PMID- 35983060
OWN - NLM
STAT- MEDLINE
DCOM- 20220822
LR  - 20221012
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 13
DP  - 2022
TI  - Utomilumab in Patients With Immune Checkpoint Inhibitor-Refractory Melanoma and 
      Non-Small-Cell Lung Cancer.
PG  - 897991
LID - 10.3389/fimmu.2022.897991 [doi]
LID - 897991
AB  - SECTION HEAD: Clinical/translational cancer immunotherapy. BACKGROUND: The goal 
      of this study was to estimate the objective response rate for utomilumab in 
      adults with immune checkpoint inhibitor (ICI)-refractory melanoma and 
      non-small-cell lung cancer (NSCLC). METHODS: Utomilumab was dosed intravenously 
      every 4 weeks (Q4W) and adverse events (AEs) monitored. Tumor responses by 
      RECIST1.1 were assessed by baseline and on-treatment scans. Tumor biopsies were 
      collected for detection of programmed cell death ligand 1, CD8, 4-1BB, perforin, 
      and granzyme B, and gene expression analyzed by next-generation sequencing. CD8+ 
      T cells from healthy donors were stimulated with anti-CD3 +/- utomilumab and 
      compared with control. RESULTS: Patients with melanoma (n=43) and NSCLC (n=20) 
      received utomilumab 0.24 mg/kg (n=36), 1.2 mg/kg (n=26), or 10 mg/kg (n=1). 
      Treatment-emergent AEs (TEAEs) occurred in 55 (87.3%) patients and serious TEAEs 
      in 18 (28.6%). Five (7.9%) patients discontinued owing to TEAEs. Thirty-two 
      (50.8%) patients experienced treatment-related AEs, mostly grade 1-2. Objective 
      response rate: 2.3% in patients with melanoma; no confirmed responses for 
      patients with NSCLC. Ten patients each with melanoma (23.3%) or NSCLC (50%) had 
      stable disease; respective median (95% confidence interval, CI) progression-free 
      survival was 1.8 (1.7-1.9) and 3.6 (1.6-6.5) months. Utomilumab exposure 
      increased with dose. The incidences of antidrug and neutralizing antibodies were 
      46.3% and 19.4%, respectively. Efficacy was associated with immune-active tumor 
      microenvironments, and pharmacodynamic activity appeared to be blunted at higher 
      doses. CONCLUSIONS: Utomilumab was well tolerated, but antitumor activity was low 
      in patients who previously progressed on ICIs. The potential of 4-1BB agonists 
      requires additional study to optimize efficacy while maintaining the tolerable 
      safety profile.
CI  - Copyright (c) 2022 Hong, Gopal, Shoushtari, Patel, He, Doi, Ramalingam, Patnaik, 
      Sandhu, Chen, Davis, Fisher, Huang, Fly and Ribas.
FAU - Hong, David S
AU  - Hong DS
AD  - Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, 
      University of Texas MD Anderson Cancer Center, Houston, TX, United States.
FAU - Gopal, Ajay K
AU  - Gopal AK
AD  - National Cancer Center Hospital East, Kashiwa, Seattle, WA, United States.
FAU - Shoushtari, Alexander N
AU  - Shoushtari AN
AD  - Melanoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 
      New York, NY, United States.
FAU - Patel, Sandip P
AU  - Patel SP
AD  - University of California San Diego Moores Cancer Center, La Jolla, CA, United 
      States.
FAU - He, Aiwu R
AU  - He AR
AD  - Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 
      Washington, DC, United States.
FAU - Doi, Toshihiko
AU  - Doi T
AD  - National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
FAU - Ramalingam, Suresh S
AU  - Ramalingam SS
AD  - Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory 
      University, Atlanta, GA, United States.
FAU - Patnaik, Amita
AU  - Patnaik A
AD  - START San Antonio, San Antonio, TX, United States.
FAU - Sandhu, Shahneen
AU  - Sandhu S
AD  - Department of Medical Oncology, Peter MacCallum Cancer Centre and the University 
      of Melbourne, Melbourne, VIC, Australia.
FAU - Chen, Ying
AU  - Chen Y
AD  - Pfizer Oncology, San Diego, CA, United States.
FAU - Davis, Craig B
AU  - Davis CB
AD  - Pfizer Oncology, San Diego, CA, United States.
FAU - Fisher, Timothy S
AU  - Fisher TS
AD  - Pfizer Oncology, San Diego, CA, United States.
FAU - Huang, Bo
AU  - Huang B
AD  - Pfizer Oncology, Groton, CT, United States.
FAU - Fly, Kolette D
AU  - Fly KD
AD  - Pfizer Oncology, Groton, CT, United States.
FAU - Ribas, Antoni
AU  - Ribas A
AD  - Department of Medicine, Jonsson Comprehensive Cancer Center, University of 
      California Los Angeles, Los Angeles, CA, United States.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - UL1 TR003167/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220802
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0 (Immunoglobulin G)
RN  - 6YY8O697VF (utomilumab)
SB  - IM
MH  - Adult
MH  - Antibodies, Monoclonal, Humanized
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy
MH  - Humans
MH  - Immune Checkpoint Inhibitors/adverse effects
MH  - Immunoglobulin G
MH  - *Lung Neoplasms/drug therapy
MH  - *Melanoma/drug therapy
MH  - Tumor Microenvironment
PMC - PMC9379324
OTO - NOTNLM
OT  - 4-1BB/CD137
OT  - NSCLC
OT  - immune checkpoint inhibitor
OT  - melanoma
OT  - utomilumab
COIS- DH has disclosed consulting/advisory roles for Alpha Insights, Axiom, 
      Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, 
      Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, and Trieza 
      Therapeutics; research funding from AbbVie, Adaptimmune, Amgen, Astra Zeneca, 
      Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Fate Therapeutics, Genentech, 
      Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, Loxo, Merck, MedImmune, Mirati, 
      MiRNA, Molecular Templates, Mologen, National Cancer Institute/Cancer Therapy 
      Evaluation Program, Novartis, Pfizer, Seattle Genetics, and Takeda; 
      travel/accomodations expense reimbursement from Loxo and MiRNA; and other 
      ownership interests in Molecular Match (advisor), OncoResponse (founder), and 
      Presagia Inc. (advisor). AG received research funding from Bristol Myers Squibb, 
      Gilead, Janssen, Merck, Pfizer, Seattle Genetics, and Takeda; and consulting 
      honoraria from Amgen, Acerta, Bayer, Brim Biotechnologies, Gilead, Janssen, and 
      Seattle Genetics. AS received consulting honoraria from Bristol Myers Squibb, 
      Novartis, and Immunocore; and research funding from Bristol Myers Squibb, 
      Immunocore, Novartis, Xcovery, Targovax ASA, Polaris, Pfizer, Checkmate 
      Pharmaceuticals, and Foghorn Therapeutics. SP received research funding from 
      Bristol Myers Squibb, Eli Lilly, Incyte, MedImmune, Pfizer, Roche/Genentech, and 
      Xcovery; and speaker honoraria from Boehringer Ingelheim and Merck. AH served as 
      consultant/advisor for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, 
      Genentech, and Merck; received honoraria from Bayer, Bristol Myers Squibb, Eisai, 
      and Exelixis; and research funding from Genentech and Merck Serono. TD served as 
      consultant/advisor for AbbVie, Amgen, Bayer, Boehringer Ingelheim, Daiichi 
      Sankyo, MSD, Novartis, Rakuten Medical, Sumitomo Dainippon, Taiho, and Takeda; 
      received honoraria from AbbVie, Astellas, Bristol Myers Squibb, Oncolys 
      Biopharma, Ono, and Taiho; and institutional research funding from Abbvie, 
      Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eisai, Kyowa Hakko 
      Kirin, Lilly, Merck Serono, MSD, Novartis, Pfizer, Quintiles, Sumitomo Dainippon, 
      and Taiho. SR served as consultant/advisor for Amgen, Astra Zeneca, Bristol Myers 
      Squibb, Merck, Roche, Takeda, and Tesaro; and received institutional research 
      funding from Advaxis, Amgen, Astra Zeneca, Bristol Myers Squibb, Genmab, Merck, 
      Takeda, and Tesaro. AP has received institutional research funding from Arcus, 
      Exelixis, Surface Oncology, Upsher-Smith, Lilly, Daiichi Sankyo, Merck, Tesaro, 
      Forty Seven, Bolt, Pieris Pharmaceuticals, Vigeo Therapeutics, Syndax, Seattle 
      Genetics, Pfizer, Livzon, Klus Pharma, Fochon, Gilead Sciences, Plexxikon, Corvus 
      Pharmaceuticals, Five Prime Therapeutics, Infinity Pharmaceuticals, Ionova, 
      Abbvie, Astellas Pharma, Symphogen, Sanofi, honoraria from the Texas Society of 
      Clinical Oncology and served as a consultant/advisor for Novartis, Gilead, 
      Seattle Genetics, Silverback Therapeutics, Bayer, Daiichi Sankyo, Inc, Shenzen 
      IONOVA Life Sciences Co., Ltd., and Merck. SS received research funding from 
      Advanced Accelerator Applications (Novartis), Amgen, Astra Zeneca, Genentech and 
      MSD; and honoraria to the institution from Astra Zeneca, Bristol Myers Squibb, 
      MSD, and Novartis. YC, CD, BH, KF, and A. D. Thall are employees of and own stock 
      in Pfizer Inc. AR disclosed consulting honoraria from Amgen, Bristol Myers 
      Squibb, Chugai, Genentech, Merck, Novartis, Roche, and Sanofi; membership in 
      scientific advisory boards and stocks in Advaxis, Arcus Biosciences, Bioncotech 
      Therapeutics, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, 
      Kite/Gilead, Lutris Pharma, Merus, PACT Pharma, Rgenix and Tango Therapeutics; 
      and research funding from Agilent and Bristol Myers Squibb. The remaining authors 
      declare that the research was conducted in the absence of any commercial or 
      financial relationships that could be construed as a potential conflict of 
      interest.
EDAT- 2022/08/20 06:00
MHDA- 2022/08/23 06:00
PMCR- 2022/01/01
CRDT- 2022/08/19 02:12
PHST- 2022/03/16 00:00 [received]
PHST- 2022/05/17 00:00 [accepted]
PHST- 2022/08/19 02:12 [entrez]
PHST- 2022/08/20 06:00 [pubmed]
PHST- 2022/08/23 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2022.897991 [doi]
PST - epublish
SO  - Front Immunol. 2022 Aug 2;13:897991. doi: 10.3389/fimmu.2022.897991. eCollection 
      2022.