{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:12Z","timestamp":1792787292077,"version":"4.5.0"},"reference-count":50,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T00:00:00Z","timestamp":1665964800000},"content-version":"unspecified","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004334","name":"Merck","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100004334","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Rob and Karen Hale Distinguished Chair in Surgical Oncology","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,9,17]]},"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Preclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine (T-DM1) combined with pembrolizumab is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This was a single-arm phase Ib trial (registration date January 26, 2017) of T-DM1 plus pembrolizumab in metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible patients had HER2-positive, metastatic breast cancer previously treated with taxane, trastuzumab, and pertuzumab, and were T-DM1-na\u00efve. A dose de-escalation design was used, with a dose-finding cohort followed by an expansion cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies. The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Immune biomarkers were assessed using histology, protein\/RNA expression, and whole exome sequencing. Associations between immune biomarkers and treatment response, and biomarker changes before and during treatment, were explored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>20 patients received protocol therapy. There were no dose-limiting toxicities. The RP2D was 3.6 mg\/kg T-DM1 every 21 days plus 200\u2009mg pembrolizumab every 21 days. 85% of patients experienced treatment-related adverse events (AEs) \u2265grade 2, 20% of patients experienced grade 3 AEs, and no patients experienced grade &gt;4 AEs. Four patients (20%) experienced pneumonitis (three grade 2 events; one grade 3 event). ORR was 20% (95% CI 5.7% to 43.7%), and median PFS was 9.6 months (95%\u2009CI 2.8 to 16.0 months). Programmed cell death ligand-1 and tumor infiltrating lymphocytes did not correlate with response in this small cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>T-DM1 plus pembrolizumab was a safe and tolerable regimen. Ongoing trials will define if there is a role for checkpoint inhibition in the management of HER2-positive metastatic breast cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03032107\">NCT03032107<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2022-005119","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T11:12:46Z","timestamp":1666005166000},"page":"e005119","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":40,"title":["Phase Ib study of pembrolizumab in combination with trastuzumab emtansine for metastatic HER2-positive breast 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