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Despite decades of research, pancreatic ductal adenocarcinoma (PDAC) continues to have the worst 5-year survival of any malignancy. With 338,000 new cases diagnosed and over 300,000 deaths per year globally there is an urgent unmet need to improve the therapeutic options available. Novel immunotherapies have shown promising results across multiple solid tumours, in a number of cases surpassing chemotherapy as a first-line therapeutic option. However, to date, trials of single-agent immunotherapies in PDAC have been disappointing and PDAC has been labelled as a nonimmunogenic cancer. This lack of response may in part be attributed to PDAC’s unique tumour microenvironment (TME), consisting of a dense fibrotic stroma and a scarcity of tumour infiltrating lymphocytes. However, as our understanding of the PDAC TME evolves, it is becoming apparent that the problem is not simply the immune system failing to recognize the cancer. There is a highly complex interplay between stromal signals, the immune system and tumour cells, at times possibly restraining tumour growth and at others supporting growth and metastasis. Understanding this complexity will enable the development of rational combinations with immunotherapy, priming the TME to offer immunotherapy the best chance of success. This review seeks to describe the unique challenges of the PDAC TME, the potential opportunities it may afford and the trials in progress capitalizing on recent insights in this area.

Improvements in median overall survival in the advanced oesophagogastric (OG) setting have plateaued, underlining the need for improved therapeutic approaches in this patient population. Immunotherapeutics are inducing unexpected durable responses in an expanding list of advanced disease indications. Although OG cancers have traditionally been considered to be more challenging to treat with immunotherapy than some other malignancies because of their variable tumour mutational burden and relative scarcity of infiltrating T cells, immune checkpoint inhibitor (ICPI) trials conducted over the last few years suggest there is an important role for these treatments. ICPI efficacy may be demonstrated in specific molecular subtypes of OG cancer. This review outlines the improvements in defining predictive biomarkers of responsiveness to ICPIs. Increasingly, identification of an expanding list of ICPI resistance mechanisms will drive biomarker-directed research. In addition, the specific rationale to combine ICPIs with chemotherapies, radiotherapies, targeted therapies and other novel immunotherapeutic drugs will be discussed.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy. As a direct result, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of liposomal irinotecan in this setting. However, first-line treatment options for this disease now include the combination regimen, FOLFIRINOX, in patients with good performance status, and the role of second-line combination treatment with liposomal irinotecan in this setting is unclear. Recent advances have changed the therapeutic landscape, as clinicians are now able to choose a sequential approach to treatment tailored to the individual patient characteristics. This article reviews current treatment options for metastatic PDAC and focuses on the efficacy, safety and place in therapy of liposomal irinotecan.