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BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial.
- Source :
-
Nature medicine [Nat Med] 2020 Jun; Vol. 26 (6), pp. 878-885. Date of Electronic Publication: 2020 May 25. - Publication Year :
- 2020
-
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 <superscript>+</superscript> 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.
- Subjects :
- Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized administration & dosage
Antineoplastic Agents, Immunological
CD8-Positive T-Lymphocytes pathology
Carcinoma, Pancreatic Ductal pathology
Carcinoma, Pancreatic Ductal secondary
Female
Fluorouracil administration & dosage
Humans
Irinotecan administration & dosage
Leucovorin administration & dosage
Liver Neoplasms secondary
Lung Neoplasms secondary
Lymph Nodes pathology
Lymphatic Metastasis
Lymphocytes, Tumor-Infiltrating pathology
Male
Middle Aged
Myeloid-Derived Suppressor Cells pathology
Pancreatic Neoplasms pathology
Peptides administration & dosage
Peritoneal Neoplasms secondary
Receptors, CXCR4 antagonists & inhibitors
Retroperitoneal Neoplasms secondary
Survival Rate
T-Lymphocytes, Regulatory pathology
Treatment Outcome
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Carcinoma, Pancreatic Ductal drug therapy
Liver Neoplasms drug therapy
Lung Neoplasms drug therapy
Pancreatic Neoplasms drug therapy
Peritoneal Neoplasms drug therapy
Retroperitoneal Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1546-170X
- Volume :
- 26
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Nature medicine
- Publication Type :
- Academic Journal
- Accession number :
- 32451495
- Full Text :
- https://doi.org/10.1038/s41591-020-0880-x