{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T21:19:36Z","timestamp":1793827176630,"version":"4.6.1"},"reference-count":26,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T00:00:00Z","timestamp":1713484800000},"content-version":"unspecified","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Akeso Biopharma, Inc., Zhongshan, China","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":[[2024,3,12]]},"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Studies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1\/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously. Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients with advanced solid tumors were treated with ivonescimab 0.3, 1, 3, 10, 20 or 30\u2009mg\/kg intravenously every 2 weeks using a 3+3+3\u2009dose escalation design. Dose expansion occurred at 10 and 20\u2009mg\/kg in selected tumor types. The primary objective was to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD). The secondary objectives included pharmacokinetics, pharmacodynamics and preliminary antitumor activity based on Response Evaluation Criteria in Solid Tumors V.1.1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Between October 2, 2019 and January 14, 2021, a total of 51 patients were enrolled and received ivonescimab. Two dose-limiting toxicities were reported at 30\u2009mg\/kg. The MTD of ivonescimab was 20\u2009mg\/kg every 2 weeks. Grade\u22653 treatment-related adverse events (TRAEs) occurred in 14 patients (27.5%). The most common TRAEs of any grade were rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%) and pruritus (11.8%). The most common grade\u22653 TRAEs were hypertension (7\/51, 13.7%), alanine aminotransferase increased (3\/51, 5.2%), aspartate aminotransferase increased (2\/51, 3.9%) and colitis (2\/51, 3.9%). Of 47 patients who had at least one postbaseline assessment, the confirmed objective response rate was 25.5% (12\/47) and disease control rate was 63.8% (30\/47). Among 19 patients with platinum-resistant ovarian cancer, 5 patients (26.3%) achieved partial response (PR). Efficacy signals were also observed in patients with mismatch repair proficient (pMMR) colorectal cancer, non-small cell lung cancer, and both MMR deficient and pMMR endometrial cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Ivonescimab demonstrated manageable safety profiles and promising efficacy signals in multiple solid tumors. Exploration of alternative dosing regimens of ivonescimab monotherapy and combination therapies is warranted.<\/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=\"NCT04047290\">NCT04047290<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2023-008037","type":"journal-article","created":{"date-parts":[[2024,4,20]],"date-time":"2024-04-20T03:50:22Z","timestamp":1713585022000},"page":"e008037","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":89,"title":["Phase 1a dose escalation study of ivonescimab (AK112\/SMT112), an anti-PD-1\/VEGF-A bispecific antibody, in patients with advanced solid tumors"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct04047290","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04047290","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04736823","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04900363","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04870177","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05184712","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05499390","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05899608","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05840016","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6917-9737","authenticated-orcid":false,"given":"Sophia","family":"Frentzas","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Monash Health, Melbourne, Victoria, Australia"},{"name":"Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Rachelle","family":"Austria Mislang","sequence":"additional","affiliation":[{"name":"Icon (Adelaide) Cancer Centre, Kurralta Park, South Australia, Australia"},{"name":"Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Lemech","sequence":"additional","affiliation":[{"name":"Scientia Clinical Research Ltd, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adnan","family":"Nagrial","sequence":"additional","affiliation":[{"name":"Blacktown Cancer and Haematology Centre, Blacktown Hospital, University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Underhill","sequence":"additional","affiliation":[{"name":"Border Medical Oncology and Haematology Research Unit, Albury-Wodonga Regional Cancer Centre, Albury Wodonga, New South Wales, Australia"},{"name":"University of New South Wales, Rural Medical School, Albury Campus, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3329-7421","authenticated-orcid":false,"given":"Wenjing","family":"Wang","sequence":"additional","affiliation":[{"name":"Akeso Biopharma, Inc, Zhongshan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1683-5147","authenticated-orcid":false,"given":"Zhongmin Maxwell","family":"Wang","sequence":"additional","affiliation":[{"name":"Akeso Biopharma, Inc, Zhongshan, 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