TY - JOUR
T1 - BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer
T2 - the COMBAT trial
AU - Bockorny, Bruno
AU - Semenisty, Valerya
AU - Macarulla, Teresa
AU - Borazanci, Erkut
AU - Wolpin, Brian M.
AU - Stemmer, Salomon M.
AU - Golan, Talia
AU - Geva, Ravit
AU - Borad, Mitesh J.
AU - Pedersen, Katrina S.
AU - Park, Joon Oh
AU - Ramirez, Robert A.
AU - Abad, David G.
AU - Feliu, Jaime
AU - Muñoz, Andres
AU - Ponz-Sarvise, Mariano
AU - Peled, Amnon
AU - Lustig, Tzipora M.
AU - Bohana-Kashtan, Osnat
AU - Shaw, Stephen M.
AU - Sorani, Ella
AU - Chaney, Marya
AU - Kadosh, Shaul
AU - Vainstein Haras, Abi
AU - Von Hoff, Daniel D.
AU - Hidalgo, Manuel
N1 - Funding Information:
We thank the patients and their families for their participation in this study. This work was supported by BioLineRx and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Kenilworth, NJ, USA). Flow cytometry acquisition was performed at Sheba Medical Center (Tel HaShomer, Ramat Gan, Israel). MultiOmyx tests and analysis were performed at Neogenomics Laboratories (Aliso Viejo, CA, USA). The sponsor BioLineRx participated in the conception of this study. Data were analyzed and interpreted by BioLineRx in collaboration with the academic authors. The sponsor staff, M.H. and B.B., had access to all of the data. All authors vouch for the accuracy and completeness of the data and analyses reported and for the fidelity of the study to the protocol.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085302071&partnerID=8YFLogxK
U2 - 10.1038/s41591-020-0880-x
DO - 10.1038/s41591-020-0880-x
M3 - Article
C2 - 32451495
AN - SCOPUS:85085302071
SN - 1078-8956
VL - 26
SP - 878
EP - 885
JO - Nature Medicine
JF - Nature Medicine
IS - 6
ER -