Drug Development Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Department of Obstetrics and Gynecology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Illinois, USA.
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-004233.
Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling.
In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored.
Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009).
Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.
联合免疫疗法和抗血管生成药物是子宫内膜癌有前途的治疗策略。迄今为止，尚未确定反应的生物标志物，并且缺乏免疫治疗后进展的数据。我们探索了在免疫治疗初治的子宫内膜癌患者和以前免疫治疗后疾病进展的患者中，使用检查点抑制剂（nivolumab）和抗血管生成药物（cabozantinib）联合治疗，并对基线活检进行免疫分析。
在这项 II 期试验（ClinicalTrials.gov NCT03367741，于 2017 年 12 月 11 日注册）中，患有复发性子宫内膜癌的女性按 2:1 的比例随机分配至 nivolumab 联合 cabozantinib（A 组）或 nivolumab 单药治疗（B 组）。主要终点是实体瘤反应评估标准定义的无进展生存期（PFS）。患有癌肉瘤或先前免疫检查点抑制剂的患者接受联合治疗（C 组）。对基线活检和连续外周血单核细胞（PBMC）样本进行分析，并探讨患者结局与 CyTOF 和 PBMC 免疫数据之间的关联。
A 组（n=36）的中位 PFS 为 5.3 个月（90%CI 3.5 至 9.2），B 组（n=18）为 1.9 个月（90%CI 1.6 至 3.4）（HR=0.59，90%CI 0.35 至 0.98；log-rank p=0.09，符合预设的统计学显著性标准）。A 组最常见的治疗相关不良事件是腹泻（50%）和肝酶升高（天冬氨酸氨基转移酶 47%，丙氨酸氨基转移酶 42%）。在 A 组（n=40）中进行了全面的基线 CyTOF 分析，鉴定出 35 种免疫细胞亚群。在 C 组中接受过免疫治疗的患者中，非进展者的活化组织驻留（CD103+CD69+）γδ T 细胞比例显著高于进展者（调整后的 p=0.009）。
在经过大量预处理的子宫内膜癌患者中，加用 cabozantinib 可显著改善 nivolumab 的疗效。通过基线免疫谱确定的亚组患者可能受益于与抗血管生成药物联合治疗，需要进一步研究。
