{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:45:14Z","timestamp":1787064314451,"version":"build-2736575974"},"reference-count":32,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82002409"],"award-info":[{"award-number":["82002409"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072558"],"award-info":[{"award-number":["82072558"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82073396"],"award-info":[{"award-number":["82073396"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272789"],"award-info":[{"award-number":["82272789"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2018A0303130243"],"award-info":[{"award-number":["2018A0303130243"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2020A1515010020"],"award-info":[{"award-number":["2020A1515010020"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,4,26]]},"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>KN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of KN046 in patients with advanced solid tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients who failed standard treatment were included. KN046 was administered at doses of 1, 3, and 5\u2009mg\/kg every 2 weeks (Q2W), 5\u2009mg\/kg every 3 weeks (Q3W), and 300\u2009mg Q3W based on the modified toxicity probability interval method in the dose-escalation phase; the recommended dose was used in the expansion phase. Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) in escalation and preliminary efficacy in expansion. Secondary objectives included PK, pharmacodynamics, safety, and tolerability of KN046. We also explored biomarkers based on PD-L1 expression, multiplex immunofluorescence (mIF) staining, and RNAseq-derived nCounter platform.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Totally, 100 eligible patients were enrolled, including 59 with nasopharyngeal carcinoma (NPC), 36 with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and those with other advanced solid tumors. The most common treatment-related adverse events (TRAEs) were rash (33.0%), pruritus (31.0%), and fatigue (20.0%). Grade \u22653 TRAEs were observed in 14.0% of participants. No dose-limiting toxicity occurred in the dose-escalation phase, and the MTD was not reached. The RP2D was determined as 5\u2009mg\/kg Q2W according to the pharmacokinetic\u2013pharmacodynamic model, the preliminary exposure\u2013response analysis, and the overall safety profile. Among 88 efficacy-evaluable participants, the objective response rate (ORR) was 12.5%, and the median duration of response was 16.6 months. In the NPC subgroup, the ORR was 15.4%, and the median overall survival (OS) was 24.7 (95% CI 16.3 to not estimable) months. In the EGFR-mutant NSCLC subgroup, the ORR was 6.3%. mIF analysis results showed patients with high CD8 expression showed longer median OS (27.1 vs 9.2 months, p=0.02); better prognosis was observed in patients with high CD8 and PD-L1 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>KN046 was well tolerated and showed promising antitumor efficacy in advanced solid tumors, especially in patients with NPC. The combination of both CD8 and PD-L1 expression improved the prediction of KN046 response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration numbers<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03733951\">NCT03733951<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2022-006654","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T10:30:28Z","timestamp":1685615428000},"page":"e006654","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors"],"prefix":"10.1136","volume":"11","clinical-trial-number":[{"clinical-trial-number":"nct03733951","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03529526","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Yuxiang","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9791-2940","authenticated-orcid":false,"given":"Jinhui","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 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