三靶向药物联合治疗三阴性乳腺癌

　　三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对内分泌治疗和HER2靶向治疗无效。临床前研究表明，血管内皮生长因子受体VEGFR-2抑制剂和多腺苷二磷酸核糖聚合酶PARP抑制剂可能使三阴性乳腺癌对免疫检查点PD-1或PD-L1抑制剂敏感。

　　2022年10月3日，英国生物医学中心《医学》在线发表哈尔滨医科大学附属肿瘤医院张清媛、北京大学肿瘤医院邵彬、李惠平、天津医科大学肿瘤医院佟仲生、湖南省肿瘤医院欧阳取长、恒瑞医药王昱婷、徐国英、李少荣等学者的FZPL-Ib-105研究报告，首次探讨了PD-1抑制剂卡瑞利珠单抗＋VEGFR-2抑制剂阿帕替尼＋PARP抑制剂氟唑帕利联合治疗三阴性乳腺癌复发或转移患者的耐受性、安全性和初步抗肿瘤活性。

FZPL-Ib-105 (NCT03945604): A Phase Ib, Open-labeled, Multi-center, Dose-exploring Trial of SHR-1210 (Anti-PD-1 Antibody) in Combination With Apatinib and Fluzoparib in Subjects With Recurrent and Metastatic Triple Negative Breast Cancer

　　该多中心单组非盲1b期临床研究包括剂量爬坡部分和剂量扩展部分。剂量爬坡部分为3＋3剂量递增方案。患者每28天接受卡瑞利珠单抗（每2周200毫克）＋阿帕替尼（每天375毫克或500毫克）＋氟唑帕利（起始剂量每天2次100毫克）。评估给药方案的耐受性和安全性后，确定剂量扩展部分的临床推荐剂量。主要终点为剂量限制性毒性。该研究未对BRCA、PD-1或PD-L1进行探索性分析。

　　结果，该研究于2019年6月4日至2020年8月25日共入组32例患者：3例患者接受卡瑞利珠单抗200毫克＋阿帕替尼375毫克＋氟唑帕利100毫克，29例患者接受卡瑞利珠单抗200毫克＋阿帕替尼500毫克＋氟唑帕利100毫克（临床推荐剂量），均未见剂量限制性毒性。

　　最常见的≥3级治疗相关不良事件为白细胞减少（20.7%）、高血压（13.8%）、中性粒细胞减少（10.3%）和谷草转氨酶升高（10.3%）。2例患者停止研究治疗，其中1例由于免疫性肝炎，另1例由于贫血、血小板减少、白细胞减少、谷丙转氨酶升高、谷草转氨酶升高和γ谷氨酰转移酶升高。1例患者死于不明原因。

　　对于29例卡瑞利珠单抗200毫克＋阿帕替尼500毫克＋氟唑帕利100毫克的患者：

• 客观缓解率：6.9%（95%置信区间：0.9～22.8）
• 疾病控制率：62.1%（95%置信区间：42.3～79.3）
• 无进展生存：中位5.2个月（95%置信区间：3.6～7.3）
• 总体生存率：12个月64.2%（95%置信区间：19.0～88.8）

　　因此，该研究结果表明，卡瑞利珠单抗＋阿帕替尼＋氟唑帕利对三阴性乳腺癌复发或转移患者安全性可控、客观缓解率较低、疾病控制率和无进展生存尚可，故有必要开展进一步研究优化该联合治疗的给药方案，并对相关靶点进行探索性分析。

相关链接

• 晚期三阴性乳腺癌双靶治疗新方案
• 三阴性乳腺癌一线四靶三联新方案
  
• 三阴性乳腺癌一线双靶三联新方案
  
• 新见：晚期三阴性乳腺癌三艾疗法
• 难治型三阴性乳腺癌分型精准治疗
  

BMC Med. 2022 Oct 3;20(1):321. IF: 11.150

A phase Ib study of camrelizumab in combination with apatinib and fuzuloparib in patients with recurrent or metastatic triple-negative breast cancer.

Zhang Q, Shao B, Tong Z, Ouyang Q, Wang Y, Xu G, Li S, Li H.

Harbin Medical University Cancer Hospital, Harbin, China; Peking University Cancer Hospital and Institute, Beijing, China; Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Hunan Cancer Hospital, Changsha, China; Jiangsu Hengrui Pharmaceuticals Co. Ltd., Shanghai, China.

BACKGROUND: Strategies to improve activity of immune checkpoint inhibitors for triple-negative breast cancer (TNBC) are needed. Preclinical studies showed that antiangiogenic agents and poly (ADP-ribose) polymerase (PARP) inhibitors might sensitize tumors to immunotherapy. Here, we investigated the tolerability, safety, and preliminary antitumor activity of camrelizumab, an anti-PD-1 antibody, in combination with apatinib, a vascular endothelial growth factor receptor-2 inhibitor, and fuzuloparib, a PARP inhibitor, in patients with recurrent or metastatic TNBC.

METHODS: This phase Ib study included a dose-finding part and a dose-expansion part. In the dose-finding part, a 3 + 3 dose escalation scheme was introduced. Patients were given camrelizumab (200 mg every 2 weeks) plus apatinib (375 mg or 500 mg once daily) and fuzuloparib (starting dose 100 mg twice daily) every 28-day cycle. After evaluation of the tolerability and safety of the dosing regimens, a clinical recommended dose was determined for the dose-expansion part. The primary endpoint was dose-limiting toxicity (DLT).

RESULTS: A total of 32 patients were enrolled. Three patients received camrelizumab 200 mg + apatinib 375 mg + fuzuloparib 100 mg, and 29 received camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg (clinical recommended dose). No DLTs were observed in either group. The most common grade ≥ 3 treatment-related adverse events were decreased white blood cell count (20.7%), hypertension (13.8%), decreased neutrophil count (10.3%), and increased aspartate aminotransferase (10.3%). Two patients discontinued study treatment due to immune-mediated hepatitis (n = 1) and anemia, decreased platelet count, decreased white blood cell count, increased alanine aminotransferase, increased aspartate aminotransferase, and increased γ-glutamyltransferase (n = 1). One patient died of unknown cause. Two (6.9% [95% CI, 0.9-22.8]) of 29 patients with camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg had objective response. The disease control rate was 62.1% (95% CI, 42.3-79.3). The median progression-free survival was 5.2 months (95% CI, 3.6-7.3), and the 12-month overall survival rate was 64.2% (95% CI, 19.0-88.8).

CONCLUSIONS: Combination of camrelizumab plus apatinib and fuzuloparib showed manageable safety profile and preliminary antitumor activity in patients with recurrent or metastatic TNBC.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03945604

KEYWORDS: Apatinib; Camrelizumab; Fuzuloparib; Immunotherapy; PARP; PD-1; TNBC; Triple-negative breast cancer; VEGFR

PMID: 36184642

DOI: 10.1186/s12916-022-02527-6