早期三阴性乳腺癌术前化疗＋英飞凡
三阴性乳腺癌三大受体（雌激素受体、孕激素受体、HER2）均为阴性，对内分泌治疗和HER2靶向治疗不佳，故全身治疗主要依靠化疗。杀伤型T淋巴细胞等免疫细胞具有抗肿瘤活性，有助提高化疗的病理完全缓解比例，而肿瘤细胞表面程序性死亡配体PD-L1与免疫细胞表面程序性死亡受体PD-1结合以后，可抑制免疫细胞的抗肿瘤活性，引起免疫逃避和化疗耐药。度伐利尤单抗（英飞凡）是完全人源化抗PD-L1单克隆抗体，可阻断PD-L1与PD-1结合，恢复免疫细胞抗肿瘤活性和肿瘤细胞化疗敏感性。
2021年2月8日，英国《自然》旗下《乳腺癌》在线发表美国耶鲁大学医学院的研究报告，探讨了早期三阴性乳腺癌术前度伐利尤单抗＋密集化疗的有效性和安全性。
NCT02489448: Single Arm Neoadjuvant Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) Concomitant With Weekly Nab-paclitaxel and Dose-dense Doxorubicin / Cyclophosphamide (ddAC) Chemotherapy for Clinical Stage I-III Triple Negative Breast Cancer
该单中心单组前瞻一期＋二期临床研究于2015年12月18日～2018年11月21日从美国耶鲁癌症中心入组I～III期三阴性乳腺癌术前患者60例，给予度伐利尤单抗＋密集化疗（每周白蛋白紫杉醇＋剂量密集多柔比星和环磷酰胺）。该研究主要终点为病理完全缓解（手术时病理检查发现浸润癌消失且淋巴结阴性）。根据美国西南肿瘤学组（SWOG）S0800研究结果，单用该密集化疗方案的病理完全缓解比例仅30%。该研究次要终点包括药物安全性、PD-L1表达水平、肿瘤间质浸润淋巴细胞计数。
结果，其中1例退出研究、7例完成一期临床研究（4例3mg/kg、3例10mg/kg）、52例完成二期临床研究（10mg/kg），故对59例进行毒性分析、对55例进行10mg/kg疗效分析。
一期临床研究未见限制剂量的毒性反应。
二期临床研究病理完全缓解比例为44%（95%置信区间：30%～57%）。
18例患者（31%）发生3～4级治疗相关不良事件，其中4例中性粒细胞减少和4例血红蛋白减少。3～4级免疫相关不良事件包括1例格林巴利综合征、2例结肠炎、2例高血糖。
50例患者的PD-L1水平可定性分析，其中31例（62%）PD-L1阳性。
病理完全缓解患者、残癌患者的PD-L1阳性比例分别为74%、52%（P=0.148）。
PD-L1阳性患者、PD-L1阴性患者的病理完全缓解比例分别为55%、32%（95%置信区间：0.38～0.71、0.12～0.56，P=0.15）。
52例患者的肿瘤间质浸润淋巴细胞可定量分析，病理完全缓解患者与残癌患者相比，肿瘤间质浸润淋巴细胞比例显著较高（中位20%比5%，P=0.0167）。
因此，该单中心小样本初步临床研究结果表明，对于早期三阴性乳腺癌术前患者，经过度伐利尤单抗＋密集化疗，将病理完全缓解比例提高至44%，PD-L1阳性患者更可达55%，病理完全缓解患者与残癌患者相比，肿瘤间质浸润淋巴细胞比例显著较高，故有必要进一步开展三期临床研究进行验证。
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NPJ Breast Cancer. 2021 Feb 8;7(1):9.
Neoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer.
Julia Foldi, Andrea Silber, Emily Reisenbichler, Kamaljeet Singh, Neal Fischbach, Justin Persico, Kerin Adelson, Anamika Katoch, Nina Horowitz, Donald Lannin, Anees Chagpar, Tristen Park, Michal Marczyk, Courtney Frederick, Trisha Burrello, Eiman Ibrahim, Tao Qing, Yalai Bai, Kim Blenman, David L. Rimm, Lajos Pusztai.
Yale School of Medicine, New Haven, CT, USA.
The goal of this Phase I/II trial is to assess the safety and efficacy of administering durvalumab concurrent with weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide (ddAC) neoadjuvant therapy for stages I-III triple-negative breast cancer. The primary endpoint is pathologic complete response (pCR:ypT0/is, ypN0). The response was correlated with PDL1 expression and stromal tumor-infiltrating lymphocytes (sTILs). Two dose levels of durvalumab (3 and 10 mg/kg) were assessed. PD-L1 was assessed using the SP263 antibody; ≥1% immune and tumor cell staining was considered positive; sTILs were calculated as the area occupied by mononuclear inflammatory cells over the total intratumoral stromal area. 59 patients were evaluable for toxicity and 55 for efficacy in the Phase II study (10 mg/kg dose). No dose-limiting toxicities were observed in Phase I. In Phase II, pCR rate was 44% (95% CI: 30-57%); 18 patients (31%) experienced grade 3/4 treatment-related adverse events (AE), most frequently neutropenia (n = 4) and anemia (n = 4). Immune-related grade 3/4 AEs included Guillain-Barre syndrome (n = 1), colitis (n = 2), and hyperglycemia (n = 2). Of the 50 evaluable patients for PD-L1, 31 (62%) were PD-L1 positive. pCR rates were 55% (95% CI: 0.38-0.71) and 32% (95% CI: 0.12-0.56) in the PD-L1 positive and negative groups (p = 0.15), respectively. sTIL counts were available on 52 patients and were significantly higher in the pCR group (p = 0.0167). Concomitant administration of durvalumab with sequential weekly nab-paclitaxel and ddAC neoadjuvant chemotherapy resulted in a pCR rate of 44%; pCR rates were higher in sTIL-high cancers.
DOI: 10.1038/s41523-021-00219-7