美国纽约长老会医院Manuel Hidalgo研究团队，评估了CXCR4拮抗剂BL-8040联合派姆单抗化疗及化疗，在胰腺癌治疗中的作用。相关论文于2020年5月25日发表在《自然—医学》杂志上。

他们进行了一项IIa期、开放标签的两组研究，以评估CXC趋化因子受体4（CXCR4）拮抗剂BL-8040（莫替卡福特）与派姆单抗和化疗在转移性胰腺导管腺癌（PDAC）（NCT02826486）中的安全性、疗效和免疫生物学作用。主要结果是客观缓解率（ORR）。次要结果是总生存期（OS）、疾病控制率（DCR）和安全性。

在第一组中，对37例化疗耐药的患者进行了BL-8040和派姆单抗给药处理。在可评估人群中，DCR为34.5％（改良治疗意图，mITT； N = 29），包括9例病情稳定的患者（31％）和1例部分缓解的患者（3.4％）。ITT人群的OS中位数（mOS）为3.3个月。值得注意的是，在接受研究药物作为二线治疗的患者中，mOS为7.5个月。BL-8040增加CD8 +效应T细胞肿瘤浸润，减少髓样来源的抑制细胞（MDSCs），并进一步减少循环调节性T细胞。

在第二组中，有22名患者接受了BL-8040和派姆单抗的化疗，其ORR、DCR和中位反应持续时间分别为32％、77％和7.8个月。这些数据表明，联合使用CXCR4和程序性细胞死亡1（PD-1）阻断剂可以扩大PDAC化疗的获益，并在随后的随机试验中得到证实。

研究人员表示，PD-1抑制剂在PDAC中的作用有限，强调了需要共同靶向替代途径。在PDAC小鼠模型中，CXCR4阻滞促进T细胞肿瘤浸润，并且与抗PD-1治疗具有协同作用。

附：英文原文

Title: BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial

Author: Bruno Bockorny, Valerya Semenisty, Teresa Macarulla, Erkut Borazanci, Brian M. Wolpin, Salomon M. Stemmer, Talia Golan, Ravit Geva, Mitesh J. Borad, Katrina S. Pedersen, Joon Oh Park, Robert A. Ramirez, David G. Abad, Jaime Feliu, Andres Muoz, Mariano Ponz-Sarvise, Amnon Peled, Tzipora M. Lustig, Osnat Bohana-Kashtan, Stephen M. Shaw, Ella Sorani, Marya Chaney, Shaul Kadosh, Abi Vainstein Haras, Daniel D. Von Hoff, Manuel Hidalgo

Issue&Volume: 2020-05-25

Abstract: Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N=29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8+ effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.

DOI: 10.1038/s41591-020-0880-x

Source: https://www.nature.com/articles/s41591-020-0880-x