{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T01:57:51Z","timestamp":1780451871639,"version":"3.54.1"},"reference-count":14,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T00:00:00Z","timestamp":1670457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Human epidermal growth factor receptor 2 (HER2) is the most prominent therapeutic target for advanced gastric (G)\/GEJ cancer. However, targeted therapy did not significantly improve survival. Currently, there are no regimens for the treatment of HER-2 amplification that exclude targeted agents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Case presentation<\/jats:title><jats:p>A 42-year-old man was diagnosed with adenocarcinoma of GEJ (stage IV) with liver metastasis and lung metastasis. The patient was enrolled in a trial that excluded patients with known HER2-positivity: AK104, a PD-1\/CTLA-4 bispecific antibody, combined with chemotherapy (mXELOX) as first-line therapy for advanced gastric G\/GEJ cancer (NCT03852251). After six cycles of AK104 combined with chemotherapy therapy, immune-related pulmonary toxicity was observed. We rechallenged AK104 after hormone therapy, and no further pulmonary toxicity was observed. Immune-related hepatitis occurred in the patient during immunotherapy combined with single-drug capecitabine therapy. After combining steroid therapy with mycophenolate mofetil, the patient\u2019s immune hepatitis improved. Nevertheless, the patient was excluded from the clinical study due to the long-term absence of medication. Antitumor therapy was also discontinued in view of the patient\u2019s adverse immune response. The patient did not receive subsequent immune antitumor therapy, and immune-related hepatitis still occurred intermittently, but the disease evaluation was maintained at PR. A complete response was confirmed by PET\/CT and the biopsy specimen from gastroscopy on 2020-06-10. Next generation sequencing of biopsy tissue was used to guide subsequent therapy at a recent follow-up visit. The results indicated that ERBB2 mutations occurred at copy number 58.4934 (HER-2), TMB = 3.1, MSS. IHC: EBV (\u2212), PD-L1 CPS = 3, HER-2 (3+).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Patients with HER-2-positive advanced GEJ cancer received PD-1\/CTLA-4 bispecific immunotherapy combined with chemotherapy and achieved complete remission. It offers a novel, highly specific, and highly potent therapeutic option for HER-2-positive patients. Its use should be considered as a new treatment when trastuzumab is not viable. Currently, we are working to overcome this resistance.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1049518","type":"journal-article","created":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T13:44:30Z","timestamp":1670507070000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Patients with positive HER-2 amplification advanced gastroesophageal junction cancer achieved complete response with combined chemotherapy of AK104\/cadonilimab (PD-1\/CTLA-4 bispecific): A case report"],"prefix":"10.3389","volume":"13","author":[{"given":"Jieqiong","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziru","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuantao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/s41571-019-0268-3","article-title":"HER2-targeted therapies - a role beyond breast cancer","volume":"17","author":"Oh","year":"2020","journal-title":"Nat Rev Clin Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)61121-X","article-title":"Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial [published correction appears in lancet","volume":"376","author":"Bang","year":"2010","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-2827","article-title":"First-in-human HER2-targeted bispecific antibody KN026 for the treatment of patients with HER2-positive metastatic breast cancer: Results from a phase I study","volume":"28","author":"Zhang","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol29030131","article-title":"Immunotherapy in gastric cancer","volume":"29","author":"H\u00f6gner","year":"2022","journal-title":"Curr Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.12214","article-title":"Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: A single-arm phase II study","volume":"41","author":"Peng","year":"2021","journal-title":"Cancer Commun (Lond)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.08.001","article-title":"Targeting the complexity of ERBB2 biology in gastroesophageal carcinoma","volume":"33","author":"Augustin","year":"2022","journal-title":"Ann Oncol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/S0140-6736(21)00797-2","article-title":"First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial","volume":"398","author":"Janjigian","year":"2021","journal-title":"Lancet"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2021.08.2133","article-title":"Sintilimab plus chemotherapy (chemo) versus chemo as first-line treatment for advanced gastric or gastroesophageal junction (G\/GEJ) adenocarcinoma (ORIENT-16).2021 ESMO","author":"Xu","year":"","journal-title":"LBA53"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04161-3","article-title":"The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer","volume":"600","author":"Janjigian","year":"2021","journal-title":"Nature"},{"key":"B10","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1200\/JCO.2022.40.4_suppl.308","article-title":"A phase Ib\/II, multicenter, open-label study of AK104, a PD-1\/CTLA-4 bispecifc antibody, combined with chemotherapy (chemo) as frst-line therapy for advanced gastric (G) or gastroesophageal junction (GEJ) cancer [abstract no. 308]","volume":"40","author":"Ji","year":"2022","journal-title":"J Clin Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3850","article-title":"Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes","volume":"21","author":"Cristescu","year":"2015","journal-title":"Nat Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000328","article-title":"Il-12 enhances the antitumor actions of trastuzumab via NK cell IFN-\u03b3 production","volume":"186","author":"Jaime-Ramirez","year":"2011","journal-title":"J Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402891","article-title":"Trastuzumab triggers phagocytic killing of high HER2 cancer cells in vitro and in vivo by interaction with fc\u03b3 receptors on macrophages","volume":"194","author":"Shi","year":"2015","journal-title":"J Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1001\/jamaoncol.2021.0275","article-title":"Assessment of pembrolizumab therapy for the treatment of microsatellite instability-high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials","volume":"7","author":"Chao","year":"2021","journal-title":"JAMA Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1049518\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T13:44:32Z","timestamp":1670507072000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1049518\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,8]]},"references-count":14,"alternative-id":["10.3389\/fimmu.2022.1049518"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1049518","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,8]]},"article-number":"1049518"}}