PMID- 35596791
OWN - NLM
STAT- MEDLINE
DCOM- 20221025
LR  - 20240426
IS  - 1432-0851 (Electronic)
IS  - 0340-7004 (Print)
IS  - 0340-7004 (Linking)
VI  - 71
IP  - 12
DP  - 2022 Dec
TI  - Treatment with a retinoic acid-inducible gene I (RIG-I) agonist as monotherapy 
      and in combination with pembrolizumab in patients with advanced solid tumors: 
      results from two phase 1 studies.
PG  - 2985-2998
LID - 10.1007/s00262-022-03191-8 [doi]
AB  - BACKGROUND: We evaluated MK-4621, an oligonucleotide that binds and activates 
      retinoic acid-inducible gene I (RIG-I), as monotherapy (NCT03065023) and in 
      combination with the anti-programmed death 1 antibody pembrolizumab 
      (NCT03739138). PATIENTS AND METHODS: Patients were >/= 18 years with 
      histologically/cytologically confirmed advanced/metastatic solid tumors with 
      injectable lesions. MK-4621 (0.2‒0.8 mg) was administered intratumorally as a 
      stable formulation with jetPEI twice weekly over a 4-week cycle as monotherapy 
      and weekly in 3-week cycles for up to 6 cycles in combination with 200 mg 
      pembrolizumab every 3 weeks for up to 35 cycles. Primary endpoints were 
      dose-limiting toxicities (DLTs), treatment-related adverse events (AEs), and 
      treatment discontinuation due to AEs. RESULTS: Fifteen patients received MK-4621 
      monotherapy and 30 received MK-4621 plus pembrolizumab. The only DLT, grade 3 
      pleural effusion that subsequently resolved, occurred in a patient who received 
      MK-4621/jetPEI 0.8 mg plus pembrolizumab. 93% of patients experienced >/= 1 
      treatment-related AE with both monotherapy and combination therapy. No patients 
      experienced an objective response per RECIST v1.1 with MK-4621 monotherapy; 4 
      (27%) had stable disease. Three (10%) patients who received combination therapy 
      had a partial response. Serum and tumor biomarker analyses provided evidence that 
      MK-4621 treatment induced an increase in gene expression of interferon signaling 
      pathway members and associated chemokines and cytokines. CONCLUSIONS: Patients 
      treated with MK-4621 monotherapy or in combination with pembrolizumab experienced 
      tolerable safety and modest antitumor activity, and there was evidence that 
      MK-4621 activated the RIG-I pathway. At the doses tested, MK-4621 did not confer 
      meaningful clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03065023 
      and NCT03739138.
CI  - (c) 2022. Springer-Verlag GmbH Germany, part of Springer Nature.
FAU - Moreno, V
AU  - Moreno V
AUID- ORCID: 0000-0001-6099-4236
AD  - START Madrid-FJD, Hospital Fundacion Jimenez Diaz, Av. de los Reyes Catolicos, 
      28040, Madrid, Spain. victor.moreno@startmadrid.com.
FAU - Calvo, E
AU  - Calvo E
AD  - START Madrid-CIOCC, Centro Integral Oncologico Clara Campal, Madrid, Spain.
FAU - Middleton, M R
AU  - Middleton MR
AD  - Department of Oncology, University of Oxford, Oxford, UK.
FAU - Barlesi, F
AU  - Barlesi F
AD  - CEPCM CLIP2, Assistance Publique Hopitaux de Marseille, Aix Marseille University, 
      Marseille, France.
AD  - Medical Oncology Department, Gustave Roussy, Villejuif, France.
FAU - Gaudy-Marqueste, C
AU  - Gaudy-Marqueste C
AD  - CEPCM CLIP2, Assistance Publique Hopitaux de Marseille, Aix Marseille University, 
      Marseille, France.
FAU - Italiano, A
AU  - Italiano A
AD  - Department of Medical Oncology, University of Bordeaux, Bordeaux, France.
AD  - Early Phase Trials Unit, Institut Bergonie, Bordeaux, France.
FAU - Romano, E
AU  - Romano E
AD  - Center for Cancer Immunotherapy, Dept of Oncology, INSERM U932, PSL Research 
      University, Institut Curie, Paris, France.
FAU - Marabelle, A
AU  - Marabelle A
AD  - Medical Oncology Department, Gustave Roussy, Villejuif, France.
FAU - Chartash, E
AU  - Chartash E
AD  - Merck & Co., Inc., Rahway, NJ, USA.
FAU - Dobrenkov, K
AU  - Dobrenkov K
AD  - Merck & Co., Inc., Rahway, NJ, USA.
FAU - Zhou, H
AU  - Zhou H
AD  - Merck & Co., Inc., Rahway, NJ, USA.
FAU - Connors, E C
AU  - Connors EC
AD  - Merck & Co., Inc., Rahway, NJ, USA.
FAU - Zhang, Y
AU  - Zhang Y
AD  - Merck & Co., Inc., Rahway, NJ, USA.
FAU - Wermke, M
AU  - Wermke M
AD  - Technische Universitat Dresden, Medizinische Fakultat, NCT/UCC Early Clinical 
      Trial Unit, Dresden, Germany.
LA  - eng
SI  - ClinicalTrials.gov/NCT03739138
SI  - ClinicalTrials.gov/NCT03065023
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20220521
PL  - Germany
TA  - Cancer Immunol Immunother
JT  - Cancer immunology, immunotherapy : CII
JID - 8605732
RN  - DPT0O3T46P (pembrolizumab)
RN  - 0 (Biomarkers, Tumor)
RN  - 9008-11-1 (Interferons)
RN  - 0 (Cytokines)
RN  - 0 (Oligonucleotides)
RN  - 5688UTC01R (Tretinoin)
SB  - IM
MH  - Humans
MH  - *Neoplasms/pathology
MH  - Biomarkers, Tumor
MH  - Interferons
MH  - Cytokines
MH  - Oligonucleotides/therapeutic use
MH  - Tretinoin
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects
PMC - PMC10991664
OTO - NOTNLM
OT  - Innate immunity
OT  - Interferon type I
OT  - Intratumoral injection
OT  - Pembrolizumab
OT  - RIG-I
COIS- V. Moreno: consulting fees from: Bayer, Pieris, BMS, Janssen. Traveling support 
      from: Regeneron/Sanofi, BMS, Bayer. Speaker s Bureau: Nanobiotix, BMS, Bayer. 
      Educational Grant: Medscape/Bayer. E. Calvo: Advisory: Adcendo, Alkermes, Amunix, 
      Anaveon, Amcure, AstraZeneca, BMS, Janssen, MonTa, MSD, Nanobiotix, Nouscom, 
      Novartis, OncoDNA, PharmaMar, Roche/Genentech, Sanofi, Servier, SyneosHealth, 
      TargImmune, T-knife; Research grants: Achilles, BeiGene (IDMC steering 
      committee), EORTC IDMC (non-financial interest), MedSIR (steering committee); 
      Scientific Board: Adcendo, Chugai Pharmaceuticals, PsiOxus Therapeutics; 
      Employee: HM Hospitals Group and START Program of Early Phase Clinical Drug 
      Development in Oncology; Medical Oncologist, Clinical Investigator; Director, 
      Clinical Research Ownership: START corporation; Oncoart Associated; International 
      Cancer Consultants; Non-profit Foundation INTHEOS (Investigational Therapeutics 
      in Oncological Sciences): founder and president. M. R. Middleton: Dr. Middleton 
      reports grants from Roche and AstraZeneca; grants and personal fees from GSK, 
      personal fees and other from Novartis, Immunocore, Bristol-Myers Squibb, other 
      from Millenium, Pfizer, Regeneron, personal fees, non-financial support, and 
      other from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, 
      NJ, USA; personal fees and other from BiolineRx, personal fees and non-financial 
      support from Replimune, personal fees from Kineta and Silicon Therapeutics, and 
      personal fees from Silicon Therapeutics outside the submitted work. F. Barlesi: 
      personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb, 
      Boehringer-Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd, Novartis, 
      Merck, MSD, Pierre Fabre, Pfizer, and Takeda. C. Gaudy-Marqueste: Honoraria for 
      lectures by Bristol-Myers Squibb; travel support from MSD, BMS, Pierre Fabre. A. 
      Italiano: grants to institution from Bayer, AstraZeneca, Bristol-Myers Squibb, 
      MSD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, 
      Roche, Springworks, Epizyme; and consulting fees from AstraZeneca, Bayer, Roche, 
      Daiichi-Sankyo. E. Romano: travel support from MSD for participation in a 
      scientific meeting outside the topic of the submitted work. A. Marabelle: 
      institutional research funding from MSD; grant from Fondation MSD Avenir outside 
      the topic of the manuscript; and honoraria and travel expenses for participation 
      in a scientific advisory board from MSD outside the topic of the submitted work. 
      E. Chartash: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., 
      Inc., Rahway, NJ, USA and stockholder in Merck & Co., Inc., Rahway, NJ, USA. K. 
      Dobrenkov: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., 
      Inc., Rahway, NJ, USA and stockholder in Merck & Co., Inc., Rahway, NJ, USA. H. 
      Zhou: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., 
      Rahway, NJ, USA. E.C. Connors: employee of Merck Sharp & Dohme LLC, a subsidiary 
      of Merck & Co., Inc., Rahway, NJ, USA and stockholder in Merck & Co., Inc., 
      Rahway, NJ, USA. Y. Zhang: employee of Merck Sharp & Dohme LLC, a subsidiary of 
      Merck & Co., Inc., Rahway, NJ, USA and stockholder in Merck & Co., Inc., Rahway, 
      NJ, USA. M. Wermke: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., 
      Rahway, NJ, USA for funding of study and professional medical writing; research 
      funding to institution from Roche; consulting fees from Novartis, Pfizer, 
      Boehringer-Ingelheim, Gemoab, Roche, Takeda, Lilly, MSD, AstraZeneca, Amgen, 
      Bristol-Myers Squibb, Immatics; honoraria from Novartis and Roche; travel support 
      from Roche, Bristol-Myers Squibb, Amgen, Pfizer; and participation on data safety 
      monitoring board or advisory board for ISA Therapeutics.
EDAT- 2022/05/22 06:00
MHDA- 2022/10/26 06:00
PMCR- 2022/05/21
CRDT- 2022/05/21 11:13
PHST- 2021/10/26 00:00 [received]
PHST- 2022/03/14 00:00 [accepted]
PHST- 2022/05/22 06:00 [pubmed]
PHST- 2022/10/26 06:00 [medline]
PHST- 2022/05/21 11:13 [entrez]
PHST- 2022/05/21 00:00 [pmc-release]
AID - 10.1007/s00262-022-03191-8 [pii]
AID - 3191 [pii]
AID - 10.1007/s00262-022-03191-8 [doi]
PST - ppublish
SO  - Cancer Immunol Immunother. 2022 Dec;71(12):2985-2998. doi: 
      10.1007/s00262-022-03191-8. Epub 2022 May 21.