The CXCR4 antagonist BL-8040 in combination with the PD-1 inhibitor pembrolizumab has been shown to elicit encouraging responses in patients with pancreatic ductal adenocarcinoma.
Erkut Borazanci, MD, MS
The CXCR4 antagonist BL-8040 (motixafortide) in combination with the PD-1 inhibitor pembrolizumab (Keytruda) has been shown to elicit encouraging responses in patients with pancreatic ductal adenocarcinoma (PDAC), according to updated data from the phase 2a COMBAT trial (NCT02826486) published in Nature Medicine.1
Thirty-seven patients with chemotherapy-resistant disease were enrolled to cohort 1; in 29 evaluable patients (modified intention-to-treat [mITT] population), treatment with the doublet resulted in a disease control rate (DCR) of 34.5%; 31% of these patients experienced stable disease (n = 9) and 3.4% achieved a partial response (n = 1).
Twenty-two patients were given BL-8040 in combination with pembrolizumab and chemotherapy (cohort 2). Results showed an objective response rate of 32%, a DCR of 77%, and a median duration of response of 7.8 months with the triplet.
“The percentage of meaningful tumor shrinkage was 32% in cohort 2, which is double what is available for individuals with pancreatic cancer with traditional chemotherapy,” Erkut Borazanci, MD, MS, a medical oncologist and physician-investigator at HonorHealth Research Institute, a clinical associate professor at the Translational Genomics Research Institute, and an author on the paper, stated in a press release.2 “While the study is small, these preliminary results are encouraging, and there is hope that we will be able to do larger trials to see whether the response to therapy is high and whether it is better in comparison with traditional treatment.”
Previous data have suggested that PD-1 inhibitors have a limited effect in PDAC, which has led investigators to seek methods to co-target alternative pathways. CXCR4 blockade has not only been shown to encourage T-cell tumor infiltration, but it is also proven to be synergistic when paired with anti–PD-1 therapy in PDAC mouse models.
In the prospective, open label, phase 2a clinical trial, investigators set out to examine the efficacy, safety, and immunobiological effects of BL-8040 with pembrolizumab and chemotherapy in patients with metastatic PDAC.3
To be eligible for enrollment, patients had to be 18 years of age or older; have histologically confirmed metastatic unresectable pancreatic adenocarcinoma, including with intraductal papillary mucinous neoplasm; have measurable disease per RECIST v1.1 criteria; have received previous lines of treatment; have an ECOG performance status of 0 to 1; a life expectancy of at least 3 months; and acceptable organ function.
If patients had a pancreatic tumor other than adenocarcinoma, active infection requiring systemic therapy, a known additional malignancy that was progressing or needs active treatment, and a disease suitable for curative-intent treatment, they were not permitted to participate.
The primary end point of the trial was ORR, while key secondary end points included ORR assessed by imaging in accordance with Immune-related Response Evaluation Criteria in Solid Tumors, overall survival (OS), DCR, and safety.
In cohort 1, patients received BL-8040 monotherapy for the duration of 5 days followed by combination treatment with BL-8040 and pembrolizumab. During the monotherapy period of treatment, eligible participants received daily subcutaneous injections of the CXCR4 antagonist on days 1 to 5. On day 8, participants began the combination treatment, which was comprised of subcutaneous BL-8040 given three times weekly and pembrolizumab once every 3 weeks. Combination treatment continued for up to 35 cycles of pembrolizumab, until disease progression, clinical deterioration, or early termination of treatment, whichever came first.
In cohort 2, patients who had progressed on first-line therapy with gemcitabine-based chemotherapy received single-agent BL-8040 for 5 days followed by BL-8040, pembrolizumab, and chemotherapy. These patients received the same treatment as those in cohort 1 for the monotherapy treatment period. On day 8, patients received intravenous (IV) nanoliposomal irinotecan (Onivyde) followed by IV leucovorin, followed by IV 5-fluourouracil every 2 weeks. Pembrolizumab was administered every 3 weeks and BL-8040 was given twice weekly.
When used in cohort 1, investigators observed that the combination therapy was able to work in tandem with the immune systems, according to the release. This is significant, as previous studies have indicated that immunotherapies such as pembrolizumab have not previously been able to impact these “cold” cancers.
Additional data showed that the median OS in the ITT population within cohort 1 was 3.3 months with BL-8040/pembrolizumab. Moreover, those who received the regimen within the second-line setting experienced an even longer median OS of 7.5 months. The CXCR4 antagonist was also found to enhance CD8-positive effector T-cell tumor infiltration, decrease myeloid-derived suppressor cells, and further reduce circulating regulatory T cells.
The findings warrant further confirmation through subsequent randomized trials, according to the study authors. The COMBAT trial is within its follow-up phase with more data anticipated.
Previous data from the phase 2a trial presented during the 2018 ESMO Congress showed a median OS of 3.4 months in the entire population and a median OS of 7.5 months in those whp received at least 1 prior line of therapy.4