Pembrolizumab Plus BL-8040 Shows Promise in Pancreatic Cancer

Manuel Hidalgo, MD, PhD

The CXCR4 antagonist BL-8040 in combination with the PD-1 inhibitor pembrolizumab (Keytruda) showed promising survival data in a phase IIa trial of patients with metastatic pancreatic adenocarcinoma (NCT02826486). This study may serve as the gateway to immunotherapy for this population, according to lead investigator Manuel Hidalgo, MD, PhD.

Patients enrolled on the trial (n = 37) received 5 days of BL-8040 monotherapy followed by repeated 3-week cycles of pembrolizumab combined with BL-8040 every 3 weeks. At the time of report, which was presented at the 2018 ESMO Congress, 29 patients were evaluable. In the entire population, the median overall survival (OS) was 3.4 months, and 7.5 months for those who received at least 1 previous line of treatment.

OncLive: Can you please give an overview of this trial?

In an interview with OncLive, Hidalgo, professor of Medicine, Harvard Medical School, chief, Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, discussed the potential with BL-8040 and pembrolizumab in pancreatic adenocarcinoma.Hidalgo: This was a phase IIa trial of BL-8040, which is a CXCR4 inhibitor. By inhibiting this receptor, the drug facilitates the infiltration of T cells in the tumor. The trial was conducted in patients with advanced pancreatic cancer who had progressed after at least 1 prior line of chemotherapy. Many patients had more than 1 line [of treatment]. BL-8040 was given in combination with pembrolizumab. The idea behind this study is to prime the tumor by inhibiting CXCR4 signaling with BL-8040, allowing lymphocytes into the tumor, and then pembrolizumab is given with the intention to activate them to kill the tumor. Those are the basics.

What is the rationale for testing this agent in metastatic pancreatic adenocarcinoma?

Could you discuss the next phase in more detail?

Is there anything else you would like to mention about immunotherapy in pancreatic cancer?

The study is fully enrolled; we are seeing about a 33% disease control rate, with 1 patient having a very pronounced partial response. We have seen very nice biomarker data, meaning that BL-8040 is doing what it is supposed to do—both in peripheral blood, as well as in the tumor by infiltrating the tumor with lymphocytes in the biopsies that we have taken after treatment. In the group of patients who received the drug in the second-line setting, the median OS was 7.5 months, which is reasonable for a nonchemotherapy-containing regimen. We are now going to narrow the study with an amendment to enroll patients with second-line treatment in combination with chemotherapy.These patients have extremely poor prognosis, and it is one of the very few tumors in which immunotherapy has not made any positive impact. They are resistant to some of the checkpoint inhibitors, so there is a lot of interest in making tumors susceptible to checkpoint inhibitors. BL-8040 is one strategy, but there are others being studied. My impression is that at the end, we will need to combine several of them, including chemotherapy. This is clearly a step forward.These patients are going to be receiving the standard of care 5-fluorouracil and liposomal irinotecan. On top of that, we are going to add BL-8040 and pembrolizumab. It is a very complex 4-drug combination, which we hope will not create a lot of toxicity, but impact the outcome. The end of this study, which will enroll 40 patients, will serve as the basis for our registration randomized trial. This study is a good opportunity for patients with chemotherapy-refractory pancreatic cancer.Immunotherapy in pancreatic cancer is still in early stages. Thus far, the things that we have tried have not worked as they have in other tumor times. However, this is not the only tumor type in which immunotherapy is not very effective. Clearly, there is a lot of interest in understanding why. There are a number of different strategies trying to sort out why, where we can potentially take advantage of that for clinical trials. It is a very exciting area of research that I hope will result in some meaningful clinical applications.

Hidalgo M, Epelbaum R, Wolpin BM, et al. A Phase 2a trial to assess the safety and efficacy of BL-8040 and pembrolizumab in patients with metastatic pancreatic adenocarcinoma (PDAC). Ann Oncol. 2018;29(8). doi: 10.1093/annonc/mdy288.006.