What are the key challenges in the pharmacological management of cholangiocarcinoma?

KEYWORDS:

• Biliary tract cancers
• chemotherapy
• molecular targeted therapy
• immunotherapy

1. Introduction

Cholangiocarcinomas are rare cancers that originate from within the biliary tract. There are three main types of cholangiocarcinoma defined by their location within the biliary tract, intrahepatic, perihilar, or distal [1]. These cancers are characterized by low overall survival rates and contribute to ~3% of all cancer-related mortality in the United States. For early stage disease, surgical resection can be curative. However, the tumors may remain asymptomatic until diagnosis at an advanced stage when curative surgery with their removal or with an R0 resection may not be feasible. While locally directed approaches such as photodynamic therapy, radiation, or ablative therapies have been used, their success rates have been modest, and their benefit for advanced disease have been limited. This highlights the dire need for earlier timely diagnosis as well as for an expanded armamentarium of more effective systemic therapies for advanced or metastatic disease. Until recently, pharmacotherapeutic options for systemic therapy were limited to chemotherapy. However, several new therapies targeting specific molecular pathways have now been approved for cholangiocarcinoma. The advent of these and other options dramatically alters the treatment landscape and management approach to these cancers.

2. Pharmacological therapies for Cholangiocarcinoma

2.1. Chemotherapy

These malignancies have been highly resistant to most chemotherapeutic agents and furthermore can acquire further resistance during chemotherapy treatment. This has resulted in a limited role for chemotherapy in all therapeutic contexts, including use in first-line therapy, adjuvant, neo-adjuvant or palliative settings. Based on the landmark ABC-02 trial [2], the standard of care first-line chemotherapy consists of combination therapy of gemcitabine and cisplatin, with alternative or second-line regimens being less efficacious. In a phase 2 study, the addition of nab-paclitaxel prolonged median progression-free survival (mPFS) and median overall survival (mOS) compared with historical controls treated with gemcitabine and cisplatin [3]. There is an established use of neo-adjuvant first-line therapy with gemcitabine/cisplatin or capecitabine aimed at controlling tumor growth or shrinking tumors to permit transplantation or R0 resection for curative treatment. A median overall survival of 34.6 months was reported with adjuvant therapy with S-1 monotherapy [4]. Other combination therapies have also been explored. For example, hepatic arterial infusion of floxuridine with gemcitabine plus oxaliplatin reported mOS of 25.0 months and mPFS of 11.8 months in unresectable cholangiocarcinoma [5]. A phase II study (ABC-06) of a combination of leucovorin, fluorouracil, and oxaliplatin (FOLFOX) with symptom control versus symptom control alone reported a mOS of 6.2 months in the FOLFOX group compared with 5.3 months in the control group in this second-line study [6]. FOLFOX is the standard of care for second-line therapy. However, with all these therapies, disease progression occurs frequently.

2.2. Molecular targeted therapies

2.2.1. FGFR2 fusions and aberrations

Fibroblast growth factor receptor (FGFR) mutations can drive tumor progression, specifically in intrahepatic and very rarely with other types of cholangiocarcinoma. Fusions and genetic mutations involving FGFR2 occur in 10–20% of intrahepatic cholangiocarcinoma. An FGFR inhibitor, pemigatinib was the first molecular targeted therapeutic approved by the US Food and Drug Administration (FDA) for cholangiocarcinoma. In a phase II study (FIGHT-202), 82% of 107 patients with FGFR fusion/rearrangement treated with pemigatinib achieved disease control, with an overall response rate (ORR) of 35% and a median overall survival of 21.1 months and median progression-free survival of 6.9 months [7]. Similarly, in a phase II study of 108 patients with advanced cholangiocarcinoma and FGFR2 fusion or rearrangement who had been previously treated with systemic therapy, treatment with the kinase inhibitor infigratinib achieved an ORR of 23%, at a median follow-up of 11.3 months, with 24 partial responses and 1 complete response. The median progression-free survival was 7.3 months, while the median overall survival was 12.2 months [8]. Infigratinib has also now been approved by the FDA as an orphan drug for previously treated advanced cholangiocarcinoma.

Other agents targeting FGFR2 driven cholangiocarcinoma are emerging. In a phase I dose-escalation study (FOENIX-101), the FGFR1-4 inhibitor futibatinib had acceptable safety and tolerability. Partial responses were observed in three of 24 patients with FGFR2 fusion intrahepatic cholangiocarcinoma, and 18 of 24 patients had a partial response or stable disease [9]. In a phase II study of 103 patients, futibatinib had an ORR of 41.7% with one patient having a complete response and 42 with partial responses. Disease control rate was 82.5%, with most patients with stable disease showing tumor reduction. Consequently, the FDA has approved a breakthrough therapy designation for futibatinib in cholangiocarcinoma with FGFR2 fusion/rearrangement. Other FGFR inhibitors undergoing evaluation in cancers include the orally active agents derazantinib and Debio 1347.

The duration of response and acquired resistance remain challenges to the use of FGFR targeting agents. Nevertheless, these promising results emphasize their important role for systemic therapy of previously treated, advanced disease in the small subset of patients with aberrant FGFR2 driven cholangiocarcinoma.

2.2.2. IDH1/2 mutations

Isocitrate dehydrogenase 1 (IDH1) mutations represent another targetable driver and may be present in as many as ~13% of intrahepatic cholangiocarcinoma tumors. In the phase III ClarIDHy trial, 185 patients with advanced cholangiocarcinoma and mutant IDH1 received either ivosidenib (n = 124) or matched placebo (n = 61). The median survival rate with ivosidenib was 10.8 months compared with 9.7 months with placebo. The study had a cross-over design that complicates the analysis of overall survival, but the median progression-free survival with ivosidenib was 2.7 months compared with 1.4 months for placebo [10]. There was a 63% reduction in disease progression risk or death with ivosidenib compared with placebo in patients. Despite a low objective response rate, the experience with Ivosidenib shows the potential role and need for continued development of IDH inhibitors.

2.2.3. Kinase inhibitors

Targeting kinase driven pathways such as the MEK-MAPK pathway offer further opportunities for pharmacotherapy. In a phase II study (REACHIN) in patients who had previously failed gemcitabine and cisplatin, the tyrosine kinase inhibitor (TKI) regorafenib had a mPFS 3.0 months compared with 1.5 months in placebo controls with a mOS of 5.3 months vs 5.1 months with placebo [11]. A phase II study in 26 patients with unresectable cancer treated with monotherapy with the TKI lenvatinib reported 3 partial responses and a mOS of 7.35 months and mPFS of 4.11 months [12]. In contrast to these, a phase II SWOG S1310 study in intrahepatic cholangiocarcinoma reported a higher mOS and mPFS in controls than with trametinib treatment [13]. Although trametinib as monotherapy was ineffective in unselected patients, promising activity of trametinib in combination with dabrafenib was observed in patients in unresectable biliary tract cancers enrolled in a basket trial of patients with BRAFv600E mutations [14].

2.3. Immune checkpoint inhibitors (ICI)

A limitation of molecular targeted therapies targeting tumors with FGFR or IDH mutations has been the durability of response. Immune checkpoint inhibitors such as monoclonal antibodies targeting programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have the potential for more durable responses, particularly in tumors with high tumor mutational burden and high levels of microsatellite instability. The experience with single agent ICI has been limited, with emphasis now being placed on evaluating combination therapies of ICIs with other therapies [15]. Most notably, immunotherapies such as pembrolizumab, nivolumab, and durvalumab, ipilimumab, and tremelimumab are being evaluated in combination with chemotherapy for cholangiocarcinoma. Some interesting preliminary results are emergingfor example, a 97.8% disease control rate with a mOS of 18.1 months and a mPFS of 20.7 months have been reported with combination therapy with durvalumab, tremelimumab, and gemcitabine/cisplatin [16]. The results of these and other ongoing studies will contribute to defining the role and appropriate use of ICI in the management of cholangiocarcinoma.

2.4. Emerging therapies

Elucidation of molecular targets by sequencing studies will further expand therapeutic options by suggesting potential novel treatments. Polyadenosine diphosphate-ribose polymerase (PARP) inhibitors like niraparib and olaparib are undergoing trials to test their efficacy, with olaparib being tested as potential monotherapy, in combination with checkpoint immunotherapies, and with chemotherapies. EZH2/ARID1A inhibitors are promising agents, but data on their efficacy in cholangiocarcinoma is currently lacking. Other novel drug agents that are undergoing testing in cholangiocarcinoma include the PI3K inhibitor copanlisib, and antimetabolite-conjugated thymidine phosphorylase inhibitor TAS-102.

3. Expert opinion

The promising results with molecular-targeted therapies have highlighted the essential need for sequencing to detect genetic alterations. However, tissue sampling may be challenging from highly desmoplastic tumors. Strategies to identify cancers at an early, resectable stage, and to obtain sufficient material with which to perform genomic analysis are needed. The presence of aberrations and mutations in FGFR2 or IDH1 may guide the directed use of specific therapies but are present in a small proportion of patients. While the approval of different drugs with similar molecular targets, e.g., for FGFR, will provide new drug options, they will drive drug selection to safety, efficacy, and cost considerations and further influenced by marketing strategies. Trials that directly compare agents with similar molecular targets with each other or with standard of care for first-line indications could help us to understand the optimal approach, but these are unlikely to be performed. Several questions remain unanswered, such as the efficacy of these agents for first-line use, the appropriate timing of sequential use of therapies, the role of first-line combination approaches, the duration of response and mechanisms of primary or acquired resistance to these agents. Specific research into optimal therapies for those tumors in which drug targeting therapies are not available remains an unmet need of high priority. The increasing pharmacological armamentarium will complicate future efforts to determine the most optimal therapies to improve overall survival outcomes in cholangiocarcinoma and place a greater emphasis on personalized approaches to optimize outcomes for individual patients. However, even a personalized approach using mutation analysis profiling can identify therapeutic options for a minority of patients, leaving a huge unmet need for more effective pharmacotherapy for cholangiocarcinoma.

Declaration of Interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are supported by the James C and Sarah K Kennedy Deanship and Alfred D and Audrey Petersen Professorship to TP.