Pembrolizumab Combo Extends Chemotherapy Benefit in Pancreatic Cancer

Positive data from the phase IIa COMBAT clinical trial indicate that CXCR4 and PD-1 blockade with the combination of pembrolizumab (Keytruda) and BL-8040 (motixafortide) can improved upon the benefit of chemotherapy as treatment of pancreatic ductal adenocarcinoma (PDAC).¹

The COMBAT study (NCT02826486) is one of the first clinical trials to demonstrate a benefit for patients with metastatic pancreatic cancer with immunotherapy, according to the study authors.^1,2

This 4-year trial looked at 2 cohorts of patients: Cohort 1 received the combination after progressing on prior therapies and Cohort 2 received the regimen plus chemotherapy of 5-fluorouracil and nano-liposomal irinotecan after 1 line of chemotherapy.

“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 TGen, and one of the paper’s authors, said 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 if the response to therapy is high and if it is better in comparison to traditional treatment.”

In the prospective, open-label, phase 2a trial of this combination, 22 patients in Cohort 2 had an overall response rate of 32%, a disease control rate of 77%, and a median duration of response of 7.8 months in the preliminary results. There is expected to be about 40 patients total in this cohort at the time of follow-up.

For the intent-to-treat (ITT) population, out of the 37 patients in Cohort 1, 29 patients experienced a disease control rate of 34.5%. This included a partial response in 1 patient and stable disease in 9 patients. The median overall survival was 3.3 months in the ITT patients, and it was 7.5 months for those who received pembrolizumab and BL-8040 as a second-line treatment.

BL-8040, a CXCR4 antagonist, displayed a decrease in myeloid-derived suppressor cells in circulating regulatory T cells, and an increase in CD8+ effector T cell tumor infiltration for patients in Cohort 1.

“These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in pancreatic ductal adenocarcinomaand warrants confirmation in subsequent randomized trials,” the study authors concluded in their abstract.

In Cohort 1, patients received monotherapy of BL-8040 at 1.25 mg/kg subcutaneously on days 1 through 5 of the first week of treatment; after this, pembrolizumab was given at 200 mg every 3 weeks intravenously (IV) and BL-8040 was given 3 times a week from day 10 onwards subcutaneously. For patients in Cohort 2, treatment with pembrolizumab and BL-8040 was the same, but while receiving the combination, they also were given IV Onivyde® at 70 mg/m2 over 90 minutes followed by IV leucovorin at 400 mg/m2 over 30 minutes or according to local standard, followed by IV fluorouracil 2400 mg/m2 over 46 hours, every 2 weeks.

_References:

_{1. Bockorny B, Semenisty V, Macarulla, et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med. 2020;26:878-885. doi:10.1038/s41591-020-0880-x}

_{2. Combat study preliminary results show response of 32% in treatment of pancreatic tumors. News Release. TGen. August 11, 2020. Accessed August 12, 2020. https://bit.ly/3fOAjNF}