联合血管生成和 PD-1 抑制治疗免疫调节性三阴性乳腺癌：FUTURE-C-Plus 试验的概念探索和生物标志物分析。
Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial.
机构信息
Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
出版信息
Mol Cancer. 2022 Mar 25;21(1):84. doi: 10.1186/s12943-022-01536-6.
BACKGROUND
Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients.
METHODS
We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes.
RESULTS
CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival.
CONCLUSION
This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.
背景
免疫检查点抑制剂在三阴性乳腺癌（TNBC）中具有显著疗效；然而，它们仅使一部分患者受益，这凸显了需要共同靶向替代途径并选择最佳患者的必要性。在此，我们研究了更有可能从免疫治疗中获益的患者亚群，并为 TNBC 患者提供了更有效的联合治疗方案。
方法
我们在 FUSCC 队列中进行了探索性分析，以确定一种新的 TNBC 免疫治疗患者选择方法和作用靶点。我们在体内进行了研究，并启动了一项 2 期试验，以评估此类标准和联合方案的临床价值。此外，我们收集了临床病理和下一代测序数据，以阐明患者结局的生物标志物。
结果
CD8 阳性可识别出 TNBC 中具有更高免疫治疗获益可能性的免疫调节亚群，而血管生成是促进检查点阻断的作用靶点。我们开展了 2 期 FUTURE-C-Plus 试验，以评估在晚期免疫调节性 TNBC 患者中联合使用法米替尼（一种血管生成抑制剂）、卡瑞利珠单抗（一种 PD-1 单克隆抗体）和化疗的可行性。在入组的 48 例患者中，客观缓解率为 81.3%（95%CI，70.2-92.3），中位无进展生存期为 13.6 个月（95%CI，8.4-18.8）。无治疗相关死亡报告。CD8-和/或 PD-L1-阳性肿瘤的患者从该方案中获益更多。PKD1 体细胞突变提示无进展生存期和总生存期更差。
结论
本研究证实了三联方案在免疫调节性 TNBC 中的疗效和安全性，并揭示了联合 CD8、PD-L1 和体细胞突变以指导临床决策和治疗的潜力。
临床试验注册
ClinicalTrials.gov：NCT04129996。于 2019 年 10 月 11 日注册。
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