Journal Article

Immunological biomarkers of response and resistance to treatment with cabozantinib and nivolumab in recurrent endometrial cancer

Wang, Lisa, Suarez-Farinas, Mayte, Streicher, Howard, CzinCzin, Benito, Thompson, Ryan, Atale, Swati, Haymaker, Cara L, Gonzalez-Kozlova, Edgar, Kim-Schulze, Seunghee, Kelly, Geoffrey, Tuballes, Kevin, Hui, Xie, Manyam, Ganiraju, Wistuba, Ignacio I, Gnjatic, Sacha, Zhang, Jianjun, Roudko, Vladimir, Radkevich, Emir, Al-Atrash, Gheath, Del Valle, Diane Marie, Patel, Manishkumar, Lheureux, Stephanie

2025

Overview

BackgroundAntiangiogenics combined with immune checkpoint blockade have become standard of care for recurrent endometrial cancer after standard platinum-based chemotherapy. To dissect mechanisms and define biomarkers associated with clinical outcomes to these combinations, we applied multidimensional immune monitoring to peripheral blood specimens collected from a randomized phase 2 trial of nivolumab with or without cabozantinib in 75 evaluable patients with recurrent endometrial cancer (NCI ETCTN 10104, NCT03367741). This trial demonstrated superiority of the combination to nivolumab alone.Methods and resultsUsing Olink proteomics, mass cytometry, tumor antigen-specific ELISA, and whole exome tumor sequencing, we identified longitudinal immune signatures specific to cabozantinib use, including an increase in plasma HO-1 and reduction in plasma vascular endothelial growth factor receptor 2, interleukin-12, and circulating plasmacytoid dendritic cells. Prior exposure to immunotherapy and carcinosarcoma histology had no adverse impact on clinical benefit or biomarkers, and copy-number high tumors were associated with increased plasma granzymes on combination treatment. Higher baseline plasma levels of myeloid-related markers (chemokine ligand 23/CCL23, colony-stimulating factor-1/macrophage colony-stimulating factor/CSF1) were associated with poor overall and progression-free survival, and lack of clinical benefit (defined as progressive or stable disease <6 months) following combination treatment (Kaplan-Meier, multivariate Cox, false discover rate <0.05). Patients with favorable outcomes had higher levels of activated T-cell markers (plasma ICOS-L, CD28) and exhibited spontaneous autoantibody titers to tumor antigen NY-ESO-1. Patients experiencing severe adverse events from the combination therapy had higher baseline levels of neutrophil-derived markers (CXCL1).ConclusionsOverall, this study highlights potential resistance and response mechanisms to nivolumab+cabozantinib and suggests prioritizing combination treatment in patients with activated T-cell immunogenicity profiles while exploring future combinatorial therapies targeting myeloid populations to overcome resistance.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Aged / Anilides - pharmacology / Anilides - therapeutic use / Antibody / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Biomarker / Biomarkers / Biomarkers, Tumor - blood / Biomarkers, Tumor - immunology / Cancer therapies / Cell death / Chemotherapy / Clinical trials / Combination therapy / Drug dosages / Drug Resistance, Neoplasm / Endometrial cancer / Endometrial Neoplasms - blood / Endometrial Neoplasms - drug therapy / Endometrial Neoplasms - immunology / Endometrial Neoplasms - pathology / FDA approval / Female / Genomes / Humans / Immune Checkpoint Inhibitor / Immune checkpoint inhibitors / Immunotherapy / Immunotherapy Biomarkers / Inhibitor drugs / Kinases / Medical prognosis / Middle Aged / Monoclonal antibodies / Neoplasm Recurrence, Local - drug therapy / Neoplasm Recurrence, Local - immunology / Next generation sequencing - NGS / Nivolumab - pharmacology / Nivolumab - therapeutic use / Original Research / Patients / Precision medicine / Proteins / Pyridines - pharmacology / Pyridines - therapeutic use / Targeted cancer therapy / Tumors