PMID- 36564126 OWN - NLM STAT- MEDLINE DCOM- 20221227 LR - 20230111 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 10 IP - 12 DP - 2022 Dec TI - Intratumoral oncolytic virus V937 plus ipilimumab in patients with advanced melanoma: the phase 1b MITCI study. LID - 10.1136/jitc-2022-005224 [doi] LID - e005224 AB - BACKGROUND: Intratumoral administration of V937, a bioselected, genetically unmodified coxsackievirus A21, has previously demonstrated antitumor activity in patients with advanced melanoma as monotherapy and in combination with the programmed cell death 1 (PD-1) antibody pembrolizumab. We report results from an open-label, single-arm, phase 1b study (NCT02307149) evaluating V937 plus the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab in patients with advanced melanoma. METHODS: Adult patients (aged >/=18 years) with histologically confirmed metastatic or unresectable stage IIIB/C or IV melanoma received intratumoral V937 on days 1, 3, 5, 8, and 22 and every 3 weeks (Q3W) thereafter for up to 19 sets of injections plus intravenous ipilimumab 3 mg/kg Q3W administered for four doses starting on day 22. Imaging was performed at screening, on days 43 and 106 and every 6 weeks thereafter; response was assessed by immune-related response criteria per investigator assessment. Primary endpoints were safety in all treated patients and objective response rate (ORR) in all treated patients and in patients with disease that progressed on prior anti-PD-1 therapy. RESULTS: Fifty patients were enrolled and treated. ORR was 30% (95% CI 18% to 45%) among all treated patients, 47% (95% CI 23% to 72%) among patients who had not received prior anti-PD-1 therapy, and 21% (95% CI 9% to 39%) among patients who had experienced disease progression on prior anti-PD-1 therapy. Tumor regression occurred in injected and non-injected lesions. Median immune-related progression-free survival was 6.2 months (95% CI 3.5 to 9.0 months), and median overall survival was 45.1 months (95% CI 28.3 months to not reached). The most common treatment-related adverse events (AEs) were pruritus (n=25, 50%), fatigue (n=22, 44%), and diarrhea (n=16, 32%). There were no V937-related dose-limiting toxicities and no treatment-related grade 5 AEs. Treatment-related grade 3 or 4 AEs, all of which were considered related to ipilimumab, occurred in 14% of patients (most commonly dehydration, diarrhea, and hepatotoxicity in 4% each). CONCLUSIONS: Responses associated with intratumoral V937 plus ipilimumab were robust, including in the subgroup of patients who had experienced disease progression on prior anti-PD-1 therapy. Toxicities were manageable and consistent with those of the individual monotherapies. CI - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Curti, Brendan D AU - Curti BD AUID- ORCID: 0000-0003-3948-2708 AD - Providence Cancer Institute, Earle A Chiles Research Institute, Portland, Oregon, USA brendan.curti@providence.org. FAU - Richards, Jon AU - Richards J AD - Advocate Aurora Health, Park Ridge, Illinois, USA. FAU - Hyngstrom, John R AU - Hyngstrom JR AD - University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah, USA. FAU - Daniels, Gregory A AU - Daniels GA AD - Moores Cancer Center, UC San Diego Health, La Jolla, California, USA. FAU - Faries, Mark AU - Faries M AD - Cedars-Sinai Medical Center, Angeles Clinic and Research Institute, Los Angeles, California, USA. FAU - Feun, Lynn AU - Feun L AD - Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA. FAU - Margolin, Kim A AU - Margolin KA AUID- ORCID: 0000-0002-5248-4356 AD - City of Hope National Medical Center, Duarte, California, USA. FAU - Hallmeyer, Sigrun AU - Hallmeyer S AD - Advocate Aurora Health, Park Ridge, Illinois, USA. FAU - Grose, Mark AU - Grose M AD - Viralytics Limited, Sydney, New South Wales, Australia. FAU - Zhang, Yiwei AU - Zhang Y AD - Merck & Co, Inc, Rahway, New Jersey, USA. FAU - Li, Anlong AU - Li A AD - Merck & Co, Inc, Rahway, New Jersey, USA. FAU - Andtbacka, Robert H I AU - Andtbacka RHI AD - University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah, USA. LA - eng SI - ClinicalTrials.gov/NCT02307149 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Ipilimumab) SB - IM MH - Adult MH - Humans MH - Adolescent MH - Ipilimumab/pharmacology/therapeutic use MH - *Oncolytic Viruses MH - *Melanoma/drug therapy/pathology MH - Progression-Free Survival MH - Disease Progression PMC - PMC9791411 OTO - NOTNLM OT - Combined Modality Therapy OT - Immunotherapy OT - Melanoma OT - Oncolytic Viruses COIS- Competing interests: BDC: data safety monitoring board for Merck; institutional funding from Bristol Myers Squibb and Viralytics; honoraria from Cullinan Oncology, Nektar Therapeutics, and Clinigen. JR: none. JRH: institutional funding from Merck, BMS, Takara, and Amgen; advisory boards for BMS/Nektar Therapeutics. GAD: none. MF: advisory boards for Merck, Bristol Myers Squibb, Novartis, Nektar, Sanofi, and Array Biopharma. LF: none. KAM: consultant for ImaginAb, Oncosec, Werewolf, Xilio, Instil, IOvance, and Checkmate Pharmaceuticals; institutional funding from Merck, BMS, Roche, BioNTech, Checkmate Pharmaceuticals, IO Biotech, Regeneron, and Agenus. SH: none. MG: consultant/independent contractor (contracted directly by Viralytics). YZ and AL: employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, USA and stockholders in Merck & Co, Inc, Rahway, New Jersey, USA. RHIA: institutional research funding from Viralytics; in the past 3 years, employee of Seven and Eight Biopharmaceuticals Inc. EDAT- 2022/12/24 06:00 MHDA- 2022/12/28 06:00 PMCR- 2022/12/23 CRDT- 2022/12/23 20:53 PHST- 2022/09/26 00:00 [accepted] PHST- 2022/12/23 20:53 [entrez] PHST- 2022/12/24 06:00 [pubmed] PHST- 2022/12/28 06:00 [medline] PHST- 2022/12/23 00:00 [pmc-release] AID - jitc-2022-005224 [pii] AID - 10.1136/jitc-2022-005224 [doi] PST - ppublish SO - J Immunother Cancer. 2022 Dec;10(12):e005224. doi: 10.1136/jitc-2022-005224.