Pancreatic cancer is considered to be one of the most aggressive solid tumours; despite low incidence, it remains the fourth leading cause of cancer-related deaths in the US. Poor prognosis due to advanced presentation and limited therapeutic options continues to characterise the disease. With a growing need for early diagnosis of the disease, pharmaceutical research and development is focused on identifying actionable genetic mutations and developing effective targeted therapies. KRAS, BRCA1/2, CDKN2A, PALB2, NTRK, and MSI-MMR are some of the commonly identified biomarkers related to pancreatic cancer, with several approved agents on the market or currently in clinical development targeting these respective mutations. Therapeutic modalities such as immunotherapy and personalised therapy are being considered for use in the first line and maintenance settings for patients with advanced stages of the disease, and are deemed promising based on data from pre-clinical studies and early-stage development.
In the US, the FDA recently offered orphan drug designation status to zenocutuzumab (MCLA-128) and racemetyrosine (SM-88) for their respective indications in pancreatic cancer. With successful trial data and demonstrated survival benefit, this designation will reduce potential wait time for drug approval and help increase the number of targeted therapeutic agents for pancreatic cancer.
Human epidermal growth factor receptor 2 (HER2) and HER3, prominently associated with tumorigenesis in a subset of breast cancers, are being investigated as potential targets in pancreatic cancer. Zenocutuzumab, a bispecific antibody that binds to HER2 and HER3 receptors, thereby blocking HER3-NRG1 interaction in patients with NRG1 fusions, has shown strong inhibition of HER2- and HER3-based signalling in preclinical studies and is being developed by Merus Pharmaceuticals in the US as second-line therapy in pancreatic ductal adenocarcinoma.
Racemetyrosine, an investigational therapy targeting metabolic mechanisms of the disease, is currently in Phase I/II and is being developed by Tyme Technologies for use in the third-line setting in advanced pancreatic cancer for patients who have failed two lines of any prior systemic therapy. The drug’s mechanism is to target cancer-specific metabolites and alter MUC1 protein synthesis, which is over-expressed in tumour cells across different cancer types, making the tumour vulnerable to attack from the immune system. Even after significant efforts to identify effective treatment regimens for pancreatic cancer in recent years, the FOLFIRINOX combination regimen and gemcitabine combined with Abraxane (nabpaclitaxel) remain the standard of care in patients with advanced and metastatic disease in both first- and second-line settings, with no approved therapy for use in the third-line setting. The TYME-88-Panc study of racemetyrosine recently demonstrated promising data on improved overall survival in a Phase II study of advanced pancreatic cancer with poor prognosis, thus demonstrating potential to resolve high unmet need inpatient segments where supportive and palliative care are the only therapies being considered currently.