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This study evaluates the impact of DDIs on clinical outcomes in patients with metastatic melanoma treated with BRAF\/MEK inhibitors. This multicenter, observational, retrospective study assessed DDIs using the Drug\u2010PIN software. Associations between the Drug\u2010PIN continuous score, Drug\u2010PIN light, and treatment outscomes were analyzed along with the specific drugs involved in the DDIs. A total of 177 patients with BRAF\u2010mutant metastatic melanoma undergoing BRAF\/MEK inhibitor therapy were included. Of these, 94 patients (55.9%) were exposed to complex drug regimens related to comorbidities, supportive care, and symptom management. A significant change in Drug\u2010PIN scores was observed before and after therapy initiation. Patients with low\u2010grade DDIs demonstrated significantly longer median overall survival (OS) and progression\u2010free survival (PFS) compared to those with high\u2010grade DDIs (log\u2010rank <jats:italic>p<\/jats:italic>\u2009=\u20090.0045 and <jats:italic>p<\/jats:italic>\u2009=\u20090.012, respectively); this observation was further validated by multiple regression analysis. By combining clinical and DDI data, we identified four patient subgroups with distinct prognoses, showing statistically significant differences in OS and PFS (log\u2010rank <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). The subgroup with the highest clinical risk and high DDI had markedly poorer outcomes (HR 2.87, 95% CI [1.7\u20134.8], <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). The drugs involved in high\u2010level pharmacological interactions were analyzed. DDIs significantly contribute to poorer OS and PFS outcomes, independent of other clinical risk factors. Optimizing pharmacological regimens to minimize DDIs should be prioritized to enhance treatment efficacy in oncology. Prospective clinical trials are warranted to further validate the advantages of individualized, preemptive therapy optimization.<\/jats:p>","DOI":"10.1111\/pcmr.70026","type":"journal-article","created":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T22:41:07Z","timestamp":1748817667000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Impact of Drug\u2013Drug Interactions on Clinical Outcomes in Metastatic Melanoma Patients Treated With Combined <scp>BRAF<\/scp>\/<scp>MEK<\/scp> Inhibitors: A Real\u2010World Study"],"prefix":"10.1111","volume":"38","author":[{"given":"Silvia","family":"Mezi","sequence":"first","affiliation":[{"name":"Department of Radiological Science, Oncology and Anatomical Pathology, Faculty of Medicine and Dentistry \u201cSapienza University of Rome\u201d and Unit Medical Oncology Policlinico Umberto I University Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Botticelli","sequence":"additional","affiliation":[{"name":"Department of Radiological Science, Oncology and Anatomical Pathology, Faculty of Medicine and Dentistry \u201cSapienza University of Rome\u201d and Unit Medical Oncology Policlinico Umberto I University Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Pomati","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4943-5622","authenticated-orcid":false,"given":"Simone","family":"Scagnoli","sequence":"additional","affiliation":[{"name":"Department of Radiological Science, Oncology and Anatomical Pathology, Faculty of Medicine and Dentistry \u201cSapienza University of Rome\u201d and Unit Medical Oncology Policlinico Umberto I University Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3354-8203","authenticated-orcid":false,"given":"Giulia","family":"Fiscon","sequence":"additional","affiliation":[{"name":"Department of Computer, Control, and Management Engineering \u201cAntonio Ruberti\u201d \u201cSapienza\u201d University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"de Galitiis","sequence":"additional","affiliation":[{"name":"Istituto Dermopatico Dell'immacolata, IDI\u2010IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca Romana","family":"di Pietro","sequence":"additional","affiliation":[{"name":"Istituto Dermopatico Dell'immacolata, IDI\u2010IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Verkhovskaia","sequence":"additional","affiliation":[{"name":"Istituto Dermopatico Dell'immacolata, IDI\u2010IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sasan","family":"Amirhassankhani","sequence":"additional","affiliation":[{"name":"Department of Urology S. 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