Background: Conjunctival melanoma is a rare type of ocular melanoma, which is prone to local recurrence and metastasis and can lead to patient death. Novel therapeutic strategies have revolutionized cutaneous melanoma management. The efficacy of these therapies in conjunctival melanoma, however, has not been evaluated in larger patient cohorts., Methods: In this multi-center retrospective cohort study with additional screening of the ADOREG database, data were collected from 34 patients with metastatic conjunctival melanoma who received targeted therapy (TT) (BRAF ± MEK inhibitors) or immune checkpoint inhibitors (ICI) (anti-PD-1 ± anti-CTLA4). In 15 cases, tissue was available for targeted next-generation-sequencing (611 genes) and RNA sequencing. Driver mutations, tumor mutational burden, copy number variations and inflammatory/IFNγ gene expression signatures were determined., Results: Genetic characterization identified frequent BRAF (46.7%, 7/15), NRAS (26.7%, 4/15), NF1 (20%, 3/15), and TERT promoter (46.7%, 7/15) mutations. UV associated C>T and CC>TT mutations were common. Median follow-up time after start of first TT or ICI therapy was 13.2 months. In 26 patients receiving first-line ICI, estimated one-year progression-free survival (PFS) rate was 42.0%, PFS and overall survival (OS) 6.2 and 18.0 months, respectively. First-line TT was given to 8 patients, estimated one-year PFS rate was 54.7%, median PFS and OS 12.6 and 29.1 months, respectively., Conclusions: Our findings support the role of UV irradiation in conjunctival melanoma and the genetic similarity with cutaneous melanoma. Conjunctival melanoma patients with advanced disease benefit from both targeted therapies (BRAF ± MEK inhibitors) and immune checkpoint inhibitors., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GL has received travel support for congress participation: Sun Pharma. PJ declares no conflicts of interest. IM declares no conflicts of interest. AS declares no conflicts of interest. JCH receives a scientific grant from BMS, payments ad consultant from Pierre Fabre, MSD, Sunpharma and speaker honoraria from BMS, MSD, Roche, Novartis, Pfizer, Sanofi, GSK, Amgen, Almirall. AF Advisory board: Pierre-Fabre, Roche, Novartis, BMS, MSD, travel support for congress participation: Pierre-Fabre, Roche, Novartis, BMS, honoraria for talks: Roche, Novartis, BMS, MSD, CeGaT, research funding: Stiftung Immunonkologie BMS. All outside the submitted work. JE declars no conflicts of interest. FM has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. LR declares no conflicts of interest. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. MZ has served as consultant or/and has received honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, Novartis, Sanofi Genzyme and SUN Pharma. MS Consultancy, speaker fees or travel grants: BMS, MSD, Roche, Kyowa Kirin, Novartis, Sanofi Genzyme, Pierre Fabre, Sun Pharma, Immunocore. FR declares no conflicts of interest. AS declares no conflicts of interest. KS declares no conflicts of interest. FM served as consultant and/or has received honoraria from Novartis, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi Genzyme and travel support from Novartis, Sunpharma and Bristol-Myers Squibb, outside the submitted work. RG Honoraria for lectures (personally): Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Honoraria for advice (personally): BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, MerckSerono, Pfizer, Immunocore. Research grants (to institution): Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi, Almirall Hermal. Support for meeting participation: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, SUNPHARMA, UCB, Allergy Therapeutics, Pierre Fabre, Kyowa Kirin and LEO. PT declares honoraria from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre-Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin, Biofrontera, Almirall, and 4SC; travel support from Bristol-Myers Squibb and Pierre-Fabre, outside the submitted work.BS is on the advisory board or has received honoraria from Almirall, Pfizer, Sanofi, Incyte, Novartis, Roche, Bristol-Myers Squibb (BMS) and MSD Sharp & Dohme, research funding from Novartis, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb and MSD Sharp & Dohme and travel support from Novartis, Roche, Bristol-Myers Squibb, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme and Amgen, outside the submitted work. MS declares no conflict of interest. MH has been a member of advisory boards of Almirall Hermal, Sanofi-Aventis, MSD, 622 BMS, Novartis, and received speaker's honoraria from Galderma and Biofrontera. UL speaker fees: Roche, Novartis, Sanofi, MSD; consultancy: Roche, Sanofi, MSD, Novartis. AZ received travel support from Novartis, Sanofi Grenzyme, Sun Pharma, and Bristol-Myers Squibb, outside the submitted work. CM declares no conflicts of interest. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. LZ served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sunpharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. EH declares no conflicts of interest. NB declares no conflicts of interest. DS D.S. Served as consultant, advisory board and/or speaker and has received honoraria from Amgen, Array, Bristol-Myers Squibb, Helsinn, Immunocore, InflarX, Merck Sharp & Dohme, Merck-Serono, Nektar, Novartis, OncoSec, Pfizer, Philogen, Regeneron, Replimune, Sandoz, Sanofi, Sunpharma, 4SC and travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, Merck-Serono, Nektar, Novartis, Pierre Fabre, Sandoz, Sanofi, and 4SC, outside the submitted work. HW declares no conflicts of interest. EL served as consultant and/or has received honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sunpharma and travel support from Medac, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. KG declares no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)