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Introduction: Biliary tract cancers (BTCs) include four uncommon primary biliary malignancies characterized by poor prognosis: intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer. To date, the available therapeutic options are limited; nevertheless, with the advent of targeted therapy and immunotherapy, the treatment scenario is constantly changing, opening toward future possibilities for the personalized treatment of BTC. Among these treatments, nivolumab is currently being investigated in BTC. Areas covered: This review provides a comprehensive overview of the recent progress and future perspectives of immunotherapy for the treatment of BTC, with a particular focus on nivolumab, which has demonstrated its effectiveness in many malignancies and is in its initial phase of evaluation in BTC. Expert opinion: BTCs are not among those tumors that demonstrated remarkable sensitivity to immunotherapy, such as melanoma or non-small-cell lung cancer. However, the results obtained with nivolumab are not disappointing if we analyze the population of the trials testing its efficacy, including pretreated patients, unselected for PD-L1 expression and with different BTCs. In our opinion, ICIs such as nivolumab could fill an empty spot in the treatment of selected BTC patients, especially in combination with other agents, and the results of ongoing clinical trials are awaited.

Introduction: Biliary tract cancers (BTCs) are poor prognosis malignancies usually classified in intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer. In the last few years, novel treatment targets have been identified in iCCA patients, including fibroblast growth factor receptor (FGFR) aberrations; thus, several FGFR inhibitors are currently being developed, some of which have already suggested interesting efficacy and adequate safety in phase I and phase II trials regarding refractory iCCA. Areas covered: This review provides an overview regarding the current scenario of FGFR2 targeted therapies in iCCA, especially focusing on the mechanism of action and clinical development of futibatinib (TAS-120), a highly selective irreversible pan-FGFR antagonist. According to the interim analysis of the FOENIX-CCA2 trial, whose results have been presented at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting, futibatinib could lead to meaningful benefit in patients affected by previously treated iCCA with FGFR2 gene fusions or other rearrangements. Expert opinion: Because of its promising and durable activity, futibatinib has the potential to become a novel therapeutic option in the treatment of iCCAs harboring FGFR2 aberrations. Further studies are warranted to confirm the efficacy of this investigational molecule.

Introduction Immune checkpoint inhibitor (ICI) monotherapy appears to be effective in a small cohort of patients with metastatic triple negative breast cancer (mTNBC). This supports the exploration of strategies for increasing the efficacy of immunotherapy. To enhance overall response and clinical outcomes, several immune-based combinations are being investigated. Areas covered The authors present a synopsis of current, state of art immune-based combinations in this setting and reflect on future possibilities. They shed light on recently presented and published clinical trials and ongoing studies. A literature search was conducted in October 2021; in addition, abstracts of international cancer meetings were reviewed. Expert opinion Clinical trials suggest that ICI monotherapy could be beneficial in a minority of mTNBC patients; conversely, several immune-based combinations have reported notable results in recently presented or published studies. Some of these combination strategies have been approved for mTNBC - as in the case of chemoimmunotherapy in PD-L1 positive patients. Numerous trials are investigating novel ICI-based combinations and their results are eagerly awaited.

INTRODUCTION The treatment algorithm of advanced hepatocellular carcinoma (HCC) has evolved since the introduction of immunotherapy. The IMbrave150 trial set atezolizumab-bevacizumab as a new standard-of-care first-line treatment for unresectable HCC patients. However, for patients with intermediate or advanced stage with portal vein thrombosis but without distant metastases, 90Yttrium transarterial radioembolization (90Y-TARE) is considered the treatment of choice. AREAS COVERED We discuss the main evidence regarding the use of 90Y-TARE in HCC, the recent progress of immunotherapy in this tumor, and the preclinical rationale of combining VEGF blockade with the other two treatment strategies. EXPERT OPINION HCC has an extremely heterogeneous tumor immune microenvironment. This may explain the inconsistent outcomes obtained with immune-checkpoint inhibitors. The identification of patients who could benefit most from immunotherapy is crucial; however, reliable markers of response are lacking. Radiation therapy and VEGF inhibition have an established synergism with immunotherapy, mainly linked to enhanced antigen presentation and reduced immunosuppressive immune infiltrate. Combining an immune-checkpoint inhibitor with VEGF blockade and 90Y-TARE might hence overcome primary resistances observed when each of these treatments is administerd alone.

While sorafenib monotherapy represented the mainstay of medical treatment for advanced hepatocellular carcinoma (HCC) patients for more than a decade, novel agents and combination therapies have recently produced unprecedented paradigm shifts. The combination of lenvatinib plus pembrolizumab is now being evaluated as a front-line treatment in advanced HCC patients; early phase clinical trials have already reported promising results.This paper reviews the combination of lenvatinib plus pembrolizumab for the treatment of advanced HCC. The preclinical rationale and completed and ongoing trials are examined and later, the authors reflect on biomarkers of predictive of response to immune-based combinations and future treatment decision-making on the basis of tolerability and clinical benefits provided by these novel therapeutics. A literature search was conducted in April 2021 of Pubmed/Medline, Cochrane library and Scopus databases; moreover, abstracts of international cancer meetings were reviewed.The landscape of new agents and combinations continues to expand. Recently, immune-based combinations have reported important results in advanced HCC, as witnessed by the landmark IMbrave150 trial. Based on the promising results of early phase clinical trials, lenvatinib plus pembrolizumab has the potential to represent a novel treatment option in this setting.

Introduction: The prognosis of patients with advanced biliary tract cancer (BTC) remains dismal, with a 5-year overall survival rate of less than 10%. Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of several hematological and solid tumors, controversial results have been reported in BTC. In this setting, the anti-PD-L1 inhibitor durvalumab is currently under investigation in several clinical trials as monotherapy, or in combination with other pharmacological agents. Areas covered: We offer an overview of immunotherapies for BTC, discuss recently published or presented data on durvalumab pharmacology, safety, and efficacy in the treatment of BTC and consider future research directions for the agent in this setting. Expert opinion: The promising antitumor activity shown by durvalumab in early trials warrants further investigation because it may provide more effective, much needed treatment options. The results of clinical trials of this PD-L1 inhibitor, as a monotherapy or in combination, are eagerly awaited. Future efforts should focus on the identification and development of reliable biomarkers of response to durvalumab in BTC, clarifying the role of PD-L1 expression, microsatellite instability (MSI), mismatch repair (MMR), tumor mutational burden (TMB) and other emerging predictors.

Welcome to the ‘Expert Opinion on Investigational Drugs’ special issue on biliary tract cancers (BTCs). BTCs are the second most common primary liver tumor; they are a heterogeneous group of malign...