The impact of molecular profiling on cholangiocarcinoma clinical trials and experimental drugs

KEYWORDS:

• Cholangiocarcinoma
• genetics
• fibroblast growth factor receptor
• genomic profiling
• isocitrate dehydrogenase
• targeted therapies
• biliary tract cancer
• intrahepatic cholangiocarcinoma
• extrahepatic cholangiocarcinoma

1. Cholangiocarcinoma, molecular profiling and experimental drugs

Cholangiocarcinomas (CCAs) are a heterogeneous group of malignancies arising from the biliary tract. CCAs are categorized as intrahepatic (iCCA) and extrahepatic CCA (eCCA) depending on their anatomical site of origin. The eCCA further splits into perihilar (pCCA) and distal (dCCA) CCA [1]. Heterogeneity at genomic, epigenetic, and molecular level dramatically impacts the efficacy of available systemic therapies [1]. Adding to the complexity, most patients present at an advanced stage, and potentially curative resection is feasible in only 20% of the patients [2]. Adjuvant capecitabine should be considered for all patients with resected biliary tract cancer, particularly those with lymph node involvement or a margin-positive resection [3]. Unfortunately, most patients will either recur after potentially curative treatment or present with unresectable or metastatic disease. The standard of care for patients with unresectable biliary tract cancer is a combination of cisplatin and gemcitabine, though this combination has only demonstrated a median overall survival (mOS) of 11.7 months [4]. Multiple efforts are underway to try to build on this backbone. For instance, based on promising results in a single-arm phase 2 study, SWOG 1815 is currently testing a triplet regimen of cisplatin, gemcitabine, and nab-paclitaxel (NCT03768414) [5] and KHBO1401-MITSUBA study in Japan is testing a triplet regimen of (gemcitabine, cisplatin, and S-1) in first-line setting [6]. Following progression first-line therapy, only 15–25% of patients can receive second-line systemic therapy depending on their performance status and organ function [7]. The ABC-06 trial was the first prospective, phase III study in second-line setting, comparing FOLFOX to active symptom control. While there was a significant improvement in mOS, the results remain underwhelming [8]. Most patients receiving second-line therapy have an mOS of 3–7 months [7]. Immunotherapy is rarely an option as the role is limited to patients with deficient mismatch repair pathway and microsatellite instability (MSI-high). MSI-high is rare (1%), and most of these are seen in tumors harboring a high tumor mutation burden. Studies have demonstrated low PD-L1 expression (9%) and low PD-L1 amplification (0.27%) in these tumors and there is no evidence that PD-L1 expression is correlated with response to immunotherapy [9].

Recent advances in next-generation sequencing (NGS) techniques and routine tumor profiling has helped define the genomic landscape of CCAs [10,11]. CCAs are genetically heterogeneous diseases with specific patterns based on anatomic location (iCCAs vs. eCCA), geographical location (Eastern vs. Western), and etiology (fluke, Hepatitis B, other causes) [12–14]. Similarly, an integrative clustering analysis by an international collaborative effort defined four CCA clusters – Fluke-Positive CCAs (Clusters 1/2) were enriched in ERBB2 amplification and TP53 mutations, and Fluke-Negative CCAs (Clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements [15]. Somatic alterations with therapeutic implications can be found in up half of these patients [11]. KRAS, SMAD4, and STK11 alterations are common in extrahepatic cholangiocarcinoma, whereas mutations in IDH1, BAP1, TP53, and FGFR2 fusions occur with greater frequency in intrahepatic cases. BAP1 mutations and FGFR2 gene fusions are exclusively in patients with intrahepatic cholangiocarcinoma [11]. The evolving knowledge about the genomic profile of CCA is leading to the development of targeted therapies and supporting the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers.

The MOSCATO-01 trial offered early supportive evidence (median OS 17 vs. 5 months; p = 0.008) in favor of personalized treatment of CCAs after years of negative trials involving drugs targeting pathways such as angiogenesis or the human epidermal growth factor receptor (HER [or ERBB]) family, HGF/c-MET, Hedgehog, KRAS/BRAF/MEK/ERK, and PI3K/AKT/mTOR [16,17]. The sea change in drug development and clinical trial activity in CCAs is revealed by a search on clinicaltrials.gov, resulting in more than 500 trials with a steady increase in trials since 2010 (Figure 1). Several early phase clinical trials are either completed or underway testing drugs targeting the fibroblast growth factor receptor 2 (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, chromatin remodeling genes (ARID1, BAP1, and PBRM1), DNA damage repair (DDR) pathways, BRAF, and RNF43 mutations [9,14,17].

Figure 1. Increasing trends in registration of cholangiocarcinoma clinical trials in the last decade

Targeting FGFR2 fusions and IDH mutations has demonstrated encouraging results (Table 1) [18]. In fact, targeting FGFR2 with pemigatinib, and FGFR inhibitor, is currently the only FDA approved strategy for the treatment of CCAs. FGFRs are a family of four transmembrane receptors with intracellular tyrosine kinase domains (FGFR1-4). FGFR2 tyrosine kinase fusions are seen in about 15% of iCCAs and activate multiple downstream canonical signaling events to propagate oncogenesis [17,19]. Hence, tyrosine kinase inhibitors (TKIs) such as ponatinib, pazopanib, regorafenib, infigratinib, derazantinib, futibatinib, and pemigatinib have been studied in several phase 1 and 2 clinical trials with encouraging results. FDA recently approved pemigatinib for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangements based on the results of FIGHT-202. Among the 107 patients, the overall responserate (ORR) was 36%, with 3 complete responses. The median duration of response (DOR) was 7.5 months with responses lasting ≥6 months in 24 of the 38 (63%) responding patients and ≥12 months in 7 (18%) patients. No responses were observed among patients with other FGF/FGFR alterations, and hence the use of pemigatinib should be currently limited to patients with FGFR2 fusions [18].

Table 1. Selected published targeted therapy trials in advanced cholangiocarcinoma

NCT	Study Drug/Target	Author	Trial Name	Design	Sample size (n)	Outcomes
NCT02150967	Infigratinib(BGJ398)/FGFR2 (FGFR pathway)	Javle, M	A Phase II, Single Arm Study of BGJ398 in Patients with Advanced Cholangiocarcinoma	Phase II, multicenter, single arm study	160	ORR = 14.8%, Disease control rate = 83.6%, mPFS = 6.8 months, mOS = 12.5 months
NCT03230318	Derazantinib (ARQ 087)/FGFR2 (FGFR pathway)	Mazzaferro,V	Derazantinib in Subjects with FGFR2 Gene Fusion-, Mutation- or Amplification- Positive Inoperable or Advanced Intrahepatic Cholangiocarcinoma (FIDES-01)	Phase II, open label, single arm study	143	ORR = 20.7%, Disease control rate = 82.8%, mPFS = 5.7 months
NCT02924376	Pemigatinib (FIGHT-202)/FGFR2 (FGFR pathway)	Abou-Alfa, GK	Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma	Phase II, multicenter, open-label study	147	ORR = 35.5%, Disease control rate = 82%, mPFS = 6.93 months, mOS = 21.1 months
NCT02989857	Ivosidenib (AG-120)/IDH1 (TCA cycle)	Abou-Alfa, GK	Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma with IDH1 Mutations (ClarIDHy)	Phase 3, multicenter, randomized, double-blind, placebo-controlled study	187	ORR = 2.4%, mPFS = 2.7 months vs 1.4 months
NCT02034110	Dabrafenib and Trametinib/BRAF, MEK (RAS/RAF/MEK pathway)	Subbiah,V	Dabrafenib plus trametinib in patients with BRAF V600E-mutated biliary tract cancer (ROAR)	Phase II, open-label, single-arm, multicenter basket trial	206	ORR = 47%, mPFS = 9 months, mOS = 14 months

Abbreviations: National Clinical Trial (NCT), Overall Response Rate (ORR), Median Progression-free survival (mPFS), Fibroblast growth factor receptors (FGFR), Median Overall Survival (mOS), Isocitrate dehydrogenase 1 (IDH1)

Targeting IDH has also yielded promising results. The prevalence of IDH mutation is approximately 20% in patients with CCA. IDH1 mutations are more common as compared to IDH2 mutations and are mostly seen in noninfectious (Opistorchis viverrine [OV] unrelated and hepatitis-negative) iCCA. Somatic gain-of-function mutations in IDH1 and IDH2 result in the accumulation of the 2-hydroxyglutarate (2-HG), which promotes a hypermethylated phenotype and tumorigenesis by inhibiting DNA and protein demethylation [20]. The recently published ClarIDHy phase III trial showed that the IDH1 inhibitor ivosidenib could lower the risk of death by 63% in CCA patients who harbor IDH1-mutations and have progressed on prior chemotherapy [21]. The results of multiple ongoing trials may expand the role of IDH inhibitors beyond a limited subset of IDH-1-mutated patients, especially when IDH inhibitors are combined with chemotherapy or PARP inhibitors, as the IDH mutations can induce a homologous recombination defect similar to a ‘BRCAness’ phenotype [22]. Targeting other pathways such as HER2, RAS/ERK pathway, PI3K/AKT/mTOR, DNA repair mechanisms, and BAP-1 mutations and VEGF have shown modest activity but continue to be under investigation [17]. That said, impressive results were seen in BRAF mutated CCA patients in the ROAR basket trial with the dual inhibition of BRAF and MEK pathways using dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). Here, an overall response rate of 47%, a median PFS of 9 months, and a median OS of 14 months in patients with CCA (Table 1) [23].

2. Expert opinion

A personalized approach to cholangiocarcinoma continues to evolve but should be considered an option for all patients with targetable alterations (Figure 2). This underscores the importance of biomarker testing for every advanced CCA patient. Increasing the feasibility of conducting targeting therapy trials through international collaborations and with advances in liquid biopsy represent major advances to support personalized medicine. Several ongoing trials (the National Cancer Institute [NCI] Molecular Analysis for Therapy Choice [MATCH], GOZILA study (UMIN000029315) [24] and the ASCO Targeted Agent and Profiling Utilization Registry [TAPUR] trials) are using next-generation sequencing (NGS) to identify molecular abnormalities in the tumors of patients with refractory cancers that may potentially match molecularly targeted therapies that are either in clinical trials or approved for the treatment of other cancer types. This approach can and should be leveraged in CCA too. Molecular profiling, new drug development, and availability of clinical trials have opened up the possibility of long-term survival, at least for select patients, in this devastating disease.

Figure 2. Approach to targeted therapies in cholangiocarcinoma after progression on 1^st line treatment

Declaration of interest

R Shroff is an Advisory Board Member for Merck, Seattle Genetics, QED Therapeutics, DebiPharm, Agios, Clovis, Exelixis, and Incyte. She also receives research funding from Merck, Haloyzme, Pieris, Taiho, Rafael Pharmaceuticals, and Exelixis Pharmaceuticals. 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. 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.

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Funding

This paper was not funded.