{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T15:26:44Z","timestamp":1793114804855,"version":"4.5.0"},"reference-count":45,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T00:00:00Z","timestamp":1633651200000},"content-version":"unspecified","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015539","name":"Australian Government","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015539","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,8,20]]},"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib\u2013trametinib and ipilimumab\u2013nivolumab have similar intracranial response rates (50%\u201355%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab\u2013nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Patients who received first-line ipilimumab\u2013nivolumab for MBMs or second\/third line ipilimumab\u2013nivolumab for intracranial metastases with BRAF<jats:sup>V600<\/jats:sup> mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded samples of BRAF<jats:sup>V600<\/jats:sup> mutant MBMs that were na\u00efve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs na\u00efve to systemic treatment versus BRAF-MEKi progression were performed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Twenty-five and 30 patients who received first and second\/third line ipilimumab\u2013nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5\u2009mm for the first and second\/third line ipilimumab\u2013nivolumab groups, respectively. Intracranial response rate was 75.0% (12\/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab\u2013nivolumab. Efficacy of second\/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1\/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab\u2013nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between na\u00efve and MBMs with progression on BRAF-MEKi treatment (p value &lt;0.05, false discovery rate (FDR) &lt;0.1). No distinct pathways were identified from gene set enrichment analyses using Kyoto Encyclopedia of Genes and Genomes, Gene Ontogeny or Hallmark libraries; however, enrichment of DEG from the Innate Anti-PD1 Resistance Signature (IPRES) was identified (p value=0.007, FDR=0.03).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Second-line ipilimumab\u2013nivolumab for MBMs after BRAF-MEKi progression has poor activity. MBMs that are resistant to BRAF-MEKi that also conferred resistance to second-line ipilimumab\u2013nivolumab showed enrichment of the IPRES gene signature.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2021-002995","type":"journal-article","created":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T02:04:48Z","timestamp":1633831488000},"page":"e002995","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":29,"title":["Melanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES)"],"prefix":"10.1136","volume":"9","clinical-trial-number":[{"clinical-trial-number":"nct03340129","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03776136","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02224781","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02631447","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1071-7956","authenticated-orcid":false,"given":"Peter Kar Han","family":"Lau","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia"},{"name":"Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Breon","family":"Feran","sequence":"additional","affiliation":[{"name":"Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, 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