Toward personalized therapy for cholangiocarcinoma: new insights and challenges

KEYWORDS:

• Cholangiocarcinoma
• circulating tumor DNA
• intrahepatic cholangiocarcinoma
• biliary tract cancer
• targeted therapies

1. Introduction

Cholangiocarcinoma (CCA) encompasses a group of rare and aggressive hepatobiliary malignancies, including extrahepatic cholangiocarcinoma (eCCA) and intrahepatic cholangiocarcinoma (iCCA), with the former further subdivided into perihilar (pCCA) and distal cholangiocarcinoma (dCCA) [1]. Despite CCAs have been historically considered rare tumors, the incidence of CCA is on the rise in several countries, representing the second most frequently diagnosed primary liver cancer worldwide and accounting approximately for the 15–20% of all liver malignancies [2]. Radical surgery is the only curative approach for CCA, but unfortunately, less than one-third of patients are diagnosed with resectable disease, and recurrence rates remain high, even following radical resection with negative tumor margins [3].

More than ten years ago, the Advanced Biliary tract Cancer (ABC)-02 phase III trial established the combination of cisplatin plus gemcitabine (CisGem) as the standard of care in the front-line setting [4]; more recently, the ABC-06 trial highlighted the survival benefit provided by modified oxaliplatin plus 5-fluorouracil (mFOLFOX) plus active symptom control (ASC) over ASC alone in CCA patients whose disease progressed on first-line CisGem [5]. However, systemic chemotherapy is marginally effective in locally advanced/unresectable or metastatic CCA, being associated with a median overall survival (mOS) shorter than 1 year.

As previously stated, the term CCA includes a heterogeneous group of malignancies with important anatomical, epidemiological, and molecular differences [6]. As regards the latter, several types of genetic aberrations have been observed in CCA, ranging from single-nucleotide mutations (such as missense, nonsense, and splice-site mutations) from insertions and deletions (e.g. BAP1, TP53, ARID1A) as well as copy number alterations and chromosomal rearrangements or fusions (e.g. FGFR2, ALK, ROS1, and NTRK) [7]. Of note, these genetic aberrations cluster in specific CCA subgroups: IDH1 mutations and FGFR2 fusions are the most frequent actionable alterations in iCCAs, while ERBB2 amplifications and ARID1A and PIK3CA mutations are more common in eCCA patients [8].

In the current Editorial, we provide a critical overview of personalized therapies in CCA management, especially focusing on current and future challenges in this setting.

2. Expert opinion

Certainly, not all CCAs are suitable for molecularly driven treatments, and several issues are to be faced, including the quality of tissue sample [9]. We know from everyday clinical practice that the pathologic confirmation of diagnosis is necessary before any non-surgical treatment and may be challenging in CCA, especially in patients affected by primary sclerosing cholangitis and biliary strictures. In addition, despite endoscopic imaging and tissue sampling are useful, biopsy samples are often inadequate for molecular profiling, and the highly desmoplastic nature of CCA limits the accuracy of cytological and pathological approaches [10]. Based on these premises, these issues have remarked the urgent need to develop novel strategies and methodologies able to anticipate the CCA diagnosis at an early stage, as well as to obtain sufficient material to perform genomic analysis. Among these strategies, liquid biopsy has received growing attention in several malignancies, including CCA [11]. In fact, liquid biopsy has shown high concordance with tissue biopsy, representing a noninvasive method able to capture heterogeneous resistance alterations. However, these methodologies are still preliminary and quite far from everyday clinical practice for now.

Targeted therapies have provided no benefit in ‘non-selected’ CCA, and since approximately 60% of all CCAs are not suitable for targeted therapies, only a relatively small and specific population of CCA patients may benefit from these approaches [12]. As regards clinical trials design, the CCA medical community has proposed three main different approaches aimed to evaluate targeted therapies in these hepatobiliary malignancies: 1) target-specific clinical trials on CCA patients (e.g. IDH1 mutations, FGFR2 fusions); 2) target-specific basket trials including a CCA cohort (e.g. NTRK fusions, BRAF mutations, MMR deficiency and other disease-agnostic aberrations); 3) CCA umbrella or basket trials with target-specific arms. As regards the former type of studies on CCA, several trials on specific actionable targets have been presented and published in the last years. A key example is FGFR2 fusions, with these genetic aberrations representing an important molecular driver in iCCA, as witnessed by the Food and Drug Administration (FDA) approval of infigratinib and pemigatinib and the large number of FGFR-targeted therapies under evaluation in this setting [13–15].

In the ROAR phase II basket trial, the combination of dabrafenib plus trametinib has reported a promising activity and a manageable safety profile in the cohort of patients with BRAF^V600E-mutated CCA [16]. In particular, median progression-free survival (PFS) and median overall survival (OS) were 9 months and 14 months, respectively, in CCA patients receiving dabrafenib plus trametinib, with a median duration of response of 9 months and an overall response rate of 47% [16]. Lastly, as regards umbrella trials with target-specific arms, the SAFIR-ABC10 study will see the evaluation of multiple targeted therapies for CCA patients that will be stratified into multiple subgroups based on molecular features screened by FoundationOne testing.

In addition, immunotherapy is currently under assessment in advanced CCA, as monotherapy or in combination with targeted therapies, including targeted therapies and tyrosine kinase inhibitors including lenvatinib [17]. In terms of monotherapy, data from CCA patients treated with pembrolizumab in the phase Ib KEYNOTE-028 and the phase II KEYNOTE-158 trials have been recently published [18,19]. As regards the former, monotherapy with the PD-1 inhibitor pembrolizumab (10 mg/kg every 2 weeks) has been evaluated in previously treated patients with PD-L1 positive metastatic solid malignancies, including 20 CCAs and 4 gallbladder cancers [18]. After a median follow-up of 5.7 months, overall response rate (ORR) was 13%, with median OS and PFS of 5.7 and 1.8 months, respectively [18]. MSI status was not available in approximately 30% of CCA patients enrolled in this study. Similarly, the KEYNOTE-158 basket trial evaluated single-agent pembrolizumab as second- or later-line treatment in advanced solid tumors, including 104 biliary tract cancers [18,19], where the PD-1 inhibitor reported a disappointing ORR of 5.8% [18]. Median PFS and OS were 2.0 (95% CI, 1.9–2.1) and 7.4 (95% CI, 5.5–9.6) months, respectively. Of note, KEYNOTE-028 and KEYNOTE-158 enrolled patients showing disease progression following at least 1 prior systemic therapy, many of whom were heavily pretreated. In 2017, the US Food and Drug Administration approved the anti-PD-1 agent pembrolizumab for the treatment of any dMMR or MSI-H malignancies, regardless of tumor type, including CCA; in addition, in June 2020 the PD-1 inhibitor pembrolizumab was approved by the FDA also for TMB high (more than 10 mutations per megabase) non-colorectal malignancies. Thus, these agents are currently used for CCA with putative predictive biomarkers.

In summary, molecularly targeted therapies are providing CCA patients new treatment options, and we are witnessing important efforts aiming to expand the role of other emerging agents as well as to evaluate novel strategies able to overcome drug resistance [20]. We have recently seen important changes in the treatment paradigm of CCA, and the close collaboration between clinicians and researchers is and will be of great importance to improve clinical outcomes of CCA patients [21]. On the horizon, there is a host of phase II and phase III trials of novel treatments, including studies comparing targeted therapies versus standard chemotherapy in the front-line setting [22,23]; the results of these trials are highly awaited and have the potential to modify the treatment landscape of these challenging hepatobiliary malignancies with many unanswered questions.

Declaration of interests

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.