CD40 Agonist Plus Chemotherapy Hypothesized to Improve Outcomes in Metastatic PDAC

SEA-CD40, an investigational monoclonal antibody against CD40, is being evaluated in phase 1 study in combination with gemcitabine, nab-paclitaxel, and pembrolizumab (Keytruda) as a potential treatment option for patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

According to a poster presented during the American Society of Clinical Oncology (ASCO) Virtual Scientific Program, the standard treatment for metastatic PDAC in the frontline setting is gemcitabine plus nab-paclitaxel, and the objective response rate (ORR) observed with this combination historically is about 23%. The median survival is only 8.5 months, showing poor outcomes overall.

Effector T cells are not properly infiltrated in metastatic PDAC, and based on this disease characteristic, chemotherapy in combination with PD-1 blockade is likely ineffective in enabling immune response in these patients. However, preclinical data indicate that chemotherapy and a CD40 agonist can lead T cell-dependent destruction, which induces durable remissions. This belief severed as the rationale for the phase 1 study of SEA-CD40 plus gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic PDAC.

In an interview with Targeted Oncology, Andrew L. Coveler, MD, oncologist, Seattle Cancer Care Alliance and University of Washington Medical Center, and associate professor, Medicine and Oncology, University of Washington, discussed the phase 1 trial study of SEA-CD40 combined with a chemotherapy regimen, which he recently presented during the ASCO Virtual Scientific Program.

TARGETED ONCOLOGY: Can you provide background on the phase 1 study of SEA-CD40 with gemcitabine, nab-paclitaxel, and pembrolizumab in patients with PDAC?

Coveler: First, this is a trial in progress. SEA-CD40 is an agent, which is going to try and stimulate the immune system. Pancreas cancer is classically a cold tumor and immunotherapy has had minimal efficacy for the treatment of this disease, unlike many others. The idea is that you need to stimulate the immune system to drive into the cancer cells. Then, you use the checkpoint inhibitors such as pembrolizumab, which has been successful in other diseases, to try and unleash the immune response.

In this study, [pembrolizumab] is being combined with chemotherapy with the idea that you will have synergy for killing off the cancer cells, as the immune system then comes in to clean up the damage that was done by the chemotherapy; the CD40 agent will stimulate the immune response, then you would use a checkpoint inhibitor such as pembrolizumab to really unleash those T cells that you just generated.

TARGETED ONCOLOGY: What data have we seen prior to this that you'd like to discuss?

Coveler: A study on the SEA-CD40 agent was presented at ASCO 2018, which had various solid tumors, and it is probably most useful and applicable to look at the adverse events, which are mostly infusion-related reactions. Unlike some medications, this infusion reaction is more driven by the immune response generated by the drug as it is administered to patients. It's stimulating the immune response in patients, and that can drive an infusion-related reaction.

TARGETED ONCOLOGY: Can you explain the study design?

Coveler: This is a phase 1 trial that is being studied in the first-line setting for patients with newly diagnosed untreated metastatic disease. Gemcitabine and nab-paclitaxel are administered, as usual, on days 1, 8, and 15. SEA-CD40 is administered on day 3 by intravenous infusion, and pembrolizumab is starting on day 8 of cycle 1 and given every 6 weeks.

The main criterion is to have no prior systemic therapy for stage VI pancreatic ductal adenocarcinoma. However, if a patient received adjuvant treatment and then have had their cancer come back, they would be able enroll in this study. Otherwise, patients need measurable disease, which most patients have. For most laboratories, patients are required to get chemotherapy.

TARGETED ONCOLOGY: What is historically known about the safety and efficacy of this drug?

Coveler: The toxicities of these drugs do not overlap based on previously publishedinformation for SEA-CD40. The chemotherapy causes the well-known standard chemotherapy-based effects, and pembrolizumab has standard risks for autoimmune diseases. They all add up to different things.

TARGETED ONCOLOGY: What is the key takeaway?

Coveler: I think the main thing to realize is that everyone has been trying to bring immunotherapy to pancreas cancer and has not been successful many times. When we just combine the checkpoint inhibitors like pembrolizumab and the SEA-CD40 agent, this is trying to turn a cold tumor into a hot tumor. I think the idea is definitely a good one. We are all excited to eventually see how it works, what the response rates are, and [then we will] go from there.

_References:

_{Coveler AL, Bajor DL, and Massod A, et al. Phase I study of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol .2002:38 (suppl; abstr TPS4671). doi: 10.1200/JCO.2020.38.15_suppl.TPS4671}