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.

Keywords: CAR-T; KRAS; immunotherapy; pancreatic adenocarcinoma.

Figure 1

KRAS mutations in pancreatic adenocarcinoma (PDAC). Over 90% of PDAC are KRAS mutant with G12D being the most common (39.2%), followed by G12V (32.5%), G12R (17.1%), G16H (4.8%) as well as G12C (1.7%). Wild-type KRAS are less frequent and seen in < 10% of PDAC cases.

Figure 2

Potential targetable mutations in PDAC along with examples of drugs in each category. Targetable mutations are seldom found in PDAC, and likely to present in KRAS wild-type status (<10%). *Approved tissue-agnostic therapies are denoted in gray; those in the green box are still not FDA-approved. **Olaparib is FDA approved as a maintenance regimen in those with germline BRCA mutations which have not progressed on at least 16 weeks of first line platinum-based chemotherapy.