三陰性乳腺癌的雌激素受體、孕激素受體、人類(lèi)表皮生長(zhǎng)因子受體HER2均為陰性,，對(duì)內(nèi)分泌治療和HER2靶向治療無(wú)效,。臨床前研究表明,，血管內(nèi)皮生長(zhǎng)因子受體VEGFR-2抑制劑和多腺苷二磷酸核糖聚合酶PARP抑制劑可能使三陰性乳腺癌對(duì)免疫檢查點(diǎn)PD-1或PD-L1抑制劑敏感,。

　　2022年10月3日，英國(guó)生物醫(yī)學(xué)中心《醫(yī)學(xué)》在線發(fā)表哈爾濱醫(yī)科大學(xué)附屬腫瘤醫(yī)院張清媛,、北京大學(xué)腫瘤醫(yī)院邵彬,、李惠平、天津醫(yī)科大學(xué)腫瘤醫(yī)院佟仲生,、湖南省腫瘤醫(yī)院歐陽(yáng)取長(zhǎng),、恒瑞醫(yī)藥王昱婷、徐國(guó)英,、李少榮等學(xué)者的FZPL-Ib-105研究報(bào)告,，首次探討了PD-1抑制劑卡瑞利珠單抗＋VEGFR-2抑制劑阿帕替尼＋PARP抑制劑氟唑帕利聯(lián)合治療三陰性乳腺癌復(fù)發(fā)或轉(zhuǎn)移患者的耐受性、安全性和初步抗腫瘤活性,。

• 客觀緩解率：6.9%（95%置信區(qū)間：0.9～22.8）
• 疾病控制率：62.1%（95%置信區(qū)間：42.3～79.3）
• 無(wú)進(jìn)展生存：中位5.2個(gè)月（95%置信區(qū)間：3.6～7.3）
• 總體生存率：12個(gè)月64.2%（95%置信區(qū)間：19.0～88.8）

• 晚期三陰性乳腺癌雙靶治療新方案
• 三陰性乳腺癌一線四靶三聯(lián)新方案
  
• 三陰性乳腺癌一線雙靶三聯(lián)新方案
  
• 新見(jiàn)：晚期三陰性乳腺癌三艾療法
• 難治型三陰性乳腺癌分型精準(zhǔn)治療
  

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