{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:02:02Z","timestamp":1791597722243,"version":"4.3.4"},"reference-count":35,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T00:00:00Z","timestamp":1611273600000},"content-version":"unspecified","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Hold\u2019em for Life Oncology Clinician Scientist Award"},{"name":"Douglas Wright Melanoma Award"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,10,25]]},"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>Anti-programmed cell death protein 1 (PD1)\u00b1anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint inhibitors (ICIs) are standard therapeutic options for metastatic melanoma. We assessed whether biologic subtype according to primary tumor type or genomic subtype can function as predictive biomarkers for anti-PD1\u00b1anti-CTLA4 ICI in patients with advanced melanoma.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed a single-center retrospective cohort analysis of patients who received anti-PD1\u00b1anti-CTLA4 ICI for advanced melanoma between 2012 and 2019. Primary tumor type, <jats:italic>BRAF<\/jats:italic> and <jats:italic>NRAS<\/jats:italic> mutation status, and other covariates were abstracted from chart review. Log-rank tests and multivariable Cox regression models were used to assess differences in clinical progression-free (cPFS) and overall survival (OS).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We identified 230 patients who received 249 lines of anti-PD1\u00b1anti-CTLA4 ICI for unresectable or metastatic disease. Of these patients, 74% were cutaneous, 11% mucosal, 8% unknown primary and 7% acral. <jats:italic>BRAF<\/jats:italic> and <jats:italic>NRAS<\/jats:italic> mutations were identified in 35% and 28% of patients, respectively. In multivariable analyses of the entire cohort, acral or mucosal primary tumor type, &gt;3 metastatic sites, elevated LDH were predictive of shorter cPFS and OS. Combination ICI therapy was associated with longer cPFS (HR 0.57, 95% CI 0.38 to 0.86, p=0.007) and OS (HR 0.42, 95% CI 0.28 to 0.65, p&lt;0.001). Combination ICI was significantly associated with longer OS in unknown primary and mucosal melanoma. There was a non-significant trend toward longer OS with anti-PD1+anti-CTLA4 in cutaneous melanoma, but not in acral melanoma. In multivariable analyses, combination ICI was associated with longer OS in <jats:italic>NRAS<\/jats:italic> (HR 0.24, 95% CI 0.10 to 0.62, p=0.003, n=69) and <jats:italic>BRAF<\/jats:italic> V600E\/K (HR 0.47, 95% CI 0.24 to 0.90, p=0.024, n=86) mutant melanoma but not <jats:italic>BRAF\/NRAS<\/jats:italic> wild-type (n=94) melanoma.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In our cohort, primary melanoma tumor type and genomic subtype were independent predictive markers of cPFS and OS for patients with metastatic melanoma receiving anti-PD1 ICI. Primary tumor type and genomic subtype\u2014including NRAS\u2014should be further evaluated in prospective clinical trials to determine their value as predictive markers. Biologic subtypes may facilitate clinical decision-making when recommending combination ICI treatment (anti-PD1\u00b1anti-CTLA4) versus anti-PD1 alone for patients with metastatic melanoma.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-001642","type":"journal-article","created":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T14:28:28Z","timestamp":1611325708000},"page":"e001642","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":41,"title":["Biologic subtypes of melanoma predict survival benefit of combination anti-PD1+anti-CTLA4 immune checkpoint inhibitors versus anti-PD1 monotherapy"],"prefix":"10.1136","volume":"9","clinical-trial-number":[{"clinical-trial-number":"nct03955354","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03991975","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9845-4603","authenticated-orcid":false,"given":"April A N","family":"Rose","sequence":"first","affiliation":[{"name":"Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada"},{"name":"Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hogg","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus O","family":"Butler","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada"},{"name":"Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada"},{"name":"Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel D","family":"Saibil","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada"},{"name":"Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada"},{"name":"Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana P","family":"Arteaga","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada"},{"name":"Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago","family":"Pimentel Muniz","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada"},{"name":"Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deirdre","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada"},{"name":"Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny","family":"Ghazarian","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"},{"name":"Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"King","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of 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