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既往研究表明，對于雌激素受體、孕激素受體、人類表皮生長因子受體HER2均為陰性的三陰性乳腺癌，無論腫瘤血管內(nèi)皮生長因子受體VEGFR-2抑制劑，還是腫瘤細(xì)胞免疫檢查點(diǎn)程序性死亡蛋白PD-1或程序性死亡蛋白配體PD-L1抑制劑，單藥治療效果均不理想，客觀緩解比例僅5.2%～18.5%。臨床前研究表明，VEGFR-2抑制劑通過對腫瘤微環(huán)境重新編程，有助于乳腺癌對PD-1或PD-L1抑制劑敏感。不過，VEGFR-2抑制劑聯(lián)合PD-1或PD-L1抑制劑治療三陰性乳腺癌的臨床效果尚不明確。 2020年5月24日，國際癌癥免疫治療學(xué)會(huì)官方期刊、英國醫(yī)學(xué)會(huì)《英國醫(yī)學(xué)雜志》旗下《癌癥免疫治療雜志》在線發(fā)表中山大學(xué)孫逸仙紀(jì)念醫(yī)院劉潔瓊、劉強(qiáng)、李穎、李倩、蘇逢錫、姚和瑞、蘇士成、金亮、汪穎、恒瑞王泉人、香港中文大學(xué)威爾斯親王醫(yī)院劉允怡、解放軍總醫(yī)院第五醫(yī)學(xué)中心江澤飛、中國科學(xué)院宋爾衛(wèi)院士等學(xué)者的研究報(bào)告，探討了中國恒瑞原研新藥PD-1抑制劑卡瑞利珠單抗聯(lián)合VEGFR-2抑制劑阿帕替尼治療晚期三陰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) 該隨機(jī)雙組兩階段非盲非對照二期臨床研究于2018年1月～2019年4月從中山大學(xué)孫逸仙紀(jì)念醫(yī)院入組晚期三陰性乳腺癌少于三線全身治療患者40例，按1∶1隨機(jī)分為兩組，每14天靜脈注射卡瑞利珠單抗、連續(xù)或第1～7天間歇口服阿帕替尼，直至疾病進(jìn)展或出現(xiàn)無法耐受的毒性反應(yīng)。主要研究終點(diǎn)為客觀緩解比例。 結(jié)果，由于研究第一階段入組的10例阿帕替尼間歇給藥組患者均未客觀緩解，故其余30例均進(jìn)入阿帕替尼連續(xù)給藥組。 阿帕替尼連續(xù)與間歇給藥相比：
部分緩解患者與疾病穩(wěn)定或進(jìn)展或無法評估患者相比，中位無進(jìn)展生存顯著較長（8.3個(gè)月比2.0個(gè)月，95%置信區(qū)間：5.9～未達(dá)終點(diǎn)、1.7～3.0） 發(fā)生比例較高的不良事件包括谷草轉(zhuǎn)氨酶或谷丙轉(zhuǎn)氨酶升高和手足綜合征。 總體而言，連續(xù)給藥組和間歇給藥組≥3級不良事件發(fā)生比例分別為26.7%和20.0%。 對于連續(xù)給藥組患者，治療前腫瘤浸潤淋巴細(xì)胞比例>10%與≤10%相比：
因此，該初步研究結(jié)果表明，對于晚期三陰性乳腺癌患者，每14天靜脈注射卡瑞利珠單抗＋連續(xù)口服阿帕替尼雙靶聯(lián)合無化療方案與既往PD-1或PD-L1抑制劑單藥或阿帕替尼單藥治療相比，客觀緩解比例顯著較高，不良事件可控，治療前腫瘤浸潤淋巴細(xì)胞比例可以作為治療效果預(yù)測指標(biāo)，故有必要進(jìn)一步開展大樣本隨機(jī)對照三期臨床研究進(jìn)行驗(yàn)證。 此外，與其他尚未上市或者尚未進(jìn)入中國內(nèi)陸的靶向治療藥物相比，卡瑞利珠單抗已于2019年和2020年被中國內(nèi)陸批準(zhǔn)用于治療淋巴瘤和肝癌，阿帕替尼已于2014年被中國內(nèi)陸批準(zhǔn)用于治療胃癌或胃食管結(jié)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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