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既往研究表明，对于雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性的三阴性乳腺癌，无论肿瘤血管内皮生长因子受体VEGFR-2抑制剂，还是肿瘤细胞免疫检查点程序性死亡蛋白PD-1或程序性死亡蛋白配体PD-L1抑制剂，单药治疗效果均不理想，客观缓解比例仅5.2%～18.5%。临床前研究表明，VEGFR-2抑制剂通过对肿瘤微环境重新编程，有助于乳腺癌对PD-1或PD-L1抑制剂敏感。不过，VEGFR-2抑制剂联合PD-1或PD-L1抑制剂治疗三阴性乳腺癌的临床效果尚不明确。 2020年5月24日，国际癌症免疫治疗学会官方期刊、英国医学会《英国医学杂志》旗下《癌症免疫治疗杂志》在线发表中山大学孙逸仙纪念医院刘洁琼、刘强、李颖、李倩、苏逢锡、姚和瑞、苏士成、金亮、汪颖、恒瑞王泉人、香港中文大学威尔斯亲王医院刘允怡、解放军总医院第五医学中心江泽飞、中国科学院宋尔卫院士等学者的研究报告，探讨了中国恒瑞原研新药PD-1抑制剂卡瑞利珠单抗联合VEGFR-2抑制剂阿帕替尼治疗晚期三阴性乳腺癌的有效性和安全性。 NCT03394287: A Phase II, Open-labeled, Randomised, Non-comparative, Two-arms Investigator-initiated Clinical Trial of SHR-1210 (Anti-PD-1 Antibody) in Combination With Apatinib in Subjects With Advanced Triple Negative Breast Cancer (SHR-1210-APTN-IIT-TNBC) 该随机双组两阶段非盲非对照二期临床研究于2018年1月～2019年4月从中山大学孙逸仙纪念医院入组晚期三阴性乳腺癌少于三线全身治疗患者40例，按1∶1随机分为两组，每14天静脉注射卡瑞利珠单抗、连续或第1～7天间歇口服阿帕替尼，直至疾病进展或出现无法耐受的毒性反应。主要研究终点为客观缓解比例。 结果，由于研究第一阶段入组的10例阿帕替尼间歇给药组患者均未客观缓解，故其余30例均进入阿帕替尼连续给药组。 阿帕替尼连续与间歇给药相比：
部分缓解患者与疾病稳定或进展或无法评估患者相比，中位无进展生存显著较长（8.3个月比2.0个月，95%置信区间：5.9～未达终点、1.7～3.0） 发生比例较高的不良事件包括谷草转氨酶或谷丙转氨酶升高和手足综合征。 总体而言，连续给药组和间歇给药组≥3级不良事件发生比例分别为26.7%和20.0%。 对于连续给药组患者，治疗前肿瘤浸润淋巴细胞比例>10%与≤10%相比：
因此，该初步研究结果表明，对于晚期三阴性乳腺癌患者，每14天静脉注射卡瑞利珠单抗＋连续口服阿帕替尼双靶联合无化疗方案与既往PD-1或PD-L1抑制剂单药或阿帕替尼单药治疗相比，客观缓解比例显著较高，不良事件可控，治疗前肿瘤浸润淋巴细胞比例可以作为治疗效果预测指标，故有必要进一步开展大样本随机对照三期临床研究进行验证。 此外，与其他尚未上市或者尚未进入中国内陆的靶向治疗药物相比，卡瑞利珠单抗已于2019年和2020年被中国内陆批准用于治疗淋巴瘤和肝癌，阿帕替尼已于2014年被中国内陆批准用于治疗胃癌或胃食管结合部癌。 Efficacy and safety of camrelizumab combined with apatinib in advanced triple-negative breast cancer: an open-label phase II trial. Liu J, Liu Q, Li Y, Li Q, Su F, Yao H, Su S, Wang Q, Jin L, Wang Y, Lau WY, Jiang Z, Song E. Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Jiangsu Hengrui Medicine Co., Ltd, Jiangsu, China; Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hongkong, China; The Fifth Medical Centre of Chinese PLA General Hospital, Beijing, China; Guangzhou Institue of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. 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 KEYWORDS: breast neoplasms; clinical trials, phase II as topic; immunotherapy; programmed cell death 1 receptor. PMID: 32448804 DOI: 10.1136/jitc-2020-000696
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