Biliary tract cancers are anatomically distinct and genetically diverse tumors, evenly characterized by poor response to standard treatments and a bleak outlook. The advent of comprehensive genomic profiling using next-generation sequencing has unveiled a plethora of potentially actionable aberrations, changing the view of biliary tract cancers from an “orphan” to a “target-rich” disease. Recently, mutations in isocitrate dehydrogenase genes (IDH1/2) and fusions of the fibroblast growth factor receptor have emerged as the most amenable to molecularly targeted inhibition, with several compounds actively investigated in advanced-phase clinical trials. Specifically, the IDH1 inhibitor ivosidenib has been the first targeted agent to show a survival benefit in a randomized phase III trial of cholangiocarcinoma patients harboring IDH1 mutations. In this review article, we will focus on the IDH1/IDH2 pathway, discussing the preclinical rationale of its targeting as well as the promises and challenges of the clinical development of IDH inhibitors in biliary tract cancers.

Intrahepatic cholangiocarcinoma (iCCA) is an anatomically and biologically distinct entity with a rising incidence and a poor prognosis on conventional treatments. Surgery followed by adjuvant chemotherapy is a potentially curative option in resectable cases, while palliative-intent chemotherapy is the standard-of-care in the advanced setting. Technological advances through massive parallel sequencing have enabled a deeper understanding of disease biology with the identification of several druggable molecular vulnerabilities in nearly 50% of cases. Among them, gene fusions involving the fibroblast growth factor receptor 2 (FGFR2) are the most therapeutically exploited so far with a number of Phase II clinical trials investigating FGFR2 inhibitors showing unprecedented efficacy results in this molecular subgroup. Over the last year, these efforts have culminated in the US FDA-approval of pemigatinib and infigratinib, the first two oral selective FGFR2 targeted agents for previously treated, locally advanced or metastatic iCCA driven by FGFR2 fusion or rearrangements. While first-line Phase III trials are currently underway to test these targeted approach against standard-of-care chemotherapy, translational studies are trying to better understand primary and secondary resistance mechanisms in order to optimize FGFR2 blockade in iCCA. In this article, we extensively reviewed the current evidence on the biological rationale, as well as preclinical and clinical development of FGFR inhibitors in iCCA.

While chemotherapy has recently been established as a standard second-line treatment in ABC, its role in the third-line setting is still controversial. In this study, we aim at describing the pattern of care, survival outcome and prognostic factors of ABC patients (pts) receiving third-line chemotherapy. Institutional registries across three academic medical centers were retrospectively reviewed to identify ABC treated third-line chemotherapy. Kaplan-Meier estimators were used to calculate survival and the log-rank test to make comparisons. The impact of variables on survival was assessed through univariate and multivariate analysis. Globally, 101 pts were included in the analysis. The median age was 64 years and 58 (57.4%) were females. Overall, 68 (67.3%), 19 (18.8%) and 14 (13.8%) pts had intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, respectively. A total of 63 (62.3%) pts received monochemotherapy, while 38 (37.6%) were treated with a doublet. The median OS and PFS were 5 and 3 months, respectively. Disease control rate was achieved in 23 (22.7%) pts, with 2 (2%) partial responses. Grade 3-4 treatment-related adverse events were reported in 22 (21.7%) pts. At multivariate analysis, ECOG PS (p<0.001), tumour burden (p=0.01) and lymphocyte-to-monocyte ratio (p=0.02) were independent predictors of survival. Third-line chemotherapy displayed limited activity in this real-world cohort, although prognostic factors have been identified that may assist in treatment decision. The results of this multicenter experience, the largest so far, highlight the need for more effective therapies and provide a benchmark for future trials of third-line chemotherapy in ABC.

Gastric and gastro-esophageal junction adenocarcinoma (GEA) remains a considerable major public health problem worldwide, being the fifth most common cancer with a fatality-to-case ratio that stands still at 70%. Angiogenesis, which is a well-established cancer hallmark, exerts a fundamental role in cancer initiation and progression and its targeting has been actively pursued as a promising therapeutic strategy in GEA. A wealth of clinical trials has been conducted, investigating anti-angiogenic agents including VEGF-directed monoclonal antibodies, small molecules tyrosine kinase inhibitors and VEGF-Trap agents both in the resectable and advanced setting, reporting controversial results. While phase III randomized trials testing the anti-VEGFR-2 antibody Ramucirumab and the selective VEGFR-2 tyrosine kinase inhibitor Apatinib demonstrated a significant survival benefit in later lines, the shift of angiogenesis inhibitors in the perioperative and first-line setting failed to improve patients’ outcome in GEAs. The molecular landscape of disease, together with novel combinatorial strategies and biomarker-selected approaches are under investigation as key elements to the success of angiogenesis blockade in GEA. In this article, we critically review the existing literature on the biological rationale and clinical development of antiangiogenic agents in GEA, discussing major achievements, limitations and future developments, aiming at fully realizing the potential of this therapeutic approach.

Pancreatic ductal adenocarcinoma (PDAC) has an aggressive tumor biology and is associated with poor survival outcomes. Most patients present with metastatic or locally advanced disease. In the 10–20% of patients with upfront resectable disease, surgery offers the only chance of cure, with the addition of adjuvant chemotherapy representing an established standard of care for improving outcomes. Despite resection followed by adjuvant chemotherapy, at best, 3-year survival reaches 63.4%. Post-operative complications and poor performance mean that around 50% of the patients do not commence adjuvant chemotherapy, and a significant proportion do not complete the intended treatment course. These factors, along with the advantages of early treatment of micrometastatic disease, the ability to downstage tumors, and the increase in R0 resection rates, have increased interest in neo-adjuvant treatment strategies. Here we review biomarkers for early diagnosis of PDAC and patient selection for a neo-adjuvant approach. We also review the current evidence for different chemotherapy regimens in this setting, as well as the role of chemoradiotherapy and immunotherapy, and we discuss ongoing trials.