{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T13:11:21Z","timestamp":1779973881191,"version":"3.53.1"},"reference-count":41,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"OncXerna Therapeutics"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Advanced gastric and gastroesophageal junction (gastric\/GOJ) adenocarcinomas have poor outcomes, and the benefit of immune checkpoint inhibitors (CPIs) remains limited. Bavituximab is a phosphatidylserine-targeting monoclonal antibody that modulates the immune and vascular tumour microenvironment. This Phase 2, open-label, multinational study evaluated bavituximab plus pembrolizumab in previously treated advanced gastric\/GOJ. Patients were stratified into CPI-na\u00efve (n = 61) and CPI-relapse (n = 19) cohorts. Bavituximab (3 mg\/kg weekly) was combined with pembrolizumab (200 mg every 3 weeks) until disease progression or unacceptable toxicity. Primary endpoints included the safety and objective response rate (ORR) per RECIST 1.1. Secondary endpoints included the disease control rate (DCR), progression-free survival, overall survival, and exploratory biomarker analyses using the Xerna TME Panel and the neutrophil-to-lymphocyte ratio (NLR). No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were fatigue (32.5%), constipation (31.3%), and decreased appetite (31.3%). The ORR was 13.1% in CPI-na\u00efve and 5.3% in CPI-relapse patients; the median duration of response was 12.5 months in the CPI-na\u00efve cohort. The DCR was 39.3% and 52.6% respectively. Higher ORRs were observed in patients with immune-high (B+) subtypes (21.9%), NLR &lt; 4 (17.9%) and B+\/NLR &lt; 4 (33%). Bavituximab plus pembrolizumab was well tolerated but showed modest activity, with greater benefit in biomarker-defined subgroups, supporting the biomarker-driven development of tumour microenvironment-targeting combinations in advanced gastric\/GOJ adenocarcinomas. NCT04099641.<\/jats:p>","DOI":"10.3390\/curroncol33060319","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T12:09:07Z","timestamp":1779970147000},"page":"319","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Phosphatidylserine in Advanced Gastric and Gastroesophageal Junction Adenocarcinomas: A Phase 2 Trial of Bavituximab Plus Pembrolizumab with Biomarker-Correlated Outcomes"],"prefix":"10.3390","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1708-3861","authenticated-orcid":false,"given":"Panagiotis","family":"Ntellas","sequence":"first","affiliation":[{"name":"Department of Medicine, The Royal Marsden Hospital, Downs Road, Sutton SM25PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haeseong","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerry","family":"Culm","sequence":"additional","affiliation":[{"name":"OncXerna Therapeutics, Waltham, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeeyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagop","family":"Youssoufian","sequence":"additional","affiliation":[{"name":"OncXerna Therapeutics, Waltham, MA 02451, USA"},{"name":"Department of Medicine, Brown University Health, Providence, RI 02912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen","family":"Mockbee","sequence":"additional","affiliation":[{"name":"OncXerna Therapeutics, Waltham, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Uhlik","sequence":"additional","affiliation":[{"name":"OncXerna Therapeutics, Waltham, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Benjamin","sequence":"additional","affiliation":[{"name":"OncXerna Therapeutics, Waltham, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0286-8703","authenticated-orcid":false,"given":"Ian","family":"Chau","sequence":"additional","affiliation":[{"name":"Department of Medicine, The Royal Marsden Hospital, Downs Road, Sutton SM25PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1038\/s41417-021-00310-y","article-title":"Recent Advances in Immune Therapies for Gastric Cancer","volume":"28","author":"Olnes","year":"2021","journal-title":"Cancer Gene Ther."},{"key":"ref_3","first-page":"CD004064","article-title":"Chemotherapy for advanced gastric cancer","volume":"8","author":"Wagner","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"pkab088","DOI":"10.1093\/jncics\/pkab088","article-title":"Immunotherapy Efficacy in the Initial Lines of Treatment in Advanced Upper Gastrointestinal Malignancies: A Systematic Review of the Literature","volume":"5","author":"Kamposioras","year":"2021","journal-title":"JNCI Cancer Spectr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1056\/NEJMoa2503701","article-title":"Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer","volume":"393","author":"Janjigian","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","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":"ref_7","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/S1470-2045(23)00515-6","article-title":"Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): A multicentre, randomised, double-blind, phase 3 trial","volume":"24","author":"Rha","year":"2023","journal-title":"Lancet Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e078876","DOI":"10.1136\/bmj-2023-078876","article-title":"Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial","volume":"385","author":"Qiu","year":"2024","journal-title":"BMJ"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Takei, S., Kawazoe, A., and Shitara, K. (2022). The New Era of Immunotherapy in Gastric Cancer. Cancers, 14.","DOI":"10.3390\/cancers14041054"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41575-022-00591-0","article-title":"The immune microenvironment in gastric adenocarcinoma","volume":"19","author":"Zavros","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.1111\/cas.14521","article-title":"Tumor microenvironment in gastric cancers","volume":"111","author":"Oya","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6888","DOI":"10.1158\/1078-0432.CCR-11-1074","article-title":"Phase I safety and pharmacokinetic study of bavituximab, a chimeric phosphatidylserine-targeting monoclonal antibody, in patients with advanced solid tumors","volume":"17","author":"Gerber","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kaynak, A., Davis, H.W., Kogan, A.B., Lee, J.-H., Narmoneva, D.A., and Qi, X. (2022). The Unique Dual-Role Biomarker for Cancer Imaging and Therapy. Cancers, 14.","DOI":"10.3390\/cancers14102536"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1194\/jlr.R200019-JLR200","article-title":"Regulation of transbilayer plasma membrane phospholipid asymmetry","volume":"44","author":"Daleke","year":"2003","journal-title":"J. Lipid Res."},{"key":"ref_15","first-page":"493","article-title":"Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts","volume":"5","author":"Gerber","year":"2015","journal-title":"Am. J. Nucl. Med. Mol. Imaging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"43","DOI":"10.2147\/LCTT.S37981","article-title":"Profile of bavituximab and its potential in the treatment of non-small-cell lung cancer","volume":"5","author":"Cappuzzo","year":"2014","journal-title":"Lung Cancer Targets Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"436","DOI":"10.4049\/jimmunol.2000763","article-title":"Phosphatidylserine-Targeting Monoclonal Antibodies Exhibit Distinct Biochemical and Cellular Effects on Anti-CD3\/CD28\u2013Stimulated T Cell IFN-\u03b3 and TNF-\u03b1 Production","volume":"207","author":"Calianese","year":"2021","journal-title":"J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1172\/JCI1112","article-title":"Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine\/paracrine mechanisms involving TGF-\u03b2, PGE2, and PAF","volume":"101","author":"Fadok","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1158\/1078-0432.CCR-07-1516","article-title":"Vascular imaging of solid tumors in rats with a radioactive arsenic-labeled antibody that binds exposed phosphatidylserine","volume":"14","author":"Jennewein","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1158\/2326-6066.CIR-13-0073","article-title":"Phosphatidylserine-targeting antibody induces M1 macrophage polarization and promotes myeloid-derived suppressor cell differentiation","volume":"1","author":"Yin","year":"2013","journal-title":"Cancer Immunol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2985","DOI":"10.4049\/jimmunol.173.5.2985","article-title":"Phosphatidylserine Regulates the Maturation of Human Dendritic Cells","volume":"173","author":"Chen","year":"2004","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1038\/cdd.2016.11","article-title":"Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer","volume":"23","author":"Birge","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12964-020-0521-5","article-title":"TIMs, TAMs, and PS- antibody targeting: Implications for cancer immunotherapy","volume":"18","author":"Dayoub","year":"2020","journal-title":"Cell Commun. Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1007\/s00424-024-02948-7","article-title":"Phosphatidylserine externalization as immune checkpoint in cancer","volume":"476","author":"Kur","year":"2024","journal-title":"Pflug. Arch."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s40880-019-0427-z","article-title":"The immune landscape of esophageal cancer","volume":"39","author":"Huang","year":"2019","journal-title":"Cancer Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1111\/jgh.13284","article-title":"Myeloid-derived suppressor cells in gastrointestinal cancers: A systematic review","volume":"31","author":"Mirghorbani","year":"2016","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"P358","DOI":"10.1186\/2051-1426-3-S2-P358","article-title":"Targeting phosphatidylserine synergizes with immune checkpoint blockade by inducing de novo tumor specific immunity","volume":"3","author":"Huang","year":"2015","journal-title":"J. Immunother. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1002\/ijc.21684","article-title":"Combination of a monoclonal anti-phosphatidylserine antibody with gemcitabine strongly inhibits the growth and metastasis of orthotopic pancreatic tumors in mice","volume":"118","author":"Beck","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"29863","DOI":"10.1074\/jbc.M605252200","article-title":"Plasma protein \u03b2-2-glycoprotein 1 mediates interaction between the anti-tumor monoclonal antibody 3G4 and anionic phospholipids on endothelial cells","volume":"281","author":"Luster","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"v487","DOI":"10.1093\/annonc\/mdx380.065","article-title":"Final clinical results from SUNRISE: A phase III, randomized, double-blind, placebo-controlled multicenter trial of bavituximab plus docetaxel in patients with previously treated stage IIIb\/IV nonsquamous non-small cell lung cancer","volume":"28","author":"Palmero","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6871","DOI":"10.1158\/1078-0432.CCR-09-1499","article-title":"Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma","volume":"15","author":"He","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.lungcan.2014.08.010","article-title":"Bavituximab plus paclitaxel and carboplatin for the treatment of advanced non-small-cell lung cancer","volume":"86","author":"Digumarti","year":"2014","journal-title":"Lung Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1038\/s41467-024-46542-y","article-title":"The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: A phase 2 trial","volume":"15","author":"Hsiehchen","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"LB-262","DOI":"10.1158\/1538-7445.AM2014-LB-262","article-title":"Abstract LB-262: Phosphatidylserine-targeting antibody synergizes with anti-PD-1 antibody to inhibit tumor growth in K1735 mouse melanoma model","volume":"74","author":"Huang","year":"2014","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4978","DOI":"10.1158\/1538-7445.AM2014-4978","article-title":"Abstract 4978: Targeting of phosphatidylserine by monoclonal antibodies enhances activity of immune checkpoint inhibitors in tumors","volume":"74","author":"Gong","year":"2014","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.1200\/JCO.21.01801","article-title":"Phase Ib Study of Navicixizumab Plus Paclitaxel in Patients with Platinum-Resistant Ovarian, Primary Peritoneal, or Fallopian Tube Cancer","volume":"40","author":"Fu","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Uhlik, M., Pointing, D., Iyer, S., Ausec, L., \u0160tajdohar, M., Cvitkovi\u010d, R., \u017dganec, M., Culm, K., Santos, V.C., and Pytowski, B. (2023). XernaTM TME Panel is a machine learning-based transcriptomic biomarker designed to predict therapeutic response in multiple cancers. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1158345"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e180013","DOI":"10.1001\/jamaoncol.2018.0013","article-title":"Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial","volume":"4","author":"Fuchs","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s10120-021-01227-z","article-title":"Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial","volume":"25","author":"Fuchs","year":"2022","journal-title":"Gastric Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4007","DOI":"10.1200\/JCO.2024.42.16_suppl.4007","article-title":"International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI)","volume":"42","author":"Kim","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1038\/s41586-024-08305-z","article-title":"Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours","volume":"637","author":"Melero","year":"2024","journal-title":"Nature"}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/33\/6\/319\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T12:40:04Z","timestamp":1779972004000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/33\/6\/319"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":41,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["curroncol33060319"],"URL":"https:\/\/doi.org\/10.3390\/curroncol33060319","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,28]]}}}