{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T08:08:29Z","timestamp":1793347709691,"version":"4.5.0"},"reference-count":27,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T00:00:00Z","timestamp":1608681600000},"content-version":"unspecified","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/100004336","name":"Novartis","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100004336","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,11,24]]},"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated\n                      <jats:italic>BRAF<\/jats:italic>\n                      <jats:sup>V600E\/K<\/jats:sup>\n                      -mutated advanced melanoma from 22 sites in seven countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab (200 mg every 3 weeks) or placebo plus dabrafenib (150 mg orally two times per day) and trametinib (2 mg orally one time a day). Primary endpoint was PFS. Secondary endpoints were objective response rate, DOR, and OS. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of study drug. This analysis was not specified in the protocol.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Between November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3\u20135 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      In\n                      <jats:italic>BRAF<\/jats:italic>\n                      <jats:sup>V600E\/K<\/jats:sup>\n                      -mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs. Interpretation of these results is limited by the post hoc nature of the analysis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2020-001806","type":"journal-article","created":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T11:23:32Z","timestamp":1608809012000},"page":"e001806","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":181,"title":["KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in\n                    <i>BRAF<\/i>\n                    -mutant melanoma"],"prefix":"10.1136","volume":"8","clinical-trial-number":[{"clinical-trial-number":"nct02130466","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02968303","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02902029","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03235245","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02858921","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\/0000-0001-6255-5851","authenticated-orcid":false,"given":"Pier Francesco","family":"Ferrucci","sequence":"first","affiliation":[{"name":"Cancer Biotherapy Unit, Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Di Giacomo","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, University Hospital of Siena; University of Siena, Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Del Vecchio","sequence":"additional","affiliation":[{"name":"Unit of Melanoma Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Atkinson","sequence":"additional","affiliation":[{"name":"University of Queensland, and Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Woolloongabba, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Oncology, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Schachter","sequence":"additional","affiliation":[{"name":"Division of Oncology, Sheba Medical Centre, Tel HaShomer Hospital, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9917-6633","authenticated-orcid":false,"given":"Paola","family":"Queirolo","sequence":"additional","affiliation":[{"name":"IEO European Institute of Oncology IRCCS, Milan, Italy"},{"name":"Ospedale Policlinico San Martino IRCCS, Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8894-3545","authenticated-orcid":false,"given":"Georgina V","family":"Long","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, and Royal North Shore Hospital, Sydney, New South Wales, Australia"},{"name":"Department of Medical Oncology and Translational Research, Mater Hospital, North Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalie","family":"Stephens","sequence":"additional","affiliation":[{"name":"Medical Oncology, Auckland City Hospital, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge Marie","family":"Svane","sequence":"additional","affiliation":[{"name":"Department of Oncology, Copenhagen University Hospital, Herlev, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Lotem","sequence":"additional","affiliation":[{"name":"Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Abu-Amna","sequence":"additional","affiliation":[{"name":"Rambam Health Care, Haifa, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard","family":"Gasal","sequence":"additional","affiliation":[{"name":"Global Drug Development, Oncology, Novartis, East Hanover, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Razi","family":"Ghori","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Merck & Co Inc, Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5422-549X","authenticated-orcid":false,"given":"Scott J","family":"Diede","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Merck & Co Inc, Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth S","family":"Croydon","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Merck & Co Inc, Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoni","family":"Ribas","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California Los Angeles and the Jonsson Comprehensive Cancer Center, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8322-475X","authenticated-orcid":false,"given":"Paolo Antonio","family":"Ascierto","sequence":"additional","affiliation":[{"name":"Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione \u201cG. Pascale\u201d, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2020,12,24]]},"reference":[{"key":"2025100301550862000_8.2.e001806.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2017.43"},{"key":"2025100301550862000_8.2.e001806.2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-4804"},{"key":"2025100301550862000_8.2.e001806.3","doi-asserted-by":"crossref","DOI":"10.1177\/1758835919830826","article-title":"Combined targeted therapy and immunotherapy in melanoma: a review of the impact on the tumor microenvironment and outcomes of early clinical trials","volume":"11","author":"Pelster","year":"2019","journal-title":"Ther Adv Med Oncol"},{"key":"2025100301550862000_8.2.e001806.4","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2479"},{"key":"2025100301550862000_8.2.e001806.5","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-1630"},{"key":"2025100301550862000_8.2.e001806.6","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaa4691"},{"key":"2025100301550862000_8.2.e001806.7","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2016.1238557","article-title":"Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma","volume":"5","author":"Deken","year":"2016","journal-title":"Oncoimmunology"},{"key":"2025100301550862000_8.2.e001806.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0476-5"},{"key":"2025100301550862000_8.2.e001806.9","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1038\/s41591-019-0474-7","article-title":"Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients","volume":"25","author":"Sullivan","year":"2019","journal-title":"Nat Med"},{"key":"2025100301550862000_8.2.e001806.10","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1200\/jco.2015.33.15_suppl.3003","article-title":"Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and\/or MEK (trametinib) inhibitors in advanced melanoma","volume":"33","author":"Ribas","year":"2015","journal-title":"J Clin Oncol"},{"key":"2025100301550862000_8.2.e001806.11","doi-asserted-by":"crossref","first-page":"9531","DOI":"10.1200\/JCO.2019.37.15_suppl.9531","article-title":"The anti\u2013PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600\u2013mutant melanoma: Updated efficacy and safety from parts 1 and 2 of COMBI-i","volume":"37","author":"Long","year":"2019","journal-title":"J Clin Oncol"},{"key":"2025100301550862000_8.2.e001806.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0448-9"},{"key":"2025100301550862000_8.2.e001806.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"2025100301550862000_8.2.e001806.14","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4780040211"},{"key":"2025100301550862000_8.2.e001806.15","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/s41416-019-0546-y","article-title":"Impact of depth of response on survival in patients treated with cobimetinib\u2009\u00b1\u2009vemurafenib: pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM","volume":"121","author":"Lewis","year":"2019","journal-title":"Br J Cancer"},{"key":"2025100301550862000_8.2.e001806.16","doi-asserted-by":"crossref","first-page":"9508","DOI":"10.1200\/JCO.2019.37.15_suppl.9508","article-title":"FDA analysis of depth of response (DpR) and survival across 10 randomized controlled trials in patients with previously untreated unresectable or metastatic melanoma (UMM) by therapy type","volume":"37","author":"Osgood","year":"2019","journal-title":"J Clin Oncol"},{"key":"2025100301550862000_8.2.e001806.17","doi-asserted-by":"publisher","DOI":"10.1186\/2051-1426-1-18"},{"key":"2025100301550862000_8.2.e001806.18","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1007\/s00262-013-1458-y","article-title":"Late divergence of survival curves in cancer immunotherapy trials: interpretation and implications","volume":"62","author":"Thor\u00e9n","year":"2013","journal-title":"Cancer Immunol Immunother"},{"key":"2025100301550862000_8.2.e001806.19","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1056\/NEJMoa1904059","article-title":"Five-Year outcomes with dabrafenib plus trametinib in metastatic melanoma","volume":"381","author":"Robert","year":"2019","journal-title":"N Engl J Med"},{"key":"2025100301550862000_8.2.e001806.20","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ejca.2017.05.033","article-title":"Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials","volume":"82","author":"Schadendorf","year":"2017","journal-title":"Eur J Cancer"},{"key":"2025100301550862000_8.2.e001806.21","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0127"},{"key":"2025100301550862000_8.2.e001806.22","unstructured":"National Comprehensive Cancer Network . NCCN clinical practice Guidlines in medical oncology. Cutaneous Melanoma. Version 4.2020 Plymouth Meeting, PA: National Comprehensive Cancer Network, 2020."},{"key":"2025100301550862000_8.2.e001806.23","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910836"},{"key":"2025100301550862000_8.2.e001806.24","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30428-X"},{"key":"2025100301550862000_8.2.e001806.25","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1016\/S0140-6736(20)30934-X","article-title":"Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial","volume":"395","author":"Gutzmer","year":"2020","journal-title":"Lancet"},{"key":"2025100301550862000_8.2.e001806.26","doi-asserted-by":"crossref","unstructured":"Nathan P , Dummer R , Long GV , et al . Spartaluzimab plus dabrafenib and trametinib (Sparta Dam-Tram)in patients (pts) with previously untreated BRAF V600-mutant unresectable or metastatic melanoma: Results from the randomized part 3 of the phase III COMBI-i trial. Ann Oncol 2020:S1142\u2013215.","DOI":"10.1016\/j.annonc.2020.08.2273"},{"key":"2025100301550862000_8.2.e001806.27","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/S1470-2045(16)30017-1","article-title":"Progression-free survival landmark analysis: a critical endpoint in melanoma clinical trials","volume":"17","author":"Ascierto","year":"2016","journal-title":"Lancet Oncol"}],"updated-by":[{"DOI":"10.1136\/jitc-2020-001806corr1","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000}}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2020-001806","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T08:55:25Z","timestamp":1759481725000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2020-001806"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12]]},"references-count":27,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,12,24]]},"published-print":{"date-parts":[[2020,12]]}},"alternative-id":["10.1136\/jitc-2020-001806"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2020-001806","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12]]}}}