Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers and an almost uniformly fatal malignancy. Treatment outcomes remain dismal with a 5-year survival of 9%. The incidence of PDAC is increasing and is projected to become the second leading cause of cancer death by 2030. Chemotherapy is currently the only effective treatment option and benefits from immunotherapy have failed to materialize in PDAC. However, responses to chemotherapy remain poor, with only 20-30% of patients receiving any benefit. Thus, new therapies are urgently needed. Semaphorins are proteins that have been implicated in premalignant and malignant states. Pepinemab is a drug that targets a specific semaphorin, Sema4D, which has been found to be significantly elevated in PDAC. In preclinical models, targeting Sema4D resulted in a shift in immune cells in the tumor microenvironment towards an anti-tumor response and allowed more cytotoxic T-cells (cancer killing immune cells) to infiltrate the tumor. Nivolumab is an immune checkpoint inhibitor that prevents cancers cells from hiding from these T-cells. The combination of these two drugs will synergize and enhance the immune system’s ability to fight cancer cells. This phase I/II study will assess the safety and overall response rate of pepinemab in combination with nivolumab in patients with newly diagnosed unresectable or metastatic PDAC.
Trial Registration: ClinicalTrials.gov Identifier: NCT05102721