目的：在上皮性卵巢癌（EOC）患者中，肿瘤内T细胞计数增加与较好的预后相关，为纳武单抗等PD-1抑制剂的联合使用提供了理论依据。本研究探索了纳武单抗联合卡铂+紫杉醇周疗新辅助方案治疗EOC。首要终点是通过剂量限制性毒性（DLTs）来评价治疗安全性和耐受性。次要终点包括完全清除率（CGR）、化疗反应评分（CRS）、无进展生存期（PFS）、总生存期及一系列转化性参数。
Method: Patients with FIGO stage 3–4 EOC who were judged to be candidates for neoadjuvant chemotherapy with interval debulking surgery (IDS) were eligible. Patients were treated with IV weekly paclitaxel (80 mg/m2), with carboplatin (AUC6) and nivolumab (360 mg) given q3 weeks. Three to six cycles were allowed prior to surgery, for a total of 6–8 cycles. After completion of chemotherapy, maintenance nivolumab could be continued for 1 year. Adverse events were graded as per CTCAE v4.0. The CRS (from 1 to 3) was graded at time of IDS as previously published. Multiplexed immunofluorescence (IF) was performed on pre- and post-treatment tumor samples.
方法：研究选择FIGO III/IV期、适用于新辅助化疗和间歇性减瘤术（IDS）治疗的EOC患者。每周静脉注射紫杉醇（80mg/m2）联合每3周给予卡铂（AUC6）和纳武单抗（360mg）治疗。允许术前3-6个周期、总计6-8个周期的化疗。化疗结束后，可持续使用纳武单抗至1年。按CTCAE v4.0标准记录不良反应。行间歇性减瘤术时评估化疗反应评分（1-3分）（结果已发表）。还会对治疗前后的肿瘤标本进行多重免疫荧光检测。
Results: A total of 21 patients were enrolled; median age was 64 years (range 38–77 years); the majority were white (81%) with high-grade serous histology (90%) and stage IV disease (67%). One patient was replaced given G3 infusion reaction with cycle 1. Therapy was well tolerated; two patients (9.5%) had DLTs that delayed IDS, including G4 pneumonitis and G4 myositis. Other grade 3–4 adverse events attributed to nivolumab included rash (10%), fever (5%), and fatigue (5%); 19% of patients had G2 hypothyroidism; 90% achieved an optimal CGR; 35% had a CRS of 3. Median PFS has not been reached; 71.9% of patients are progression free at 1 year with a median follow-up of 14.3 months (6.3–19.8). All patients remain alive. Treatment was associated with tumor microenvironment conversion to an “inflamed” phenotype, with a significant increase in percentage CD8+ T cells (P = 0.0002) (Figure 1).
结果：共纳入21例患者，中位年龄64岁（38～77岁），白种人为主（81%），多数是高级别浆液性癌（90%）并处于IV期（67%）。一名患者在第一个周期治疗中发生3级输液反应后被替换出组。治疗耐受性良好：2例患者（9.5%）出现剂量限制性毒性（4级肺炎，4级肌炎），推迟了IDS。由纳武单抗引起的其他3-4级不良事件包括：皮疹（10%）、发热（5%）、疲乏（5%）；19%的患者出现2级甲减；90%患者达到最佳CGR；35%患者的CRS评分为3分。中位PFS尚未达到；71.9%的患者在1年内无进展，中位随访时间14.3个月（6.3-19.8月）。所有患者都健在。治疗与肿瘤微环境向“炎症型”表型转化有关，CD8+ T细胞百分比显著增加（P=0.0002）（图1）。
Conclusion: In a high-risk population of EOC patients, the addition of nivolumab to upfront chemotherapy led to promising PFS and favorable changes in the tumor microenvironment.
结论：在EOC高危人群中，前期化疗加用纳武单抗有利于PFS获益和肿瘤微环境的改善。
