PMID- 37087488
OWN - NLM
STAT- MEDLINE
DCOM- 20230607
LR  - 20240108
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 128
IP  - 12
DP  - 2023 Jun
TI  - Phase I/II sequencing study of azacitidine, epacadostat, and pembrolizumab in 
      advanced solid tumors.
PG  - 2227-2235
LID - 10.1038/s41416-023-02267-1 [doi]
AB  - BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1), an interferon-inducible enzyme, 
      contributes to tumor immune intolerance. Immune checkpoint inhibition may 
      increase interferon levels; combining IDO1 inhibition with immune checkpoint 
      blockade represents an attractive strategy. Epigenetic agents trigger interferon 
      responses and may serve as an immunotherapy priming method. We evaluated whether 
      epigenetic therapy plus IDO1 inhibition and immune checkpoint blockade confers 
      clinical benefit to patients with advanced solid tumors. METHODS: ECHO-206 was a 
      Phase I/II study where treatment-experienced patients with advanced solid tumors 
      (N = 70) received azacitidine plus an immunotherapy doublet (epacadostat [IDO1 
      inhibitor] and pembrolizumab). Sequencing of treatment was also assessed. Primary 
      endpoints were safety/tolerability (Phase I), maximum tolerated dose (MTD) or 
      pharmacologically active dose (PAD; Phase I), and investigator-assessed objective 
      response rate (ORR; Phase II). RESULTS: In Phase I, no dose-limiting toxicities 
      were reported, the MTD was not reached; a PAD was not determined. ORR was 5.7%, 
      with four partial responses. The most common treatment-related adverse events 
      (AEs) were fatigue (42.9%) and nausea (42.9%). Twelve (17.1%) patients 
      experienced >/=1 fatal AE, one of which (asthenia) was treatment-related. 
      CONCLUSIONS: Although the azacitidine-epacadostat-pembrolizumab regimen was well 
      tolerated, it was not associated with substantial clinical response in patients 
      with advanced solid tumors previously exposed to immunotherapy.
CI  - (c) 2023. The Author(s).
FAU - Luke, Jason J
AU  - Luke JJ
AUID- ORCID: 0000-0002-1182-4908
AD  - UPMC Hillman Cancer Center, Pittsburgh, PA, USA. lukejj@upmc.edu.
FAU - Fakih, Marwan
AU  - Fakih M
AD  - City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
FAU - Schneider, Charles
AU  - Schneider C
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Chiorean, E Gabriela
AU  - Chiorean EG
AD  - University of Washington School of Medicine, Fred Hutchinson Cancer Research 
      Center, Seattle, WA, USA.
FAU - Bendell, Johanna
AU  - Bendell J
AD  - Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
FAU - Kristeleit, Rebecca
AU  - Kristeleit R
AUID- ORCID: 0000-0003-3825-1326
AD  - Guy's and St. Thomas' NHS Foundation Trust, London, UK.
FAU - Kurzrock, Razelle
AU  - Kurzrock R
AUID- ORCID: 0000-0003-4110-1214
AD  - University of California San Diego School of Medicine, La Jolla, CA, USA.
FAU - Blagden, Sarah P
AU  - Blagden SP
AUID- ORCID: 0000-0001-8783-3491
AD  - Early Phase Clinical Trials Unit, University of Oxford, Oxford, England, UK.
FAU - Brana, Irene
AU  - Brana I
AUID- ORCID: 0000-0002-1068-9601
AD  - Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), 
      Barcelona, Spain.
FAU - Goff, Laura W
AU  - Goff LW
AD  - Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, 
      TN, USA.
FAU - O'Hayer, Kevin
AU  - O'Hayer K
AD  - Incyte Corporation, Wilmington, DE, USA.
FAU - Geschwindt, Ryan
AU  - Geschwindt R
AD  - Incyte Corporation, Wilmington, DE, USA.
FAU - Smith, Michael
AU  - Smith M
AD  - Incyte Corporation, Wilmington, DE, USA.
FAU - Zhou, Feng
AU  - Zhou F
AD  - Incyte Corporation, Wilmington, DE, USA.
FAU - Naing, Aung
AU  - Naing A
AUID- ORCID: 0000-0002-4803-8513
AD  - The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230422
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - DPT0O3T46P (pembrolizumab)
RN  - 71596A9R13 (epacadostat)
RN  - M801H13NRU (Azacitidine)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 9008-11-1 (Interferons)
SB  - IM
MH  - Humans
MH  - *Azacitidine/adverse effects
MH  - Immune Checkpoint Inhibitors/therapeutic use
MH  - *Neoplasms/drug therapy/genetics/pathology
MH  - Interferons/therapeutic use
PMC - PMC10241827
COIS- JJL: DSMB (Abbvie and Immutep); scientific advisory board: ([no stock] 7 Hills, 
      Fstar, Inzen, RefleXion, Xilio [stock] Actym, Alphamab Oncology, Arch Oncology, 
      Kanaph, Mavu, Onc.AI, Pyxis, and Tempest); consultancy fees (Abbvie, Alnylam, 
      Avillion, Bayer, Bristol-Myers Squibb, Checkmate, Codiak, Crown, Day One, Eisai, 
      EMD Serono, Endeavor, Flame, Genentech, Gilead, HotSpot, Kadmon, KSQ, Janssen, 
      Ikena, Immunocore, Incyte, Macrogenics, Merck, Mersana, Nektar, Novartis, Pfizer, 
      Regeneron, Ribon, Rubius, Servier, Silicon, Synlogic, Synthekine, TRex, Werewolf, 
      and Xencor); research support to institution (AbbVie, Agios, Astellas, 
      Astrazeneca, Bristol-Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, 
      Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next 
      Cure, Numab, Pfizer, Replimmune, Rubius, Scholar Rock, Synlogic, Takeda, 
      Trishula, Tizona, and Xencor); provisional patents (Serial #15/612,657 [Cancer 
      Immunotherapy], PCT/US18/36052 [Microbiome Biomarkers for Anti-PD-1/PD-L1 
      Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof]). MF: 
      Speaker Bureau (Amgen and Guardant360); advisory board (Array BioPharma, Bayer, 
      BGB Group/GlaxoSmithKline, Mirati Therapeutics, Inc., Pfizer, Seattle Genetics, 
      Taiho, and Zhuhai Yufan Biotechnology Co.); consulting/steering committee for 
      study (Incyte Corp.); editorial board (Mirati Therapeutics, Inc.); research 
      support to institution (Amgen, AstraZeneca, Novartis, Verastem, and Bristol Myers 
      Squibb). CS has nothing to disclose. EGC: research funding (Boehringer-Ingelheim, 
      BMS, Celgene, Clovis, Incyte, Lilly, MacroGenics, Roche, Stemline, Halozyme, 
      Merck, Fibrogen, Rafael, Corcept, Lonza); scientific advisory boards/consultancy 
      (AstraZeneca, Celgene, Eisai, Legend, Sobi, Pfizer, Noxxon, BioNTech, Ipsen, 
      Bayer, Cardiff, Novartis, Merck). JB: research funding to institution (Gilead, 
      Genentech/Roche, BMS, Five Prime, Lilly, Merck, MedImmune, Celgene, EMD Serono, 
      Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, 
      BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Koltan,SynDevRex, Forty Seven, 
      AbbVie, Array, Onyx, Sanofi, Takeda, Eisai, Celldex, Agios, Cytomx, Nektar, ARMO, 
      Boston Biomedical, Ipsen, Merrimack, Tarveda, Tyrogenex, Oncogenex, Marshall 
      Edwards, Pieris, Mersana, Calithera, Blueprint, Evelo, FORMA, Merus, Jacobio, 
      Effector, Novocare, Arrys, Tracon, Sierra, Innate, Arch Oncology, Prelude 
      Oncology, Unum Therapeutics, Vyriad, Harpoon, ADC, Amgen, Pfizer, Millennium, 
      Imclone, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, Arcus Bio, Seattle 
      Genetics, TempestTx, Shattuck Labs, Synthorx, Inc., Revolution Medicines, Inc., 
      Bicycle Therapeutics, Zymeworks, Relay Therapeutics, Scholar Rock, NGM Biopharma, 
      Stemcentrx, Beigene, CALGB, Cyteir Therapeutics, Foundation Bio, Innate Pharma, 
      Morphotex, OncXerna, NuMab, AtlasMedx, Treadwell Therapeutics, IGM Biosciences, 
      Mabspace, Hutchinson MediPharma, REPARE Therapeutics, NeoImmune Tech, Regeneron, 
      PureTech Health); consulting/advisory role (Gilead, Genentech/Roche, BMS, Five 
      Prime, Lilly, Merck, MedImmune, Celgene, Taiho, Macrogenics, GSK, Novartis, 
      OncoMed, LEAP, TG Therapeutics, AstraZeneca, BI, Daiichi Sankyo, Bayer, Incyte, 
      Apexigen, Array, Sanofi. ARMO, Ipsen, Merrimack, Oncogenex, FORMA, Arch Oncology, 
      Prelude Therapeutics, Phoenix Bio, Cyteir, Molecular Partners, Innate, Torque, 
      Tizona, Janssen, Tolero, Amgen, Seattle Genetics, Moderna Therapeutics, Tanabe 
      Research Laboratories, Beigene, Continuum Clinical, Agios, Bicycle Therapeutics, 
      Relay Therapeutics, Evelo, Pfizer, Samsung Bioepios, Fusion Therapeutics); 
      food/beverage/travel accommodations (Gilead, Genentech/Roche, BMS, Lilly, Merck, 
      MedImmune, Celgene, Taiho, Novartis, OncoMed, BI, ARMO, Ipsen, Oncogenex, FORMA). 
      RKr: advisory board/speaking role (Incyte). RKu: research funding (Biological 
      Dynamics, Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, 
      Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, 
      Pfizer, Sequenom, Takeda, and TopAlliance); consulting fees and/or speaker fees 
      and/or advisory board (Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, 
      Biological Dynamics, EISAI, EOM Pharmaceuticals, Iylon, Merck, NeoGenomics, 
      Neomed, Pfizer, Prosperdtx, Roche, TD2/Volastra, Turning Point Therapeutics, and 
      X-Biotech); equity interest (CureMatch Inc., CureMetrix, and IDbyDNA); board 
      membership (CureMatch and CureMetrix); co-founder (CureMatch). SPB: research 
      funding to conduct clinical trials (Nucana PLC, Sierra Oncology, Astex, Incyte, 
      Tesaro, Redx, MSD, Roche, UCB); consulting (Ellipses, Amphista); director (RNA 
      Guardian ltd). IB: research funding (Incyte, Merck Sharp & Dohme, AstraZeneca, 
      Boehringer Ingelheim, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Gliknik, 
      ISA Pharmaceuticals, Janssen Oncology, Kura, Merck Serono, Nanobiotics, Novartis, 
      Northern Biologics, Orion Pharma, Regeneron, Pfizer, Seattle Genetics, Shattuck 
      Labs, VCN Biosciences); institutional grants (Cellex Foundation, La Caixa 
      Foundation, Banco Bilbao Vizcaya Argentaria Foundation); consulting fees 
      (Achilles Therapeutics, Bristol Myers Squibb, Cancer Expert Now, eTheRNA 
      Immunotherapies, Merck Serono, Merck Sharp & Dohme, Rakuten pharma); honoraria 
      (Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme); meeting/travel 
      accommodations (Merck Sharp & Dohme, Merck Serono). LWG: consulting or advisory 
      role (Lilly, Eisai, Bayer/Onyx, Newlink Genetics, QED, AstraZeneca, Incyte, 
      Genentech, and Merck); research funding (Astellas Pharma, Pfizer, Onyx, Sun 
      Pharma, Lilly, Bristol-Myers Squibb, Agios, ArQule, H3 Biomedicine, Incyte, Leap 
      Therapeutics, ASLAN Pharmaceuticals, BeiGene, and Basilea). KOH, RG, MS, and FZ 
      are employees and stockholders of Incyte Corporation. AN: research funding (NCI, 
      EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, 
      ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, 
      Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera 
      Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus 
      Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology); advisory board 
      (CytomX Therapeutics, Novartis, Genome & Company, OncoSec KEYNOTE-695, Kymab, and 
      STCube Pharmaceuticals); travel/accommodation expenses (ARMO BioSciences); 
      research funding to spouse (Immune Deficiency Foundation, Jeffery Modell 
      Foundation and chao physician-scientist, and Baxalta); advisory board 
      participation by spouse (Takeda, CSL, Behring, and Horizon Pharma).
EDAT- 2023/04/23 00:41
MHDA- 2023/06/07 06:42
PMCR- 2023/04/22
CRDT- 2023/04/22 23:18
PHST- 2022/12/12 00:00 [received]
PHST- 2023/03/31 00:00 [accepted]
PHST- 2023/03/30 00:00 [revised]
PHST- 2023/06/07 06:42 [medline]
PHST- 2023/04/23 00:41 [pubmed]
PHST- 2023/04/22 23:18 [entrez]
PHST- 2023/04/22 00:00 [pmc-release]
AID - 10.1038/s41416-023-02267-1 [pii]
AID - 2267 [pii]
AID - 10.1038/s41416-023-02267-1 [doi]
PST - ppublish
SO  - Br J Cancer. 2023 Jun;128(12):2227-2235. doi: 10.1038/s41416-023-02267-1. Epub 
      2023 Apr 22.