*Review* **Emerging Therapies for Advanced Cholangiocarcinoma: An Updated Literature Review**

**Anthony Vignone 1,\*,†, Francesca Biancaniello 1,\*,†, Marco Casadio 1, Ludovica Pesci 1, Vincenzo Cardinale 2, Lorenzo Ridola <sup>1</sup> and Domenico Alvaro <sup>1</sup>**


**Abstract:** Cholangiocarcinoma is a group of malignancies with poor prognosis. Treatments for the management of advanced-stage cholangiocarcinoma are limited, and the 5-year survival rate is estimated to be approximately 5–15%, considering all tumor stages. There is a significant unmet need for effective new treatment approaches. The present review is provided with the aim of summarizing the current evidence and future perspectives concerning new therapeutic strategies for cholangiocarcinoma. The role of targeted therapies and immunotherapies is currently investigational in cholangiocarcinoma. These therapeutic options might improve survival outcomes, as shown by the promising results of several clinical trials illustrated in the present review. The co-presence of driver mutations and markers of susceptibility to immunotherapy may lead to rational combination strategies and clinical trial development. A better understanding of immunologically based therapeutic weapons is needed, which will lead to a form of a precision medicine strategy capable of alleviating the clinical aggressiveness and to improve the prognosis of cholangiocarcinoma.

**Keywords:** cholangiocarcinoma; targeted therapy; immunotherapy

### **1. Introduction**

Cholangiocarcinoma (CCA) is a rare malignant tumor that develops from the epithelium of the bile ducts or peribiliary glands (PBGs). Although CCA is considered a rare tumor in Western countries, it represents 3% of all gastrointestinal malignant tumors worldwide and the second most common primary liver cancer [1]. In Eastern countries, the incidence is higher than in Western ones, where it is estimated to be lower than 4 cases/100,000 people/year [2]. Northeast Thailand has the highest CCA rate in the world (90 cases/100,000 people/year) [3]. The highest incidence rate is in the seventh decade, with a slight prevalence in males. Due to classification coding (four different ICD-10 sub-codes) and variable terminology, CCA burden has been underestimated. CCA is the first cause of metastasis of unknown origin, and this further highlights how we still do not know the real burden of CCA [4]. While a reduction of the mortality rate from other cancers, including breast, lung, and colon cancer, has been observed in 1990–2009 (USA data), the mortality rate for liver and bile ducts tumors increased by more than 40% and 60% in females and males, respectively. While the mortality rate from hepatocellular carcinoma (HCC) has become more uniform across Europe, intrahepatic CCA mortality has substantially increased [5].

Anatomically, three types of cholangiocarcinoma can be distinguished: intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA). Histologically, these are different kinds of tumors, considering cholangiocarcinogenesis as a process that starts from several cells of

**Citation:** Vignone, A.; Biancaniello, F.; Casadio, M.; Pesci, L.; Cardinale, V.; Ridola, L.; Alvaro, D. Emerging Therapies for Advanced Cholangiocarcinoma: An Updated Literature Review. *J. Clin. Med.* **2021**, *10*, 4901. https://doi.org/10.3390/ jcm10214901

Academic Editor: Pierluigi Toniutto

Received: 28 September 2021 Accepted: 22 October 2021 Published: 24 October 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

origin. In particular, pCCA and dCCA are mainly mucinous adenocarcinomas, while iCCA is highly heterogeneous, since it could resemble conventional mucinous adenocarcinomas (large-duct type iCCA), similar to p/dCCA, or transformed interlobular bile ducts (smallduct type iCCA).

Currently, surgical resection with negative margins represents the best potentially curative therapy of CCA. Therapeutic options for the management of advanced-stage CCA are limited, and the 5-year survival rate is estimated to be approximately 5–15%, considering all tumor stages [6]. Cisplatin plus gemcitabine (GEMCIS) represents the first-line treatment for these patients, as established by the phase II BT22 trial and the phase III ABC-02 trial [7,8].

Few studies have enrolled specifically iCCA patients or have reported the anatomic subtypes of CCA (iCCA, pCCA, and dCCA). Many studies reviewed here concerned biliary tract cancers (BTCs), enrolling together CCA and gallbladder cancer (GBC) patients. Neglecting CCA heterogeneity in the study design, in terms of anatomical, histological, and molecular subtypes, might represent a strong limitation in patients' allocation to clinical trials. Moreover, given the possibilities shown by the development of targeted therapies, molecular profiling and efficient biomarkers would be needed to select the best therapeutic option for each patient [9].

The present review aims at summarizing the current evidence and future perspectives with regards to new therapeutic strategies for advanced CCA. Most drugs summarized in the following paragraphs are already used in the management of some oncological diseases, such as PD-L1 inhibitors (Pembrolizumab) that represent the first-line monotherapy for advanced non-small cell lung cancer (NSCLC) with a programmed death ligand 1 tumor proportion score of 50% or greater and without EGFR/ALK aberrations, based on the results of the phase III trial KEYNOTE 024 [10].

#### **2. Targeted Therapy**

### *2.1. FGFR2 Inhibitors*

Approximately 15–20% of iCCAs have been observed to have FGRF2 translocations [11] (fusion or rearrangements), implicated in promoting cell proliferation and angiogenesis. These mutations are almost absent in extrahepatic cholangiocarcinomas. On this basis, several FGFR 1–3 inhibitors have been tested in advanced cholangiocarcinomas patients, showing good antitumor activity and safety. Particularly, the European Medicines Agency (EMA) approved in April 2021 the use of Pemigatinib for previously treated advanced cholangiocarcinomas showing FGFR2 fusion or rearrangement. Furthermore, a phase III study (FIGHT-302) [12] is currently ongoing to test the efficacy of Pemigatinib as a first-line treatment versus chemotherapy in patients with advanced cholangiocarcinoma with FGFR2 mutations (Table 1). The efficacy of Infigratinib (BGJ398), a reversible selective FGFR 1–3 inhibitor, is also under evaluation (NCT03773302) as a first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma harboring FGFR2 mutations (Table 1).

However, point mutations of the FGFR 2 domain have been found capable of conferring resistance to FGFR inhibitors in previously treated patients [13]. In this category of patients, Futibatinib, a selective and irreversible FGFR inhibitor, has shown inhibitory activity and partial response, and a phase III study (Table 1) is underway to test its efficacy as a first-line treatment in patients with advanced CCA (FOENIX-CCA3 and NCT04093362). Another reversible ATP competitive inhibitor, Erdafitinib, showed promising result in a phase I–II study [14].


**Table 1.** Phase III targeted-therapy trials for BTC.
