Second-Line Treatment of Pancreatic Adenocarcinoma: Shedding Light on New Opportunities and Key Talking Points from Clinical Trials

Abstract Despite improvements in overall cancer mortality, deaths related to pancreatic cancer continue to rise. Following first-line treatment, second-line options are significantly limited. Classically, first-line treatment consisted of either gemcitabine or 5-fluorouracil based systemic chemotherapy. Upon progression of disease or recurrence, subsequent second-line treatment is still gemcitabine or 5-fluorouracil based chemotherapy, depending on what was used in the first line and the timing of progression or recurrence. A better understanding of the molecular underpinnings of pancreatic adenocarcinoma (PDAC) has led to new treatment strategies including specifically targeting the desmoplastic stroma, cytokine signaling and actionable mutations. Furthermore, efforts are also directed to enhance the immunogenicity profile of PDAC’s well-established immunologically “cold” tumor microenvironment. More recently, the outstanding response rates of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies, have led to clinical trials to evaluate the treatment modality in PDAC. In this review, we summarize recently presented clinical trials for metastatic pancreatic adenocarcinoma with novel treatment approaches in the second line and beyond.