BACKGROUND Previous trials showed that antiangiogenesis or anti-programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) monotherapy only showed marginal effect in triple-negative breast cancer (TNBC). Preclinical studies demonstrated that antiangiogenic therapy could sensitize breast cancer to PD-1/PD-L1 blockade via reprogramming tumor microenvironment. Combinational treatment of checkpoint blockade and antiangiogenesis for TNBC has not been reported. METHODS Patients with advanced TNBC with less than three lines of systemic therapy were enrolled in an open-label, non-comparative, two-arm, phase II trial at Sun Yat-sen Memorial Hospital. Camrelizumab (intravenously every 2 weeks) with apatinib orally at either continuous dosing (d1-d14) or intermittent dosing (d1-d7) was given until disease progression or unacceptable toxicities. Primary endpoint was objective response rate (ORR). RESULTS From January 2018 to April 2019, 40 patients were enrolled, including 10 in the apatinib intermittent dosing cohort and 30 in the apatinib continuous dosing cohort. The ORR was 43.3% (13 of 30) in the continuous dosing cohort, while no objective response was observed in the intermittent dosing cohort. The disease control rate was 63.3% (19 of 30) in the apatinib continuous dosing cohort, and 40.0% (4 of 10) in the apatinib intermittent dosing cohort, respectively. The median progression-free survival (PFS) was 3.7 (95% CI 2.0 to 6.4) months and 1.9 (95% CI 1.8 to 3.7) months in the continuous dosing and intermittent dosing cohort, respectively. In the continuous dosing cohort, the median PFS of patients with partial response (8.3 months, 95% CI 5.9 to not reached) was significantly longer than that of patients with stable disease/progressive disease/not evaluable (2.0 months, 95% CI 1.7 to 3.0). The most common adverse events (AEs) included elevated aspartate aminotransferase/alanine aminotransferase and hand-foot syndrome. Overall, 26.7% and 20.0% of patients experienced grade ≥3 AEs in the continuous dosing and intermittent dosing cohort, respectively. In the continuous dosing cohort, a high percentage of baseline tumor-infiltrating lymphocytes (>10%) was associated with higher ORR and favorable PFS (p=0.029, 0.054, respectively). CONCLUSIONS The ORR by this chemo-free regimen was dramatically higher than previously reported ORR by anti-PD-1/PD-L1 antibody or apatinib monotherapy. Camrelizumab combined with apatinib demonstrated favorable therapeutic effects and a manageable safety profile in patients with advanced TNBC. TRIAL REGISTRATION NUMBER NCT03394287.

中文翻译：

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卡雷珠单抗联合阿帕替尼治疗晚期三阴性乳腺癌的疗效和安全性：一项开放性II期临床试验。

背景技术以前的研究表明，抗血管生成或抗程序死亡蛋白1 /程序死亡配体1（PD-1 / PD-L1）单一疗法仅在三阴性乳腺癌（TNBC）中显示出边缘作用。临床前研究表明，抗血管生成治疗可通过重新编程肿瘤微环境使乳腺癌对PD-1 / PD-L1阻断敏感。尚未报道TNBC检查站封锁和抗血管生成的联合治疗。方法在中山纪念医院进行了一项少于三行系统治疗的晚期TNBC患者，参加了一项开放性，非对照，两臂II期试验。在连续给药（d1-d14）或间歇给药（d1-d7）口服阿米替尼的卡雷珠单抗（每2周静脉注射一次），直至疾病进展或出现不可接受的毒性。主要终点为客观缓解率（ORR）。结果从2018年1月至2019年4月，共有40例患者入组，其中10例在阿帕替尼间歇给药组中，30例在阿帕替尼连续给药组中。在连续给药组中，ORR为43.3％（30分中的13分），而在间歇给药组中未观察到客观反应。阿帕替尼连续给药组的疾病控制率分别为63.3％（30分之19）和阿帕替尼间歇给药组的疾病控制率分别为40.0％（10分之4）。在连续给药组和间歇给药组中，中位无进展生存期（PFS）分别为3.7（95％CI 2.0至6.4）个月和1.9（95％CI 1.8至3.7）个月。在连续给药组中，部分缓解患者的中位PFS（8.3个月，95％CI 5。9到未达到）显着长于病情稳定/进行性疾病/无法评估的患者（2.0个月，95％CI 1.7至3.0）。最常见的不良事件（AE）包括天冬氨酸转氨酶/丙氨酸转氨酶升高和手足综合征。总体而言，在连续给药和间歇给药组中，分别有26.7％和20.0％的患者经历≥3级AE。在连续给药组中，高百分比的基线肿瘤浸润淋巴细胞（> 10％）与较高的ORR和良好的PFS相关（分别为p = 0.029、0.054）。结论采用这种无化学疗法的ORR显着高于先前报道的抗PD-1 / PD-L1抗体或apatinib单药治疗的ORR。卡那利珠单抗联合阿帕替尼在晚期TNBC患者中显示出良好的治疗效果和可控的安全性。试用注册号NCT03394287。