Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci U S A 2014;111:P267. 10.1186/2051-1426-2-S3-P267
    1. Yu G, Wu Y, Wang W, et al. . Low-Dose decitabine enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by re-modulating the tumor microenvironment. Cell Mol Immunol 2019;16:401–9. 10.1038/s41423-018-0026-y
    1. Gerecke C, Schumacher F, Edlich A, et al. . Vitamin C promotes decitabine or azacytidine induced DNA hydroxymethylation and subsequent reactivation of the epigenetically silenced tumour suppressor CDKN1A in colon cancer cells. Oncotarget 2018;9:32822–40. 10.18632/oncotarget.25999
    1. Liu M, Ohtani H, Zhou W, et al. . Vitamin C increases viral mimicry induced by 5-aza-2'-deoxycytidine. Proc Natl Acad Sci U S A 2016;113:10238–44. 10.1073/pnas.1612262113
    1. Lee Chong T, Ahearn EL, Cimmino L. Reprogramming the epigenome with vitamin C. Front Cell Dev Biol 2019;7:128. 10.3389/fcell.2019.00128
    1. Mayland CR, Bennett MI, Allan K. Vitamin C deficiency in cancer patients. Palliat Med 2005;19:17–20. 10.1191/0269216305pm970oa
    1. Franke AJ, Skelton WP, Starr JS, et al. . Immunotherapy for colorectal cancer: a review of current and novel therapeutic approaches. J Natl Cancer Inst 2019;111:1131–41. 10.1093/jnci/djz093
    1. Koopman M, Kortman GAM, Mekenkamp L, et al. . Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer 2009;100:266–73. 10.1038/sj.bjc.6604867
    1. Malander S, Rambech E, Kristoffersson U, et al. . The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer. Gynecol Oncol 2006;101:238–43. 10.1016/j.ygyno.2005.10.029
    1. Pal T, Permuth-Wey J, Kumar A, et al. . Systematic review and meta-analysis of ovarian cancers: estimation of microsatellite-high frequency and characterization of mismatch repair deficient tumor histology. Clin Cancer Res 2008;14:6847–54. 10.1158/1078-0432.CCR-08-1387
    1. Varga A, Piha-Paul S, Ott PA, et al. . Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: analysis of KEYNOTE-028. Gynecol Oncol 2019;152:243–50. 10.1016/j.ygyno.2018.11.017
    1. DT L, Uram JN, Wang H, et al. . Pd-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. Massachusetts Medical Society 2015;372:2509–20.
    1. Rugo HS, Delord J-P, Im S-A, et al. . Safety and antitumor activity of pembrolizumab in patients with estrogen Receptor-Positive/Human epidermal growth factor receptor 2-Negative advanced breast cancer. Clin Cancer Res 2018;24:2804–11. 10.1158/1078-0432.CCR-17-3452
    1. Dirix LY, Takacs I, Jerusalem G, et al. . Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1B javelin solid tumor study. Breast Cancer Res Treat 2018;167:671–86. 10.1007/s10549-017-4537-5
    1. Ali HR, Glont S-E, Blows FM, et al. . Pd-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Ann Oncol 2015;26:1488–93. 10.1093/annonc/mdv192
    1. Loi S, Sirtaine N, Piette F, et al. . Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: big 02-98. JCO 2013;31:860–7. 10.1200/JCO.2011.41.0902
    1. Desmedt C, Haibe-Kains B, Wirapati P, et al. . Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin Cancer Res 2008;14:5158–65. 10.1158/1078-0432.CCR-07-4756
    1. Savona MR, Kolibaba K, Conkling P, et al. . Extended dosing with CC-486 (oral azacitidine) in patients with myeloid malignancies. Am J Hematol 2018;93:1199–206. 10.1002/ajh.25216
    1. Cogle CR, Scott BL, Boyd T, et al. . Oral azacitidine (CC-486) for the treatment of myelodysplastic syndromes and acute myeloid leukemia. Oncologist 2015;20:1404–12. 10.1634/theoncologist.2015-0165
    1. Von Hoff DD, Rasco DW, Heath EI, et al. . Phase I study of CC-486 alone and in combination with carboplatin or nab-paclitaxel in patients with relapsed or refractory solid tumors. Clin Cancer Res 2018;24:4072–80. 10.1158/1078-0432.CCR-17-3716
    1. Choufani S, Turinsky AL, Melamed N, et al. . Impact of assisted reproduction, infertility, sex and paternal factors on the placental DNA methylome. Hum Mol Genet 2019;28:372–85. 10.1093/hmg/ddy321
    1. Issa J-PJ, Roboz G, Rizzieri D, et al. . Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol 2015;16:1099–110. 10.1016/S1470-2045(15)00038-8
    1. Fortin J-P, Triche TJ, Hansen KD, Preprocessing HKD. Preprocessing, normalization and integration of the Illumina HumanMethylationEPIC array with minfi. Bioinformatics 2017;33:558–60. 10.1093/bioinformatics/btw691
    1. Ritchie ME, Phipson B, Wu D, et al. . limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015;43:e47–7. 10.1093/nar/gkv007
    1. Bray NL, Pimentel H, Melsted P, et al. . Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol 2016;34:525–7. 10.1038/nbt.3519
    1. Law CW, Chen Y, Shi W, et al. . voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol 2014;15:R29–17. 10.1186/gb-2014-15-2-r29
    1. Newman AM, Liu CL, Green MR, et al. . Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 2015;12:453–7. 10.1038/nmeth.3337
    1. Tabish AM, Baccarelli AA, Godderis L, et al. . Assessment of changes in global DNA methylation levels by Pyrosequencing® of repetitive elements. Methods Mol Biol 2015;1315:201–7. 10.1007/978-1-4939-2715-9_15
    1. Griffiths EA, Choy G, Redkar S, et al. . SGI-110: DNA methyltransferase inhibitor oncolytic. Drugs Future 2013;38:535–43.
    1. Ishak CA, Classon M, De Carvalho DD. Deregulation of retroelements as an emerging therapeutic opportunity in cancer. Trends Cancer 2018;4:583–97. 10.1016/j.trecan.2018.05.008
    1. Wrangle J, Wang W, Koch A, et al. . Alterations of immune response of non-small cell lung cancer with Azacytidine. Oncotarget 2013;4:2067–79. 10.18632/oncotarget.1542
    1. Stone ML, Chiappinelli KB, Li H, et al. . Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden. Proc Natl Acad Sci U S A 2017;114:E10981–90. 10.1073/pnas.1712514114
    1. Azad NS, El-Khoueiry A, Yin J, et al. . Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand up 2 cancer study. Oncotarget 2017;8:35326–38. 10.18632/oncotarget.15108
    1. Li X, Zhang Y, Chen M, et al. . Increased IFNγ + T Cells Are Responsible for the Clinical Responses of Low-Dose DNA-Demethylating Agent Decitabine Antitumor Therapy. Clinical Cancer Research 2017;23:6031–43. 10.1158/1078-0432.CCR-17-1201
    1. Clouthier DL, Lien SC, Yang SYC, et al. . An interim report on the investigator-initiated phase 2 study of pembrolizumab immunological response evaluation (INSPIRE). J Immunother Cancer 2019;7:72. 10.1186/s40425-019-0541-0
    1. Kim KH, Cho J, Ku BM, et al. . The First-week Proliferative Response of Peripheral Blood PD-1+CD8+ T Cells Predicts the Response to Anti-PD-1 Therapy in Solid Tumors. Clin Cancer Res 2019;25:2144–54. 10.1158/1078-0432.CCR-18-1449
    1. Kamphorst AO, Pillai RN, Yang S, et al. . Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc Natl Acad Sci U S A 2017;114:4993–8. 10.1073/pnas.1705327114
    1. Huang AC, Postow MA, Orlowski RJ, et al. . T-Cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 2017;545:60–5. 10.1038/nature22079
    1. Wang L, Amoozgar Z, Huang J, et al. . Decitabine enhances lymphocyte migration and function and synergizes with CTLA-4 blockade in a murine ovarian cancer model. Cancer Immunol Res 2015;3:1030–41. 10.1158/2326-6066.CIR-15-0073
    1. Gang AO, Frøsig TM, Brimnes MK, et al. . 5-Azacytidine treatment sensitizes tumor cells to T-cell mediated cytotoxicity and modulates NK cells in patients with myeloid malignancies. Blood Cancer J 2014;4:e197–7. 10.1038/bcj.2014.14

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