Next Article in Journal
Assessing Drought Tolerance in a Large Number of Upland Cotton Plants (Gossypium hirsutum L.) under Different Irrigation Regimes at the Seedling Stage
Next Article in Special Issue
Second-Line Chemotherapy for Intrahepatic Cholangiocarcinomas: What Is the Real Gain?
Previous Article in Journal
Schnider and Eleveld Models for Propofol Target-Controlled Infusion Anesthesia: A Clinical Comparison
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Life
Volume 13
Issue 10
10.3390/life13102066
life-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Targeted Therapies in Advanced Cholangiocarcinoma

by
Michael H. Storandt
1,
Peter C. Kurniali
2,3,
Amit Mahipal
4 and
Zhaohui Jin
5,*
1
Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
2
Department of Hematology/Medical Oncology, Sanford Cancer Center, Bismarck, ND 58501, USA
3
Department of Internal Medicine, Division of Hematology/Oncology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203, USA
4
Department of Oncology, University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH 44106, USA
5
Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA
*
Author to whom correspondence should be addressed.
Life 2023, 13(10), 2066; https://doi.org/10.3390/life13102066
Submission received: 31 August 2023 / Revised: 2 October 2023 / Accepted: 13 October 2023 / Published: 16 October 2023
(This article belongs to the Special Issue Hepato-Pancreatic-Biliary Tract Cancers)
Browse Figures
Versions Notes

Abstract

:
Primary tumor resection and liver transplantation are the only curative treatment options for the management of cholangiocarcinoma (CCA). However, for patients with advanced or metastatic disease, palliative systemic therapy remains the only treatment option. The development of targeted therapeutics has begun to shift the treatment paradigm in CCA. Targets of interest in CCA include mutated isocitrate dehydrogenase-1 (mIDH-1), human epidermal growth factor receptor 2 (HER2) overexpression/amplification, and fibroblast growth factor receptor 2 (FGFR2) fusion, in addition to less frequently observed targets such as BRAF V600E, deficient mismatch repair/high microsatellite instability (dMMR/MSI-H), and high tumor mutation burden (TMB-H). These targets are observed in varying frequency among patients with intrahepatic CCA and extrahepatic CCA. Multiple novel therapies have been developed to exploit each of these targets, with some having received United States Food and Drug Administration approval for use in the second-line setting. In the current review, we discuss targets of interest in CCA and summarize current evidence evaluating available therapies directed at these targets.

1. Introduction

Cholangiocarcinoma (CCA) is a malignancy of the biliary epithelium that accounts for approximately 3% of gastrointestinal malignancies globally [1]. CCA is subclassified based on its anatomic location and may be categorized as intrahepatic (iCCA), which accounts for 10–20% of CCA, or extrahepatic, which accounts for 80–90% of CCA in the United States (U.S.) [2,3]. CCA exhibits geographic trends in incidence, with the highest rates observed in Southeast Asia, and substantially lower rates in Western nations [4,5]. This is related to its unique risk factor profile, with risk factors including liver flukes, hepatolithiasis, and hepatitis B virus in Asian countries, and more commonly cholangitis in the U.S. [1,5]. Of note, a recent study has suggested an increase in rates of CCA in the United States, with this increase primarily seen in iCCA [6,7,8,9]. Surgical resection or transplant in select cases are the only curative options for CCA, and cases advanced beyond surgical resection are managed with palliative systemic therapy and, in select cases, liver-directed therapy.
Previously, standard first-line systemic therapy for advanced CCA consisted of gemcitabine plus cisplatin based on the ABC-02 trial that demonstrated survival benefit with the combination regimen compared to gemcitabine monotherapy, and this remained the standard of care for over a decade [10]. More recently, a phase 2 trial evaluating gemcitabine plus cisplatin with the addition of durvalumab, a monoclonal antibody targeting programmed death-ligand 1 (PD-L1), demonstrated an objective response in 34 of 47 patients (70%) [11]. This was followed by TOPAZ-1, which is an ongoing global phase 3 trial enrolling patients with advanced, previously untreated biliary tract cancers, in which patients were randomized to receive gemcitabine plus cisplatin with or without durvalumab [6]. Interim analysis of this study found that the addition of durvalumab to chemotherapy led to improved median progression-free survival (mPFS) [7.2 vs. 5.7 months, hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.64–0.89, p = 0.001] and median overall survival (mOS) (12.8 vs. 11.5 months, HR 0.80, 95% CI 0.66–0.97, p = 0.021) [12]. The TOPAZ-1 trial established gemcitabine plus cisplatin with durvalumab as standard first-line systemic therapy for advanced CCA.
More recently, KEYNOTE-966, which was a randomized, double-blind, placebo-controlled, phase 3 trial, evaluated patients with advanced, previously untreated biliary tract cancers who were randomized to receive gemcitabine plus cisplatin with pembrolizumab, an anti-programmed cell death-1 (anti-PD-1) antibody, or placebo [13]. Patients receiving chemotherapy plus pembrolizumab manifested an improved mOS of 12.7 months versus 10.9 months in the placebo arm (HR 0.83, 95% CI 0.72–0.95, p = 0.0034). This regimen has not yet received U.S. Food and Drug Administration (FDA) approval but represents an alternative first-line option for advanced CCA.
Following progression on first-line systemic therapy, second-line therapy may consist of folinic acid, fluorouracil, and oxaliplatin (FOLFOX), after the ABC-06 trial, which was an open-label, randomized, phase 3 trial consisting of patients with advanced biliary tract cancer who had progression on first-line gemcitabine plus cisplatin and were randomized to active symptom control with or without FOLFOX, found that patients in the FOLFOX arm exhibited longer mOS (6.2 months vs. 5.3 months, HR 0.69, 95% CI 0.50–0.97, p = 0.031) [14]. Alternatively, NIFTY, a phase 2b, open-label, randomized trial conducted in South Korea, randomized patients with metastatic biliary tract cancer who had progressed on first-line gemcitabine plus cisplatin to fluorouracil plus leucovorin with or without liposomal irinotecan [15]. The irinotecan-containing arm was able to achieve its primary endpoint of improved mPFS (4.2 vs. 1.7 months, HR 0.61, 95% CI 0.44–0.86, p = 0.004) [16]. However, NALIRICC-AIO-HEP-0116, a phase 2 trial conducted in Germany in which patients were randomized to receive fluorouracil plus leucovorin with or without liposomal irinotecan, failed to demonstrate significant improvement in mPFS (2.8 vs. 2.3 months) or mOS (6.9 vs. 8.2 months), and the liposomal irinotecan-containing regimen was associated with greater toxicity [17].The difference in outcomes between these two trials may be explained by multiple differences. NIFTY was conducted in an Asian population, among which 42.5% had intrahepatic disease, while NALIRICC-AIO-HEP-0116 was conducted in a European population, among which 64% had intrahepatic disease. Additionally, the liposomal irinotecan dose was 70 mg/m2 in NIFTY but was 80 mg/m2 in NALIRICC-AIO-HEP-0116. At this time, fluoropyrimidine plus irinotecan may be considered a second- or third-line option in CCA, but the efficacy of irinotecan-based regimens is not well established. Select trials establishing first- and second-line standards of care are listed in Table 1.
Given the marginal difference in response rate and overall survival with different combinations of cytotoxic chemotherapy and immunotherapy in advanced CCA and the detection of actionable targets in nearly 50% of CCA cases, greater interest has been generated in targeted therapy for the management of CCA [18]. This has subsequently led to the development of novel therapeutics, altering the treatment paradigm for CCA [19,20]. Figure 1 depicts an increase in publications using the search terms “targeted” and “cholangiocarcinoma” over the past 10 years. The following article will review current targets of interest in advanced CCA and discuss current trial data evaluating the efficacy of novel therapies directed at these targets.

2. IDH-1 Mutation

2.1. IDH-1 Mutation Pathophysiology

Isocitrate dehydrogenase-1 (IDH-1) is a metabolic enzyme that functions to convert isocitrate to α-ketoglutarate, and mutations of this enzyme have been implicated in oncogenesis [21]. Specifically, the IDH-1 mutation (mIDH-1) may result in a gain of function, facilitating the conversion of α-ketoglutarate to D-2-hydroxyglutarate, which is an oncometabolite [21,22]. Accumulation of D-2-hydroxyglutarate is thought to result in epigenetic dysregulation, resulting in impairment of cellular differentiation [21]. Mutation of IDH-1 has been implicated in glioma and acute myeloid leukemia, as well as iCCA, where it may be detected in 13–25% of cases [23,24,25]. Detection in eCCA is rare and may be present in <1% of patients [25]. It is unclear if mIDH-1 is associated with a difference in overall survival and progression-free survival when compared to CCA patients lacking this mutation [25,26].

2.2. IDH-1 Targeted Therapy

Ivosidenib is a targeted inhibitor of mIDH-1 and was first used in the management of mIDH-1 acute myeloid leukemia [27]. It was first evaluated for use in solid malignancies in a phase 1 dose escalation and expansion study enrolling patients with an mIDH-1 solid malignancy that had progressed on at least one prior line of therapy [28]. This study included 73 patients with mIDH-1 CCA. Among patients with CCA, the most common treatment-related toxicities included fatigue (42%), nausea (34%), diarrhea (32%), abdominal pain (27%), decreased appetite (27%), and vomiting (23%). Grade 3 or worse toxicities included ascites (5%), anemia (4%), and fatigue (3%). Overall, 5% of the total study population had a partial response, and mPFS was 3.8 months (95% CI 3.6–7.3).
This trial was subsequently followed by ClarIDHy, which was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial evaluating ivosidenib in 230 patients with mIDH-1 CCA who had progressed on at least one prior line of therapy [29]. Patients were randomized 2:1 to receive ivosidenib versus placebo, and, of note, patients were allowed to crossover to the ivosidenib arm at disease progression. Only 3 patients (2%) in the ivosidenib arm had a partial response; however, 51% had stable disease, which is consistent with the known mechanism of ivosidenib, which is not a cytoxic drug but inhibits mIDH-1, allowing for cellular differentiation. This study ultimately achieved its primary endpoint of improved mPFS, primarily driven by a high rate of stable disease, with those receiving ivosidenib manifesting an mPFS of 2.7 months versus 1.4 months in the placebo arm (HR 0.37, 95% CI 0.25–0.54, p < 0.0001). Final survival analysis failed to demonstrate a statistically significant improvement in survival, with an mOS of 10.3 months in the ivosidenib arm versus 7.5 months in the placebo arm (HR 0.79, 95% CI 0.56–1.12, p = 0.09) [30]. However, the survival benefit may be diluted by the fact that crossover was allowed in this trial, and 70% of patients in the placebo arm received ivosidenib after progression. Rank-preserving structural failure time-adjusted mOS analysis accounting for crossover did demonstrate improved overall survival (HR 0.46, 95% CI 0.28–0.75, p = 0.0008). In addition to the above-mentioned benefits, those receiving ivosidenib did not experience a decline in quality of life when compared to placebo. Based on the results of ClarIDHy, the U.S. FDA granted approval of ivosidenib for patients with advanced mIDH-1 CCA who had progressed on first-line therapy.

3. HER2 Overexpression and/or Amplification

3.1. HER2 Overexpression and/or Amplification Pathophysiology

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that, when activated, results in activation of the PI3K-AKT-mTOR pathway [31,32]. Overexpression of HER2 may occur through HER2 gene amplification, which may in turn result in the formation of homodimers or heterodimers with other HER proteins, such as HER3, leading to activation of downstream signaling pathways [32,33]. HER2 amplification has been implicated in multiple malignancies, most commonly bladder cancer, followed by esophageal/gastroesophageal junction, breast, gallbladder, eCCA, gastric, and cervical cancer [34]. HER-2 amplification/overexpression may be detected in approximately 17% of cases of eCCA and 5% of cases of iCCA [35]. HER2 amplification/overexpression has been associated with shorter disease-free survival following curative resection of biliary tract malignancies [36]. Evidence is limited with regards to the prognostic implications of HER2 amplification/overexpression in advanced CCA, but some evidence may suggest that it does not impact patient prognosis significantly [37].

3.2. HER2 Overexpression/Amplification Targeted Therapy

Trastuzumab is a monoclonal antibody that binds domain IV of HER2, resulting in antibody-dependent cell-mediated cytotoxicity, while pertuzumab, which has shown synergism when used with trastuzumab, is a monoclonal antibody that binds subdomain II of HER2, blocking dimerization and therefore activation of HER2 [38]. HER2-directed therapy in CCA has been evaluated in MyPathway, which was a non-randomized, multicenter, open-label, phase 2a basket study that enrolled 39 patients with advanced, previously treated biliary tract malignancies with HER2 amplification and/or overexpression [39]. Patients enrolled would receive pertuzumab plus trastuzumab with a primary endpoint of objective response rate (ORR). ORR was 23%, with 23% of patients having a partial response. Median PFS was 2.6 months (95% CI 1.0–5.3) for seven patients with iCCA and 6.8 months (95% CI 1.3–13.5) for 7 patients with eCCA. Patients with iCCA manifested a mOS of 3.9 months (95% CI 1.2–8.1), while those with eCCA manifested a mOS of 8.0 months (95% CI 2.0–not estimable). Ninety-two percent of patients developed treatment-emergent adverse events (TEAEs), with the most common grade 1–2 events including diarrhea (33%), alanine aminotransferase (ALT) elevation (18%), aspartate aminotransferase (AST) elevation (18%), fatigue (18%), anemia (15%), pyrexia (15%), and nausea (15%). Forty-six percent of patients had a grade 3–4 TEAE, with the most common including ALT elevation (13%), AST elevation (13%), and alkaline phosphatase elevation (10%). Based on the results of this trial, pertuzumab plus trastuzumab may be considered a second-line option for HER2 overexpressing/amplified CCA.
HERIZON-BTC-01 was a global, phase 2b trial evaluating zanidatimab, a monoclonal antibody binding HER2 at two domains, resulting in the formation of HER2-antibody clusters that are internalized, reducing HER2 expression, in patients with advanced, HER2-amplified biliary tract cancers with progression on gemcitabine-based therapy [40]. Among 80 patients with HER2 2+/3+ expression, an ORR of 41.3% was observed with an mPFS of 5.5 months. Fifty-four percent experienced a grade 1 or 2 treatment-related adverse event (TRAE), the most common of which included diarrhea, infusion-related reactions (32% each), and nausea (8%). Eighteen percent had a grade 3 or greater adverse event, including diarrhea (5%), ejection fraction decrease (3%), and anemia (2%). This study demonstrates the overall tolerability of zanidatimab, with promise for use in HER2-positive biliary tract malignancies.
DESTINY-PanTumor02 was an open-label, phase 2 trial evaluating trastuzumab deruxtecan, a topoisomerase inhibitor conjugated to trastuzumab, in patients with HER2-positive, previously treated solid malignancies, excluding breast, gastric, colorectal, and non-small-cell lung cancer [41]. Among the 267 patients enrolled, an ORR of 37.1% was seen with a median duration of response (mDOR) of 11.8 months. This study included 41 patients with biliary tract cancer who had an ORR of 22.0%. When looking at 16 patients with biliary tract cancer with HER2 3+ expression by IHC, an ORR of 56.3% was seen. Among all patients, grade 3 or greater adverse events were reported in 58.4%, with 11.6% discontinuing treatment due to adverse events. Overall, this study suggests a role for trastuzumab deruxtecan in HER2-positive CCA, primarily those with 3+ expression, based on the high response rate seen in this trial.

4. FGFR2 Fusion or Rearrangement

4.1. FGFR2 Fusion or Rearrangement Pathophysiology

Fibroblast growth factor receptor 2 (FGFR2) is a member of a family of four receptor tyrosine kinases that, when activated by fibroblast growth factors, dimerize, leading to autophosphorylation of the intracellular kinase domain and activation of downstream signaling pathways [42,43,44,45]. Dysregulation of FGFR2 may play a role in oncogenesis through angiogenesis and the migration and survival of tumor cells [46,47]. FGFR2 fusion seen in CCA is most commonly due to chromosomal rearrangement causing a C-terminal substitution of FGFR2 to the region of a binding partner, allowing auto-dimerization of FGFR2 and constitutive activation of downstream signaling pathways [48,49]. FGFR2 fusion is primarily seen in iCCA and rarely other cancers, including gallbladder carcinoma, hepatocellular carcinoma, pancreatic cancer, and sarcoma. In iCCA, frequency was initially reported in approximately 15% of cases, but in advanced iCCA, the frequency may be lower in 7–10% [50,51]. FGFR2 alterations have been associated with improved survival in iCCA, even without the use of FGFR inhibitors [52,53].

4.2. FGFR2 Fusion or Rearrangement Targeted Therapy

FGFR2 is one of the best studied targets with regard to therapeutic options in CCA, and multiple FGFR inhibitors have received FDA approval for the indication of CCA, including pemigatinib, futibatinib, and infigratinib [49].

4.2.1. Pemigatinib

Pemigatinib is a selective inhibitor of FGFR1-3 and was the first FGFR inhibitor to receive FDA approval for treatment of CCA [54,55]. It was first evaluated in the phase 1/2 dose escalation/expansion trial, FIGHT-101, which ultimately determined a dose of 13.5 mg for the expansion portion of the trial [56]. This study included 21 patients with CCA, of whom 5 exhibited a partial response. The most common TEAEs included hyperphosphatemia (75.0%), fatigue (39.1%), dry mouth (38.3%), stomatitis (34.4%), diarrhea (32%), and alopecia (31.3%). The most common grade 3 or greater toxicities included fatigue (10.2%), stomatitis (8.6%), and anemia (7.0%). Clinically notable TEAEs included hyperphosphatemia (75%), nail toxicity (32%), dry eye (23.4%), blurred vision (16.4%), hypophosphatemia (15.6%), and eyelash changes (13.3%).
This was followed by FIGHT-202, which was a multicenter, open-label, phase 2 trial enrolling 3 cohorts of patients with CCA who had progressed on prior treatment: those with FGFR2 fusion or rearrangement, those with FGFR2 mutation, and those with no alteration of FGFR2 [57]. Among patients with FGFR2 fusion or rearrangement, 35.5% achieved an objective response, demonstrating clinical promise. Patients with FGFR2 fusion or rearrangement demonstrated an mPFS of 6.9 months (95% CI 6.2–9.6) and an mOS of 21.1 months (95% CI 14.8–not estimable). An additional phase 2 study evaluating pemigatinib in Chinese patients with advanced CCA who had progressed on prior therapy found an ORR of 50.0% [58]. Based on the results of FIGHT-202, pemigatinib was granted FDA approval for treatment of CCA with FGR2 fusion or rearrangement following progression on first-line therapy.
FIGHT-302 is currently ongoing, which is an open-label, randomized, active-control, phase 3 study evaluating first-line pemigatinib versus gemcitabine plus cisplatin in the treatment of CCA with FGFR2 rearrangement [59]. This study has the potential to impact the first-line treatment of CCA with FGFR2 fusion or rearrangement.

4.2.2. Futibatinib

Futibatinib is an irreversible, pan-FGFR inhibitor [60]. It was first evaluated in a phase 1 trial enrolling 86 patients with a history of advanced solid malignancy with progression on prior therapy, among whom 83% harbored an FGF/FGFR aberration [61]. This trial included 24 patients with CCA, and of the 5 patients who had a partial response, 3 were among those with CCA known to harbor an FGFR abnormality. The most frequently observed TEAEs included hyperphosphatemia (59%), diarrhea (37%), and constipation (34%), with 48% of patients experiencing grade 3 toxicity. Futibatinib was also evaluated in an additional phase 1 trial including 197 patients with advanced solid tumors, with an ORR of 25.4% in patients with FGFR2 fusion/rearrangement-positive iCCA [62].
These were followed by FOENIX-CCA2, which was a multinational, open-label, phase 2 study including 103 patients with advanced iCCA with FGFR2 fusion/rearrangement who had progressed on prior therapy [63]. An ORR of 52% was observed, and mPFS was 9.0 months (95% CI 6.9–13.1) and mOS was 21.7 months (95% CI 14.5-not evaluable). Later, updated analysis reported an ORR of 41.7%, mPFS of 8.9 months, and mOS of 20.0 months [64]. Based on the results of FOENIX-CCA2, futibatinib received FDA approval for advanced, FGFR2 fusion/rearrangement-positive iCCA with progression on prior therapy. FOENIX-CCA3 was a planned phase 3 trial to evaluate futibatinib versus gemcitabine plus cisplatin in the first-line setting; however, this trial has been halted due to slow patient accrual [65].

4.2.3. Infigratinib

Infigratinib is a pan-FGFR inhibitor that was first evaluated in a phase 1 dose escalation/expansion study that included 132 patients with solid malignancies with FGFR alterations [66,67]. This study determined a maximum tolerated dose of 125 mg based on dose-limiting toxicities.
Infigratinib was subsequently evaluated in an open-label, phase 2 trial that enrolled patients with advanced CCA harboring an FGFR2 fusion or alteration who had progressed on prior therapy [68]. An ORR of 14.8% and a disease control rate (DCR) of 75.4% were observed, and among 48 patients with an FGFR2 fusion, an ORR of 18.8% and a DCR of 83.3% were observed. The most commonly observed TEAEs included hyperphosphatemia (72.1%), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%), with grade 3 or 4 TEAEs in 41%, including hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). An additional open-label, phase 2 study enrolling 122 patients with advanced CCA with FGFR2 fusion or rearrangement with progression on prior gemcitabine-based chemotherapy found an ORR of 23.1% (95% CI 15.6–32.2) [69]. Based on the results of these phase 2 trials, the FDA has granted approval for the use of infigratinib for previously treated, advanced CCA harboring an FGFR2 fusion or rearrangement. Despite this, its manufacturer will no longer pursue this clinical indication for infigratinib, and further trials have been discontinued.

5. BRAF V600E

5.1. BRAF V600E Pathophysiology

BRAF is a proto-oncogene that functions within the mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathway and plays a role in cell proliferation [70]. BRAF V600E is the most common mutation of BRAF, resulting in constitutive activation of this signaling pathway. BRAF V600E has been implicated in multiple malignancies, including melanoma, colorectal cancer, hairy cell leukemia, and multiple myeloma [70]. BRAF V600E has been detected in 1–5% of cases of CCA and is primarily found in iCCA [71,72,73,74,75,76]. The presence of BRAF V600E has prognostic implications in iCCA and is associated with shorter overall survival and disease-free survival [71]. Additionally, when comparing patients with BRAF V600E to patients with non-V600E BRAF mutations, patients with BRAF V600E are more likely to have larger tumors, more synchronous tumors, and increased invasion of vessels or bile ducts [71].

5.2. BRAF V600E Targeted Therapy

Dabrafenib, a selective BRAF inhibitor, and trametinib, a MEK1/2 inhibitor, were evaluated via subprotocol H (EAY131-H) of the NCI-MATCH platform trial, which was an open-label, single-arm study enrolling 35 patients with a BRAF V600E mutated solid malignancy, excluding patients with melanoma, thyroid, colorectal, and non-small-cell lung cancer [77]. This study demonstrated an ORR of 38%, and among 4 patients with CCA, 3 exhibited a partial response. The most common TEAEs included fatigue (74%), nausea (57%), fever/chills (51 and 54% respectively), headache (29%), alkaline phosphatase elevation (31%), and AST elevation (29%). The most common grade 3 TEAEs included fatigue (13%), neutrophil count decrease (8.6%), white blood cell count decrease (8.6%), and hyponatremia (5.7%).
Dabrafenib plus trametinib was subsequently evaluated in ROAR, which was an open-label, single-arm, phase 2 basket study that included a biliary tract cancer cohort consisting of 43 patients with BRAF V600E-mutated, advanced biliary tract cancer with progression on prior therapy [78]. The ORR was 51% with an mPFS of 9 months (95% CI 5–10) and mOS of 14 months (95% CI 10–33). Dabrafenib and trametinib subsequently received FDA approval for advanced BRAF V600E-mutated solid malignancies with progression on prior therapy.

6. Deficient Mismatch Repair/High Microsatellite Instability

6.1. Deficient Mismatch Repair/High Microsatellite Instability Pathophysiology

Mismatch repair proteins, including MSH2, MSH6, MLH1, and PMS2, function to correct errors that occur during DNA replication [79,80]. Loss of function of one or more of these proteins is referred to as deficient mismatch repair (dMMR), which results in high microsatellite instability (MSI-H) through the accumulation of mutations within the cell. Deficient mismatch repair may occur sporadically or through germline mutation, which is referred to as Lynch syndrome. Deficient mismatch repair may be gauged by immunohistochemistry evaluation of the expression of mismatch repair proteins or through polymerase chain reaction (PCR). Deficient mismatch repair/MSI-H has been shown to be a predictive biomarker for the efficacy of immunotherapy, has been reported in approximately 2–3% of CCA, and may be found in both iCCA and eCCA with unclear distribution [81,82,83,84]. While data is limited with regard to prognostic implications, some evidence may suggest that dMMR/MSI-H status is a beneficial prognostic marker in CCA [85].

6.2. High Microsatellite Instability Targeted Therapy

6.2.1. Pembrolizumab

Pembrolizumab was evaluated for use in non-colorectal, MSI-H/dMMR, advanced solid malignancies with progression on prior therapy in the phase 2 KEYNOTE-158 study [86]. This study enrolled 233 patients, including 22 patients with CCA. Among all patients, the ORR was 34.3% with an mPFS of 4.1 months (95% CI 2.4–4.9) and mOS of 23.5 months (95% CI 13.5-not reached). TRAEs were observed in 64.8% of patients, with the most common including fatigue (14.6%), pruritis (12.9%), diarrhea (12.0%), and asthenia (10.7%). Grade 3–4 TRAEs were observed in 14.6%, with the most common including pneumonitis, severe skin reactions (1.3% each), fatigue, colitis, and hepatitis (0.9% each). The updated analysis reported an ORR of 30.8% (95% CI 25.8–36.2), with mPFS of 3.5 months (95% CI 2.3–4.2) and mOS of 20.1 months (95% CI 14.1–27.1) [87]. As a result, pembrolizumab received FDA approval for the treatment of MSI-H/dMMR solid tumors with progression on prior therapy, including CCA.

6.2.2. Dostarlimab

Similarly, dostarlimab, an anti-PD1 antibody, has been evaluated in the phase 1 GARNET trial, which included 144 patients with dMMR or POLE mutated, non-endometrial solid tumors with progression on prior therapy [88]. This study only included one patient with a biliary neoplasm but did demonstrate an ORR of 38.7% (95% CI 29.4–48.6) in patients with dMMR tumors. As such, this may be a potential option for dMMR/MSI-H CCA.

7. High Tumor Mutation Burden

7.1. High Tumor Mutation Burden Pathophysiology

Tumor mutation burden is the quantification of genetic mutations within a cell. This may be evaluated using next-generation sequencing of tumor DNA, and the presence of ≥10 mutations/megabase (mut/Mb) is frequently referred to as high tumor mutation burden (TMB-H) [89]. A high tumor mutation burden may be seen in conjunction with dMMR/MSI-H, although not exclusively, and may be predictive of responsiveness to immunotherapy [89]. In the case of CCA, different thresholds for defining TMB-H have been used, with one study reporting an incidence of 3.8% in iCCA using a TMB cutoff of 10 mut/mB [90], while another, using a cutoff of 17 mut/mB, found TMB-H in 3.5% of iCCA and 2% of eCCA [91]. There is conflicting data regarding the prognostic value of TMB-H status in iCCA [92,93]. This discrepancy may result from the varying frequency of immune checkpoint inhibitor use in these studies. Actionable targets in CCA are summarized in Table 2.

7.2. High Tumor Mutation Burden Targeted Therapy

A high tumor mutation burden is also a potential target in CCA. The previously mentioned KEYNOTE-158 trial was subsequently evaluated to determine the efficacy of pembrolizumab in patients with TMB-H advanced solid malignancies [94]. An ORR of 29% was observed in 102 patients with TMB-H tumors, whereas an ORR of 6% was observed in 688 patients without TMB-H tumors. Based on the results of this trial, the FDA granted approval of pembrolizumab for the treatment of non-colorectal, advanced, TMB-H, solid malignancies. It is important to note that this trial did not include any patients with biliary tract malignancies in the TMB-H group.
CheckMate 848 was a phase 2 trial that enrolled 212 patients with advanced TMB-H (by tissue biopsy or blood-based assay) solid malignancies who were immunotherapy naïve and had progressed on prior therapy [95]. Patients were randomized 2:1 to receive ipilimumab plus nivolumab versus nivolumab monotherapy. Those receiving ipilimumab plus nivolumab who had TMB-H status determined via tissue assay demonstrated an ORR of 35.3% (95% CI 24.1–47.8) with an mPFS of 4.1 months (95% CI 2.8–11.3) and mOS of 14.5 months (95% CI 7.7-not evaluable). Based on the results of this study, ipilimumab plus nivolumab may be considered in patients with TMB-H CCA. Pertinent clinical trials in CCA are listed in Table 3. A depiction of the various targets, as well as the therapeutics directed at these targets, is shown in Figure 2.

8. Other Uncommon/Potential Novel Targets in Cholangiocarcinoma

8.1. NTRK

Neurotrophic tyrosine receptor kinase (NTRK) is a family of three genes (NTRK1, NTRK2, and NTRK3) that encode tropomyosin receptor kinases (TRKA, TRKB, and TRKC) that play a role in neuronal development [96,97]. Binding of neurotrophins triggers TRK activation, leading to downstream signaling through phospholipase C, mitogen-activated protein kinase (MAPK), or phosphatidylinositol 3 kinase (PI3K) pathways [96,97]. NTRK fusion, similar in mechanism to FGFR2 fusion, stems from chromosomal rearrangement, resulting in the replacement of the 3′ region of NTRK with a binding partner that allows for dimerization of TRK and activation of signaling in the absence of neurotrophins [97]. NTRK fusion may be observed in <1% of solid malignancies, and has been reported in <1% of cases of CCA [96,98,99].
Entrectinib is an inhibitor of TRKA, TRKB, TRKC, ROS1, and ALK [100]. One study reported the combined results of two phase 1 trials, ALKA-372-001 and STARTRK-1, performing a subgroup analysis of patients with solid tumors having gene fusions involving NTRK1/2/3, ROS1, or ALK who were treated with the recommended phase 2 dose of entrectinib and had not received prior treatment with a tyrosine kinase inhibitor [101]. Thirty patients were included in this analysis, of which 25 were evaluable. Of these, three patients had NTRK1/2/3 gene fusion (none with CCA), and all three manifested a response, suggesting promise in using entrectinib in the management of solid malignancies with NTRK1/2/3 fusion. Among all 119 phase 1 patients, the most common TRAEs included fatigue (46%), dysgeusia (42%), paresthesia (29%), nausea (28%), and myalgia (23%). Grade 3 TRAEs included fatigue (4%), weight increase (2%), diarrhea (1%), and arthralgia (1%). A subsequent analysis was conducted, including data from three phase 1/2 trials (ALKA-372, STARTRK-1, and STARTRK-2), and included patients with NTRK fusion-positive, advanced solid malignancies who were tyrosine kinase inhibitor naïve and received entrectinib 600 mg daily [102]. Fifty-four patients were included in the final analysis, including 1 with CCA, with an ORR of 31% and a median duration of response of 10 months.
Larotrectinib is a highly selective, small-molecule TRK inhibitor that was evaluated in a combined analysis of a phase 1, a phase 1–2, and a phase 2 study, including children and adults with advanced solid malignancies harboring a TRK fusion [103]. This analysis included 55 patients, including 2 patients with CCA, and ultimately demonstrated an ORR of 75% (95% CI 61–85), with 55% of patients remaining progression-free at 1 year. The most common TRAEs included increased AST or ALT (38%), dizziness (25%), fatigue, nausea, constipation (16% each), increased body weight, and vomiting (11% each). The most common grade 3 TRAEs included increased AST or ALT (5%), dizziness, nausea, anemia, and a decreased neutrophil count (2% each).
Based on the results of these studies, NTRK fusion-targeted agents may have benefit in this small subpopulation of patients with CCA.

8.2. RET

RET proto-oncogene (RET) encodes a receptor tyrosine kinase, and fusion of the 3′ terminal of RET to the 5′ domain of RET finger protein has been implicated in oncogenesis [104]. RET fusion has been observed in thyroid, lung, colorectal, breast, and salivary gland cancers, and this mutation is rare in CCA [105].
Pralsetinib is an inhibitor of RET kinases, including fusion proteins stemming from RET fusion [106]. ARROW was a phase 1/2 trial enrolling 29 patients with RET-altered solid malignancies, including 3 patients with CCA [106]. This study demonstrated an ORR of 55% (95% CI 35–77) with mPFS of 7 months and mOS of 14 months. The most common TRAEs included increased AST (38%), increased ALT (34%), neutropenia (34%), anemia (31%), constipation (24%), decreased white blood cell count (21%), thrombocytopenia, hypertension, and asthenia (17% each). The most common grade 3 TRAEs included neutropenia (31%), anemia (14%), and increased AST (10%).
Selpercatinib is a selective RET kinase inhibitor that was evaluated in LIBRETTO-001, which is an ongoing phase 1/2 basket trial evaluating selpercatinib in patients with RET-fusion-positive advanced solid malignancies [107]. The interim analysis included 45 patients, including 2 with CCA, and of 41 efficacy-evaluable patients, the ORR was 43.9% (95% CI 28.5–60.3) with an mPFS of 13.2 months and an mOS of 18.0 months. The most common grade 1-2 TRAEs included dry mouth (29%), ALT increase, AST increase (18% each), diarrhea, QT prolongation, and thrombocytopenia (11% each). The most common grade 3 TRAEs included an ALT increase (16%), hypertension (13%), and an AST increase (11%).
These studies suggest a role for RET inhibition in patients with CCA with RET fusion, although the rarity of this mutation limits evaluation in this population.

9. Conclusions

As our understanding of oncogenesis in CCA continues to evolve, multiple targets for intervention have been identified, allowing for the development of targeted, novel therapeutics. Some of these, such as IDH-1 mutation, HER2 amplification/overexpression, or FGFR2 fusion/rearrangement, are more common, while others, including BRAF V600E, MSI-H, or TMB-H, are less common. These discoveries have paved the way for the development and clinical testing of targeted therapies aimed at these specific genetic anomalies. Multiple agents have been developed and have received FDA approval for use in the second-line setting, with ongoing phase 3 trials evaluating these agents in the first-line setting, although low enrollment has been a barrier in some instances.
Despitethis evolving treatment paradigm, limitations regarding the use of targeted therapies in CCA remain. Reviewing current trial data, most targeted therapies result in, at best, a few months of PFS improvement, with modest improvement in OS. This suggests a need to better understand the resistance mechanisms that develop. For example, in the case of FGFR2 inhibitors, multiple resistance mechanisms have been identified, including mutation of the receptor or activation of feedback survival loops, impairing the duration of response [108,109]. In the case of mIDH-1, previously identified resistance mechanisms include RTK pathway mutations, the development of secondary IDH mutations, isoform switching, mitochondrial metabolism, and clonal selection [110]. Future studies must evaluate methods to evade or limit the development of drug resistance.
Additionally, future trials should aim to assess targeted agents in combination with immunotherapy and/or chemotherapy. For example, in the case of HER2 overexpressing biliary tract cancer, a planned trial in South Korea will evaluate the combination of trastuzumab with gemcitabine, cisplatin, and nivolumab (NCT05749900). However, historically, trials evaluating targeted therapies in advanced biliary tract cancer have struggled with patient accrual. In addition to new combinations, new novel therapies are also in development, and continued improvement in the way we inhibit these mechanisms will be important going forward [111].
In summary, targeted therapies offer a new avenue of hope for patients with advanced CCA, though continued research is required to optimize these strategies, overcome resistance mechanisms, and identify the patient populations most likely to benefit. The aim of this article is to outline the current landscape and trial data evaluating targeted therapies in CCA and provide a foundational basis from which future drug optimization and development may grow.

Author Contributions

M.H.S. and Z.J. contributed to the conceptualization of the review. M.H.S. completed a literature review and drafted the original manuscript. P.C.K., A.M. and Z.J. contributed to the revision of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

M.H.S., A.M. and Z.J. declare no relevant disclosures. P.C.K. receives research funding from Onco Filtration.

References

  1. Rizvi, S.; Gores, G.J. Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma. Gastroenterology 2013, 145, 1215–1229. [Google Scholar] [CrossRef]
  2. Banales, J.M.; Cardinale, V.; Carpino, G.; Marzioni, M.; Andersen, J.B.; Invernizzi, P.; Lind, G.E.; Folseraas, T.; Forbes, S.J.; Fouassier, L.; et al. Expert Consensus Document: Cholangiocarcinoma: Current Knowledge and Future Perspectives Consensus Statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 261–280. [Google Scholar] [CrossRef]
  3. Mukkamalla, S.K.R.; Naseri, H.M.; Kim, B.M.; Katz, S.C.; Armenio, V.A. Trends in Incidence and Factors Affecting Survival of Patients With Cholangiocarcinoma in the United States. J. Natl. Compr. Canc. Netw. 2018, 16, 370–376. [Google Scholar] [CrossRef] [PubMed]
  4. Qurashi, M.; Vithayathil, M.; Khan, S.A. Epidemiology of Cholangiocarcinoma. Eur. J. Surg. Oncol. 2023. [Google Scholar] [CrossRef] [PubMed]
  5. Khan, S.A.; Tavolari, S.; Brandi, G. Cholangiocarcinoma: Epidemiology and Risk Factors. Liver Int. 2019, 39, 19–31. [Google Scholar] [CrossRef] [PubMed]
  6. Gad, M.M.; Saad, A.M.; Faisaluddin, M.; Gaman, M.A.; Ruhban, I.A.; Jazieh, K.A.; Al-Husseini, M.J.; Simons-Linares, C.R.; Sonbol, M.B.; Estfan, B.N. Epidemiology of Cholangiocarcinoma; United States Incidence and Mortality Trends. Clin. Res. Hepatol. Gastroenterol. 2020, 44, 885–893. [Google Scholar] [CrossRef]
  7. Kim, D.; Konyn, P.; Cholankeril, G.; Bonham, C.A.; Ahmed, A. Trends in the Mortality of Biliary Tract Cancers Based on Their Anatomical Site in the United States From 2009 to 2018. Am. J. Gastroenterol. 2021, 116, 1053–1062. [Google Scholar] [CrossRef]
  8. Javle, M.; Lee, S.; Azad, N.S.; Borad, M.J.; Kate Kelley, R.; Sivaraman, S.; Teschemaker, A.; Chopra, I.; Janjan, N.; Parasuraman, S.; et al. Temporal Changes in Cholangiocarcinoma Incidence and Mortality in the United States from 2001 to 2017. Oncologist 2022, 27, 874–883. [Google Scholar] [CrossRef]
  9. Jiang, Y.; Jiang, L.; Li, F.; Li, Q.; Yuan, S.; Huang, S.; Fu, Y.; Yan, X.; Chen, J.; Li, H.; et al. The Epidemiological Trends of Biliary Tract Cancers in the United States of America. BMC Gastroenterol. 2022, 22, 546. [Google Scholar] [CrossRef]
  10. Valle, J.; Wasan, H.; Palmer, D.H.; Cunningham, D.; Anthoney, A.; Maraveyas, A.; Madhusudan, S.; Iveson, T.; Hughes, S.; Pereira, S.P.; et al. Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. N. Engl. J. Med. 2010, 362, 1273–1281. [Google Scholar] [CrossRef]
  11. Oh, D.Y.; Lee, K.H.; Lee, D.W.; Yoon, J.; Kim, T.Y.; Bang, J.H.; Nam, A.R.; Oh, K.S.; Kim, J.M.; Lee, Y.; et al. Gemcitabine and Cisplatin plus Durvalumab with or without Tremelimumab in Chemotherapy-Naive Patients with Advanced Biliary Tract Cancer: An Open-Label, Single-Centre, Phase 2 Study. Lancet Gastroenterol. Hepatol. 2022, 7, 522–532. [Google Scholar] [CrossRef]
  12. Oh, D.-Y.; He, A.R.; Qin, S.; Chen, L.-T.; Okusaka, T.; Vogel, A.; Kim, J.W.; Suksombooncharoen, T.; Lee, M.A.; Kitano, M.; et al. A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Durvalumab in Combination with Gemcitabine plus Cisplatin (GemCis) in Patients (Pts) with Advanced Biliary Tract Cancer (BTC): TOPAZ-1. J. Clin. Oncol. 2022, 40, 378. [Google Scholar] [CrossRef]
  13. Kelley, R.K.; Ueno, M.; Yoo, C.; Finn, R.S.; Furuse, J.; Ren, Z.; Yau, T.; Klümpen, H.J.; Chan, S.L.; Ozaka, M.; et al. Pembrolizumab in Combination with Gemcitabine and Cisplatin Compared with Gemcitabine and Cisplatin Alone for Patients with Advanced Biliary Tract Cancer (KEYNOTE-966): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. Lancet 2023, 401, 1853–1865. [Google Scholar] [CrossRef] [PubMed]
  14. Lamarca, A.; Palmer, D.H.; Wasan, H.S.; Ross, P.J.; Ma, Y.T.; Arora, A.; Falk, S.; Gillmore, R.; Wadsley, J.; Patel, K.; et al. Second-Line FOLFOX Chemotherapy versus Active Symptom Control for Advanced Biliary Tract Cancer (ABC-06): A Phase 3, Open-Label, Randomised, Controlled Trial. Lancet Oncol. 2021, 22, 690–701. [Google Scholar] [CrossRef]
  15. Yoo, C.; Kim, K.P.; Jeong, J.H.; Kim, I.; Kang, M.J.; Cheon, J.; Kang, B.W.; Ryu, H.; Lee, J.S.; Kim, K.W.; et al. Liposomal Irinotecan plus Fluorouracil and Leucovorin versus Fluorouracil and Leucovorin for Metastatic Biliary Tract Cancer after Progression on Gemcitabine plus Cisplatin (NIFTY): A Multicentre, Open-Label, Randomised, Phase 2b Study. Lancet Oncol. 2021, 22, 1560–1572. [Google Scholar] [CrossRef] [PubMed]
  16. Hyung, J.; Kim, I.; Kim, K.P.; Ryoo, B.Y.; Jeong, J.H.; Kang, M.J.; Cheon, J.; Kang, B.W.; Ryu, H.; Lee, J.S.; et al. Treatment with Liposomal Irinotecan Plus Fluorouracil and Leucovorin for Patients with Previously Treated Metastatic Biliary Tract Cancer: The Phase 2b NIFTY Randomized Clinical Trial. JAMA Oncol. 2023, 9, 692–699. [Google Scholar] [CrossRef]
  17. Vogel, A.; Wenzel, P.; Folprecht, G.; Schutt, P.; Wege, H.; Kretzschmar, A.; Jacobasch, L.; Ziegenhagen, N.; Boeck, S.; Kanzler, S.; et al. Nal-IRI and 5-FU/LV Compared to 5-FU/LV in Patients with Cholangio- and Gallbladder Carcinoma Previously Treated with Gemcitabine-Based Therapies (NALIRICC—AIO-HEP-0116). Ann. Oncol. 2022, 33, S19–S26. [Google Scholar] [CrossRef]
  18. Lowery, M.A.; Ptashkin, R.; Jordan, E.; Berger, M.F.; Zehir, A.; Capanu, M.; Kemeny, N.E.; O’Reilly, E.M.; El-Dika, I.; Jarnagin, W.R.; et al. Comprehensive Molecular Profiling of Intrahepatic and Extrahepatic Cholangiocarcinomas: Potential Targets for Intervention. Clin. Cancer Res. 2018, 24, 4154–4161. [Google Scholar] [CrossRef]
  19. Chakrabarti, S.; Kamgar, M.; Mahipal, A. Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm. Cancers 2020, 12, 2039. [Google Scholar] [CrossRef]
  20. Tella, S.H.; Kommalapati, A.; Borad, M.J.; Mahipal, A. Second-Line Therapies in Advanced Biliary Tract Cancers. Lancet Oncol. 2020, 21, e29–e41. [Google Scholar] [CrossRef]
  21. Dang, L.; Yen, K.; Attar, E.C. IDH Mutations in Cancer and Progress toward Development of Targeted Therapeutics. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2016, 27, 599–608. [Google Scholar] [CrossRef]
  22. Dang, L.; White, D.W.; Gross, S.; Bennett, B.D.; Bittinger, M.A.; Driggers, E.M.; Fantin, V.R.; Jang, H.G.; Jin, S.; Keenan, M.C.; et al. Cancer-Associated IDH1 Mutations Produce 2-Hydroxyglutarate. Nature 2009, 462, 739–744. [Google Scholar] [CrossRef]
  23. Borger, D.R.; Tanabe, K.K.; Fan, K.C.; Lopez, H.U.; Fantin, V.R.; Straley, K.S.; Schenkein, D.P.; Hezel, A.F.; Ancukiewicz, M.; Liebman, H.M.; et al. Frequent Mutation of Isocitrate Dehydrogenase (IDH)1 and IDH2 in Cholangiocarcinoma Identified through Broad-Based Tumor Genotyping. Oncologist 2012, 17, 72–79. [Google Scholar] [CrossRef]
  24. Goyal, L.; Govindan, A.; Sheth, R.A.; Nardi, V.; Blaszkowsky, L.S.; Faris, J.E.; Clark, J.W.; Ryan, D.P.; Kwak, E.L.; Allen, J.N.; et al. Prognosis and Clinicopathologic Features of Patients with Advanced Stage Isocitrate Dehydrogenase (IDH) Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma. Oncologist 2015, 20, 1019–1027. [Google Scholar] [CrossRef] [PubMed]
  25. Boscoe, A.N.; Rolland, C.; Kelley, R.K. Frequency and Prognostic Significance of Isocitrate Dehydrogenase 1 Mutations in Cholangiocarcinoma: A Systematic Literature Review. J. Gastrointest. Oncol. 2019, 10, 751–765. [Google Scholar] [CrossRef] [PubMed]
  26. Wintheiser, G.; Zemla, T.; Shi, Q.; Tran, N.; Prasai, K.; Tella, S.H.; Mody, K.; Ahn, D.; Borad, M.; Bekaii-Saab, T.; et al. Isocitrate Dehydrogenase-Mutated Cholangiocarcinoma: Natural History and Clinical Outcomes. JCO Precis. Oncol. 2022, 6, e2100156. [Google Scholar] [CrossRef] [PubMed]
  27. DiNardo, C.D.; Stein, E.M.; de Botton, S.; Roboz, G.J.; Altman, J.K.; Mims, A.S.; Swords, R.; Collins, R.H.; Mannis, G.N.; Pollyea, D.A.; et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N. Engl. J. Med. 2018, 378, 2386–2398. [Google Scholar] [CrossRef] [PubMed]
  28. Lowery, M.A.; Burris, H.A.; Janku, F.; Shroff, R.T.; Cleary, J.M.; Azad, N.S.; Goyal, L.; Maher, E.A.; Gore, L.; Hollebecque, A.; et al. Safety and Activity of Ivosidenib in Patients with IDH1-Mutant Advanced Cholangiocarcinoma: A Phase 1 Study. Lancet Gastroenterol. Hepatol. 2019, 4, 711–720. [Google Scholar] [CrossRef]
  29. Abou-Alfa, G.K.; Macarulla, T.; Javle, M.M.; Kelley, R.K.; Lubner, S.J.; Adeva, J.; Cleary, J.M.; Catenacci, D.V.; Borad, M.J.; Bridgewater, J.; et al. Ivosidenib in IDH1-Mutant, Chemotherapy-Refractory Cholangiocarcinoma (ClarIDHy): A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 3 Study. Lancet Oncol. 2020, 21, 796–807. [Google Scholar] [CrossRef]
  30. Zhu, A.X.; Macarulla, T.; Javle, M.M.; Kelley, R.K.; Lubner, S.J.; Adeva, J.; Cleary, J.M.; Catenacci, D.V.T.; Borad, M.J.; Bridgewater, J.A.; et al. Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial. JAMA Oncol. 2021, 7, 1669–1677. [Google Scholar] [CrossRef]
  31. Yarden, Y.; Sliwkowski, M.X. Untangling the ErbB Signalling Network. Nat. Rev. Mol. Cell Biol. 2001, 2, 127–137. [Google Scholar] [CrossRef]
  32. Gajria, D.; Chandarlapaty, S. HER2-Amplified Breast Cancer: Mechanisms of Trastuzumab Resistance and Novel Targeted Therapies. Expert Rev. Anticancer Ther. 2011, 11, 263–275. [Google Scholar] [CrossRef] [PubMed]
  33. Dumbrava, E.E.I.; Balaji, K.; Raghav, K.; Hess, K.; Javle, M.; Blum-Murphy, M.; Ajani, J.; Kopetz, S.; Broaddus, R.; Routbort, M.; et al. Targeting ERBB2 (HER2) Amplification Identified by Next-Generation Sequencing in Patients With Advanced or Metastatic Solid Tumors Beyond Conventional Indications. JCO Precis. Oncol. 2019, 3, 1–12. [Google Scholar] [CrossRef] [PubMed]
  34. Yan, M.; Schwaederle, M.; Arguello, D.; Millis, S.Z.; Gatalica, Z.; Kurzrock, R. HER2 Expression Status in Diverse Cancers: Review of Results from 37,992 Patients. Cancer Metastasis Rev. 2015, 34, 157–164. [Google Scholar] [CrossRef] [PubMed]
  35. Galdy, S.; Lamarca, A.; McNamara, M.G.; Hubner, R.A.; Cella, C.A.; Fazio, N.; Valle, J.W. HER2/HER3 Pathway in Biliary Tract Malignancies; Systematic Review and Meta-Analysis: A Potential Therapeutic Target? Cancer Metastasis Rev. 2017, 36, 141–157. [Google Scholar] [CrossRef]
  36. Vivaldi, C.; Fornaro, L.; Ugolini, C.; Niccoli, C.; Musettini, G.; Pecora, I.; Cacciato Insilla, A.; Salani, F.; Pasquini, G.; Catanese, S.; et al. HER2 Overexpression as a Poor Prognostic Determinant in Resected Biliary Tract Cancer. Oncologist 2020, 25, 886–893. [Google Scholar] [CrossRef]
  37. Kim, H.; Kim, R.; Kim, H.R.; Jo, H.; Kim, H.; Ha, S.Y.; Park, J.O.; Park, Y.S.; Kim, S.T. HER2 Aberrations as a Novel Marker in Advanced Biliary Tract Cancer. Front. Oncol. 2022, 12, 834104. [Google Scholar] [CrossRef]
  38. Nami, B.; Maadi, H.; Wang, Z. Mechanisms Underlying the Action and Synergism of Trastuzumab and Pertuzumab in Targeting HER2-Positive Breast Cancer. Cancers 2018, 10, 342. [Google Scholar] [CrossRef]
  39. Javle, M.; Borad, M.J.; Azad, N.S.; Kurzrock, R.; Abou-Alfa, G.K.; George, B.; Hainsworth, J.; Meric-Bernstam, F.; Swanton, C.; Sweeney, C.J.; et al. Pertuzumab and Trastuzumab for HER2-Positive, Metastatic Biliary Tract Cancer (MyPathway): A Multicentre, Open-Label, Phase 2a, Multiple Basket Study. Lancet Oncol. 2021, 22, 1290–1300. [Google Scholar] [CrossRef]
  40. Harding, J.J.; Fan, J.; Oh, D.-Y.; Choi, H.J.; Kim, J.W.; Chang, H.-M.; Bao, L.; Sun, H.-C.; Macarulla, T.; Xie, F.; et al. Zanidatamab for HER2-Amplified, Unresectable, Locally Advanced or Metastatic Biliary Tract Cancer (HERIZON-BTC-01): A Multicentre, Single-Arm, Phase 2b Study. Lancet Oncol. 2023, 24, 772–782. [Google Scholar] [CrossRef]
  41. Meric-Bernstam, F.; Makker, V.; Oaknin, A.; Oh, D.-Y.; Banerjee, S.N.; Gonzalez Martin, A.; Jung, K.H.; Lugowska, I.A.; Manso, L.; Manzano, A.; et al. Efficacy and Safety of Trastuzumab Deruxtecan (T-DXd) in Patients (Pts) with HER2-Expressing Solid Tumors: DESTINY-PanTumor02 (DP-02) Interim Results. J. Clin. Oncol. 2023, 41, LBA3000. [Google Scholar] [CrossRef]
  42. Zheng, J.; Zhang, W.; Li, L.; He, Y.; Wei, Y.; Dang, Y.; Nie, S.; Guo, Z. Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review. Front. Chem. 2022, 10, 860985. [Google Scholar] [CrossRef] [PubMed]
  43. Schlessinger, J. Cell Signaling by Receptor Tyrosine Kinases: From Basic Concepts to Clinical Applications. Eur. J. Cancer Suppl. 2006, 4, 3–26. [Google Scholar] [CrossRef]
  44. Schlessinger, J. Receptor Tyrosine Kinases: Legacy of the First Two Decades. Cold Spring Harb. Perspect. Biol. 2014, 6, a008912. [Google Scholar] [CrossRef]
  45. Itoh, N.; Ornitz, D.M. Evolution of the Fgf and Fgfr Gene Families. Trends Genet. 2004, 20, 563–569. [Google Scholar] [CrossRef]
  46. Dienstmann, R.; Rodon, J.; Prat, A.; Perez-Garcia, J.; Adamo, B.; Felip, E.; Cortes, J.; Iafrate, A.J.; Nuciforo, P.; Tabernero, J. Genomic Aberrations in the FGFR Pathway: Opportunities for Targeted Therapies in Solid Tumors. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2014, 25, 552–563. [Google Scholar] [CrossRef]
  47. Touat, M.; Ileana, E.; Postel-Vinay, S.; André, F.; Soria, J.C. Targeting FGFR Signaling in Cancer. Clin. Cancer Res. 2015, 21, 2684–2694. [Google Scholar] [CrossRef]
  48. Katoh, M. FGFR Inhibitors: Effects on Cancer Cells, Tumor Microenvironment and Whole-Body Homeostasis (Review). Int. J. Mol. Med. 2016, 38, 3–15. [Google Scholar] [CrossRef]
  49. Storandt, M.H.; Jin, Z.; Mahipal, A. Pemigatinib in Cholangiocarcinoma with a FGFR2 Rearrangement or Fusion. Expert Rev. Anticancer Ther. 2022, 22, 1265–1274. [Google Scholar] [CrossRef]
  50. Hyung, S.; Han, B.; Jung, J.; Kim, S.T.; Hong, J.Y.; Park, S.H.; Zang, D.Y.; Park, J.O.; Park, Y.S.; Kim, K.M.; et al. Incidence of FGFR2 Amplification and FGFR2 Fusion in Patients with Metastatic Cancer Using Clinical Sequencing. J. Oncol. 2022, 2022, 9714570. [Google Scholar] [CrossRef]
  51. Mahipal, A.; Tella, S.H.; Kommalapati, A.; Anaya, D.; Kim, R. FGFR2 Genomic Aberrations: Achilles Heel in the Management of Advanced Cholangiocarcinoma. Cancer Treat. Rev. 2019, 78, 1–7. [Google Scholar] [CrossRef] [PubMed]
  52. Jusakul, A.; Cutcutache, I.; Yong, C.H.; Lim, J.Q.; Huang, M.N.; Padmanabhan, N.; Nellore, V.; Kongpetch, S.; Ng, A.W.T.; Ng, L.M.; et al. Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discov. 2017, 7, 1116–1135. [Google Scholar] [CrossRef] [PubMed]
  53. Rizzato, M.; Brignola, S.; Munari, G.; Gatti, M.; Dadduzio, V.; Borga, C.; Bergamo, F.; Pellino, A.; Angerilli, V.; Mescoli, C.; et al. Prognostic Impact of FGFR2/3 Alterations in Patients with Biliary Tract Cancers Receiving Systemic Chemotherapy: The BITCOIN Study. Eur. J. Cancer 2022, 166, 165–175. [Google Scholar] [CrossRef] [PubMed]
  54. Liu, P.C.C.; Koblish, H.; Wu, L.; Bowman, K.; Diamond, S.; DiMatteo, D.; Zhang, Y.; Hansbury, M.; Rupar, M.; Wen, X.; et al. INCB054828 (Pemigatinib), a Potent and Selective Inhibitor of Fibroblast Growth Factor Receptors 1, 2, and 3, Displays Activity against Genetically Defined Tumor Models. PLoS ONE 2020, 15, e0231877. [Google Scholar] [CrossRef] [PubMed]
  55. Wu, L.; Zhang, C.; He, C.; Qian, D.; Lu, L.; Sun, Y.; Xu, M.; Zhuo, J.; Liu, P.C.C.; Klabe, R.; et al. Discovery of Pemigatinib: A Potent and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor. J. Med. Chem. 2021, 64, 10666–10679. [Google Scholar] [CrossRef]
  56. Subbiah, V.; Iannotti, N.O.; Gutierrez, M.; Smith, D.C.; Féliz, L.; Lihou, C.F.; Tian, C.; Silverman, I.M.; Ji, T.; Saleh, M. FIGHT-101, a First-in-Human Study of Potent and Selective FGFR 1-3 Inhibitor Pemigatinib in Pan-Cancer Patients with FGF/FGFR Alterations and Advanced Malignancies. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2022, 33, 522–533. [Google Scholar] [CrossRef]
  57. Abou-Alfa, G.K.; Sahai, V.; Hollebecque, A.; Vaccaro, G.; Melisi, D.; Al-Rajabi, R.; Paulson, A.S.; Borad, M.J.; Gallinson, D.; Murphy, A.G.; et al. Pemigatinib for Previously Treated, Locally Advanced or Metastatic Cholangiocarcinoma: A Multicentre, Open-Label, Phase 2 Study. Lancet Oncol. 2020, 21, 671–684. [Google Scholar] [CrossRef]
  58. Shi, G.; Huang, X.; Wen, T.; Song, T.; Kuang, M.; Mou, H.; Bao, L.; Zhao, H.-T.; Zhao, H.; Feng, X.; et al. Pemigatinib in Chinese Patients with Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma Including FGFR2 Fusion or Rearrangement: Updated Data from an Open-Label, Single-Arm, Multicenter Phase II Study (CIBI375A201 Study). J. Clin. Oncol. 2022, 40, e16183. [Google Scholar] [CrossRef]
  59. Bekaii-Saab, T.S.; Valle, J.W.; Van Cutsem, E.; Rimassa, L.; Furuse, J.; Ioka, T.; Melisi, D.; Macarulla, T.; Bridgewater, J.A.; Wasan, H.S.; et al. FIGHT-302: Phase III Study of First-Line (1L) Pemigatinib (PEM) versus Gemcitabine (GEM) plus Cisplatin (CIS) for Cholangiocarcinoma (CCA) with FGFR2 Fusions or Rearrangements. J. Clin. Oncol. 2020, 38, TPS592. [Google Scholar] [CrossRef]
  60. Kalyukina, M.; Yosaatmadja, Y.; Middleditch, M.J.; Patterson, A.V.; Smaill, J.B.; Squire, C.J. TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure. ChemMedChem 2019, 14, 494–500. [Google Scholar] [CrossRef]
  61. Bahleda, R.; Meric-Bernstam, F.; Goyal, L.; Tran, B.; He, Y.; Yamamiya, I.; Benhadji, K.A.; Matos, I.; Arkenau, H.T. Phase I, First-in-Human Study of Futibatinib, a Highly Selective, Irreversible FGFR1-4 Inhibitor in Patients with Advanced Solid Tumors. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2020, 31, 1405–1412. [Google Scholar] [CrossRef] [PubMed]
  62. Meric-Bernstam, F.; Bahleda, R.; Hierro, C.; Sanson, M.; Bridgewater, J.; Arkenau, H.T.; Tran, B.; Kelley, R.K.; Park, J.O.; Javle, M.; et al. Futibatinib, an Irreversible FGFR1-4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study. Cancer Discov. 2022, 12, 402–415. [Google Scholar] [CrossRef] [PubMed]
  63. Goyal, L.; Meric-Bernstam, F.; Hollebecque, A.; Valle, J.W.; Morizane, C.; Karasic, T.B.; Abrams, T.A.; Furuse, J.; He, Y.; Soni, N.; et al. FOENIX-CCA2: A Phase II, Open-Label, Multicenter Study of Futibatinib in Patients (Pts) with Intrahepatic Cholangiocarcinoma (ICCA) Harboring FGFR2 Gene Fusions or Other Rearrangements. J. Clin. Oncol. 2020, 38, 108. [Google Scholar] [CrossRef]
  64. Goyal, L.; Meric-Bernstam, F.; Hollebecque, A.; Morizane, C.; Valle, J.W.; Karasic, T.B.; Abrams, T.A.; Kelley, R.K.; Cassier, P.A.; Furuse, J.; et al. Updated Results of the FOENIX-CCA2 Trial: Efficacy and Safety of Futibatinib in Intrahepatic Cholangiocarcinoma (ICCA) Harboring FGFR2 Fusions/Rearrangements. J. Clin. Oncol. 2022, 40, 4009. [Google Scholar] [CrossRef]
  65. Borad, M.J.; Bridgewater, J.A.; Morizane, C.; Shroff, R.T.; Oh, D.-Y.; Moehler, M.H.; Furuse, J.; Benhadji, K.A.; He, H.; Valle, J.W. A Phase III Study of Futibatinib (TAS-120) versus Gemcitabine-Cisplatin (Gem-Cis) Chemotherapy as First-Line (1L) Treatment for Patients (Pts) with Advanced (Adv) Cholangiocarcinoma (CCA) Harboring Fibroblast Growth Factor Receptor 2 (FGFR2) Gene Rearrangements (FOENIX-CCA3). J. Clin. Oncol. 2020, 38, TPS600. [Google Scholar] [CrossRef]
  66. Guagnano, V.; Kauffmann, A.; Wöhrle, S.; Stamm, C.; Ito, M.; Barys, L.; Pornon, A.; Yao, Y.; Li, F.; Zhang, Y.; et al. FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor. Cancer Discov. 2012, 2, 1118–1133. [Google Scholar] [CrossRef]
  67. Nogova, L.; Sequist, L.V.; Garcia, J.M.P.; Andre, F.; Delord, J.P.; Hidalgo, M.; Schellens, J.H.M.; Cassier, P.A.; Camidge, D.R.; Schuler, M.; et al. Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients with Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. J. Clin. Oncol. 2017, 35, 157–165. [Google Scholar] [CrossRef]
  68. Javle, M.; Lowery, M.; Shroff, R.T.; Weiss, K.H.; Springfeld, C.; Borad, M.J.; Ramanathan, R.K.; Goyal, L.; Sadeghi, S.; Macarulla, T.; et al. Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma. J. Clin. Oncol. 2018, 36, 276–282. [Google Scholar] [CrossRef]
  69. Javle, M.; Roychowdhury, S.; Kelley, R.K.; Sadeghi, S.; Macarulla, T.; Weiss, K.H.; Waldschmidt, D.T.; Goyal, L.; Borbath, I.; El-Khoueiry, A.; et al. Infigratinib (BGJ398) in Previously Treated Patients with Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusions or Rearrangements: Mature Results from a Multicentre, Open-Label, Single-Arm, Phase 2 Study. Lancet Gastroenterol. Hepatol. 2021, 6, 803–815. [Google Scholar] [CrossRef]
  70. Śmiech, M.; Leszczyński, P.; Kono, H.; Wardell, C.; Taniguchi, H. Emerging BRAF Mutations in Cancer Progression and Their Possible Effects on Transcriptional Networks. Genes 2020, 11, 1342. [Google Scholar] [CrossRef]
  71. Xin, H.Y.; Sun, R.Q.; Zou, J.X.; Wang, P.C.; Wang, J.Y.; Ye, Y.H.; Liu, K.X.; Hu, Z.Q.; Zhou, Z.J.; Fan, J.; et al. Association of BRAF Variants with Disease Characteristics, Prognosis, and Targeted Therapy Response in Intrahepatic Cholangiocarcinoma. JAMA Netw. Open 2023, 6, E231476. [Google Scholar] [CrossRef] [PubMed]
  72. Simbolo, M.; Fassan, M.; Ruzzenente, A.; Mafficini, A.; Wood, L.D.; Corbo, V.; Melisi, D.; Malleo, G.; Vicentini, C.; Malpeli, G.; et al. Multigene Mutational Profiling of Cholangiocarcinomas Identifies Actionable Molecular Subgroups. Oncotarget 2014, 5, 2839–2852. [Google Scholar] [CrossRef] [PubMed]
  73. Andersen, J.B.; Spee, B.; Blechacz, B.R.; Avital, I.; Komuta, M.; Barbour, A.; Conner, E.A.; Gillen, M.C.; Roskams, T.; Roberts, L.R.; et al. Genomic and Genetic Characterization of Cholangiocarcinoma Identifies Therapeutic Targets for Tyrosine Kinase Inhibitors. Gastroenterology 2012, 142, 1021–1031. [Google Scholar] [CrossRef]
  74. Jain, A.; Javle, M. Molecular Profiling of Biliary Tract Cancer: A Target Rich Disease. J. Gastrointest. Oncol. 2016, 7, 797–803. [Google Scholar] [CrossRef]
  75. Ahn, D.H.; Bekaii-Saab, T. Biliary Cancer: Intrahepatic Cholangiocarcinoma vs. Extrahepatic Cholangiocarcinoma vs. Gallbladder Cancers: Classification and Therapeutic Implications. J. Gastrointest. Oncol. 2017, 8, 239–301. [Google Scholar] [CrossRef] [PubMed]
  76. Jain, A.; Kwong, L.N.; Javle, M. Genomic Profiling of Biliary Tract Cancers and Implications for Clinical Practice. Curr. Treat. Options Oncol. 2016, 17, 58. [Google Scholar] [CrossRef]
  77. Salama, A.K.S.; Li, S.; Macrae, E.R.; Park, J.I.; Mitchell, E.P.; Zwiebel, J.A.; Chen, H.X.; Gray, R.J.; McShane, L.M.; Rubinstein, L.V.; et al. Dabrafenib and Trametinib in Patients with Tumors with BRAFV600E Mutations: Results of the NCI-MATCH Trial Subprotocol H. J. Clin. Oncol. 2020, 38, 3895–3904. [Google Scholar] [CrossRef]
  78. Subbiah, V.; Lassen, U.; Élez, E.; Italiano, A.; Curigliano, G.; Javle, M.; de Braud, F.; Prager, G.W.; Greil, R.; Stein, A.; et al. Dabrafenib plus Trametinib in Patients with BRAFV600E-Mutated Biliary Tract Cancer (ROAR): A Phase 2, Open-Label, Single-Arm, Multicentre Basket Trial. Lancet Oncol. 2020, 21, 1234–1243. [Google Scholar] [CrossRef]
  79. Bateman, A.C. DNA Mismatch Repair Proteins: Scientific Update and Practical Guide. J. Clin. Pathol. 2021, 74, 264–268. [Google Scholar] [CrossRef]
  80. Olave, M.C.; Graham, R.P. Mismatch Repair Deficiency: The What, How and Why It Is Important. Genes. Chromosomes Cancer 2022, 61, 314–321. [Google Scholar] [CrossRef]
  81. Yu, J.; Zhang, X.; Huang, Q.; Tan, S.; Xiong, X.; Gou, H. Rare DNA Mismatch Repair-Related Protein Loss in Patients with Intrahepatic Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma and Their Response to Immunotherapy. Cancer Manag. Res. 2021, 13, 4283–4290. [Google Scholar] [CrossRef] [PubMed]
  82. Le, D.T.; Durham, J.N.; Smith, K.N.; Wang, H.; Bartlett, B.R.; Aulakh, L.K.; Lu, S.; Kemberling, H.; Wilt, C.; Luber, B.S.; et al. Mismatch Repair Deficiency Predicts Response of Solid Tumors to PD-1 Blockade. Science 2017, 357, 409–413. [Google Scholar] [CrossRef] [PubMed]
  83. Ando, Y.; Kumamoto, K.; Matsukawa, H.; Ishikawa, R.; Suto, H.; Oshima, M.; Kamada, H.; Morishita, A.; Kobara, H.; Matsunaga, T.; et al. Low Prevalence of Biliary Tract Cancer with Defective Mismatch Repair Genes in a Japanese Hospital-Based Population. Oncol. Lett. 2022, 23, 4. [Google Scholar] [CrossRef]
  84. Zhao, P.; Li, L.; Jiang, X.; Li, Q. Mismatch Repair Deficiency/Microsatellite Instability-High as a Predictor for Anti-PD-1/PD-L1 Immunotherapy Efficacy. J. Hematol. Oncol. 2019, 12. [Google Scholar] [CrossRef] [PubMed]
  85. Cloyd, J.M.; Chun, Y.S.; Ikoma, N.; Vauthey, J.N.; Aloia, T.A.; Cuddy, A.; Rodriguez-Bigas, M.A.; Nancy You, Y. Clinical and Genetic Implications of DNA Mismatch Repair Deficiency in Biliary Tract Cancers Associated with Lynch Syndrome. J. Gastrointest. Cancer 2018, 49, 93–96. [Google Scholar] [CrossRef]
  86. Marabelle, A.; Le, D.T.; Ascierto, P.A.; Di Giacomo, A.M.; de Jesus-Acosta, A.; Delord, J.P.; Geva, R.; Gottfried, M.; Penel, N.; Hansen, A.R.; et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J. Clin. Oncol. 2020, 38, 1–10. [Google Scholar] [CrossRef]
  87. Maio, M.; Ascierto, P.A.; Manzyuk, L.; Motola-Kuba, D.; Penel, N.; Cassier, P.A.; Bariani, G.M.; De Jesus Acosta, A.; Doi, T.; Longo, F.; et al. Pembrolizumab in Microsatellite Instability High or Mismatch Repair Deficient Cancers: Updated Analysis from the Phase II KEYNOTE-158 Study. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2022, 33, 929–938. [Google Scholar] [CrossRef]
  88. Andre, T.; Berton, D.; Curigliano, G.; Ellard, S.; Pérez, J.M.T.; Arkenau, H.-T.; Abdeddaim, C.; Moreno, V.; Guo, W.; Im, E.; et al. Safety and Efficacy of Anti–PD-1 Antibody Dostarlimab in Patients (Pts) with Mismatch Repair-Deficient (DMMR) Solid Cancers: Results from GARNET Study. J. Clin. Oncol. 2021, 39, 9. [Google Scholar] [CrossRef]
  89. Fusco, M.J.; West, H.J.; Walko, C.M. Tumor Mutation Burden and Cancer Treatment. JAMA Oncol. 2021, 7, 316. [Google Scholar] [CrossRef]
  90. Zhang, R.; Li, Q.; Fu, J.; Jin, Z.; Su, J.; Zhang, J.; Chen, C.; Geng, Z.; Zhang, D. Comprehensive Analysis of Genomic Mutation Signature and Tumor Mutation Burden for Prognosis of Intrahepatic Cholangiocarcinoma. BMC Cancer 2021, 21. [Google Scholar] [CrossRef]
  91. Rizzo, A.; Ricci, A.D.; Brandi, G. PD-L1, TMB, MSI, and Other Predictors of Response to Immune Checkpoint Inhibitors in Biliary Tract Cancer. Cancers 2021, 13, 558. [Google Scholar] [CrossRef] [PubMed]
  92. Song, J.P.; Liu, X.Z.; Chen, Q.; Liu, Y.F. High Tumor Mutation Burden Indicates a Poor Prognosis in Patients with Intrahepatic Cholangiocarcinoma. World J. Clin. Cases 2022, 10, 790–801. [Google Scholar] [CrossRef] [PubMed]
  93. Kim, H.; Kim, H.; Kim, R.; Jo, H.; Kim, H.R.; Hong, J.; Park, J.O.; Park, Y.S.; Kim, S.T. Tumor Mutational Burden as a Biomarker for Advanced Biliary Tract Cancer. Technol. Cancer Res. Treat. 2021, 20, 15330338211062324. [Google Scholar] [CrossRef] [PubMed]
  94. Marabelle, A.; Fakih, M.; Lopez, J.; Shah, M.; Shapira-Frommer, R.; Nakagawa, K.; Chung, H.C.; Kindler, H.L.; Lopez-Martin, J.A.; Miller, W.H.; et al. Association of Tumour Mutational Burden with Outcomes in Patients with Advanced Solid Tumours Treated with Pembrolizumab: Prospective Biomarker Analysis of the Multicohort, Open-Label, Phase 2 KEYNOTE-158 Study. Lancet Oncol. 2020, 21, 1353–1365. [Google Scholar] [CrossRef]
  95. Schenker, M.; Burotto, M.; Richardet, M.; Ciuleanu, T.; Goncalves, A.; Steeghs, N.; Schöffski, P.; Ascierto, P.A.; Maio, M.; Lugowska, I.; et al. Abstract CT022: CheckMate 848: A Randomized, Open-Label, Phase 2 Study of Nivolumab in Combination with Ipilimumab or Nivolumab Monotherapy in Patients with Advanced or Metastatic Solid Tumors of High Tumor Mutational Burden. Cancer Res. 2022, 82, CT022. [Google Scholar] [CrossRef]
  96. Manea, C.A.; Badiu, D.C.; Ploscaru, I.C.; Zgura, A.; Bacinschi, X.; Smarandache, C.G.; Serban, D.; Popescu, C.G.; Grigorean, V.T.; Botnarciuc, V. A Review of NTRK Fusions in Cancer. Ann. Med. Surg. 2022, 79, 103893. [Google Scholar] [CrossRef]
  97. Cocco, E.; Scaltriti, M.; Drilon, A. NTRK Fusion-Positive Cancers and TRK Inhibitor Therapy. Nat. Rev. Clin. Oncol. 2018, 15, 731–747. [Google Scholar] [CrossRef]
  98. Demols, A.; Rocq, L.; Perez-Casanova, L.; Charry, M.; De Nève, N.; Ramadhan, A.; Van Campenhout, C.; De Clercq, S.; Maris, C.; Closset, J.; et al. A Two-Step Diagnostic Approach for NTRK Gene Fusion Detection in Biliary Tract and Pancreatic Adenocarcinomas. Oncologist 2023, 28, e520–e525. [Google Scholar] [CrossRef]
  99. Demols, A.; Perez-Casanova, L.; Rocq, L.; Charry, M.; De Nève, N.; Verrellen, A.; Ramadhan, A.; Van Campenhout, C.; De Clercq, S.; Maris, C.; et al. 71P NTRK Gene Fusions in Bilio-Pancreatic Cancers. Ann. Oncol. 2020, 31, S268. [Google Scholar] [CrossRef]
  100. Iyer, R.; Wehrmann, L.; Golden, R.L.; Naraparaju, K.; Croucher, J.L.; MacFarland, S.P.; Guan, P.; Kolla, V.; Wei, G.; Cam, N.; et al. Entrectinib Is a Potent Inhibitor of Trk-Driven Neuroblastomas in a Xenograft Mouse Model. Cancer Lett. 2016, 372, 179–186. [Google Scholar] [CrossRef]
  101. Drilon, A.; Siena, S.; Ou, S.H.I.; Patel, M.; Ahn, M.J.; Lee, J.; Bauer, T.M.; Farago, A.F.; Wheler, J.J.; Liu, S.V.; et al. Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017, 7, 400–409. [Google Scholar] [CrossRef] [PubMed]
  102. Doebele, R.C.; Drilon, A.; Paz-Ares, L.; Siena, S.; Shaw, A.T.; Farago, A.F.; Blakely, C.M.; Seto, T.; Cho, B.C.; Tosi, D.; et al. Entrectinib in Patients with Advanced or Metastatic NTRK Fusion-Positive Solid Tumours: Integrated Analysis of Three Phase 1-2 Trials. Lancet Oncol. 2020, 21, 271–282. [Google Scholar] [CrossRef] [PubMed]
  103. Drilon, A.; Laetsch, T.W.; Kummar, S.; DuBois, S.G.; Lassen, U.N.; Demetri, G.D.; Nathenson, M.; Doebele, R.C.; Farago, A.F.; Pappo, A.S.; et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N. Engl. J. Med. 2018, 378, 731–739. [Google Scholar] [CrossRef] [PubMed]
  104. Takahashi, M.; Ritz, J.; Cooper, G.M. Activation of a Novel Human Transforming Gene, Ret, by DNA Rearrangement. Cell 1985, 42, 581–588. [Google Scholar] [CrossRef] [PubMed]
  105. Takahashi, M.; Kawai, K.; Asai, N. Roles of the RET Proto-Oncogene in Cancer and Development. JMA J. 2020, 3, 175–181. [Google Scholar] [CrossRef]
  106. Subbiah, V.; Cassier, P.A.; Siena, S.; Garralda, E.; Paz-Ares, L.; Garrido, P.; Nadal, E.; Vuky, J.; Lopes, G.; Kalemkerian, G.P.; et al. Pan-Cancer Efficacy of Pralsetinib in Patients with RET Fusion-Positive Solid Tumors from the Phase 1/2 ARROW Trial. Nat. Med. 2022, 28, 1640–1645. [Google Scholar] [CrossRef]
  107. Subbiah, V.; Wolf, J.; Konda, B.; Kang, H.; Spira, A.; Weiss, J.; Takeda, M.; Ohe, Y.; Khan, S.; Ohashi, K.; et al. Tumour-Agnostic Efficacy and Safety of Selpercatinib in Patients with RET Fusion-Positive Solid Tumours Other than Lung or Thyroid Tumours (LIBRETTO-001): A Phase 1/2, Open-Label, Basket Trial. Lancet Oncol. 2022, 23, 1261–1273. [Google Scholar] [CrossRef]
  108. Goyal, L.; Saha, S.K.; Liu, L.Y.; Siravegna, G.; Leshchiner, I.; Ahronian, L.G.; Lennerz, J.K.; Vu, P.; Deshpande, V.; Kambadakone, A.; et al. Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma. Cancer Discov. 2017, 7, 252–263. [Google Scholar] [CrossRef]
  109. Zhou, Y.; Wu, C.; Lu, G.; Hu, Z.; Chen, Q.; Du, X. FGF/FGFR Signaling Pathway Involved Resistance in Various Cancer Types. J. Cancer 2020, 11, 2000–2007. [Google Scholar] [CrossRef] [PubMed]
  110. Zhuang, X.; Pei, H.Z.; Li, T.; Huang, J.; Guo, Y.; Zhao, Y.; Yang, M.; Zhang, D.; Chang, Z.; Zhang, Q.; et al. The Molecular Mechanisms of Resistance to IDH Inhibitors in Acute Myeloid Leukemia. Front. Oncol. 2022, 12, 931462. [Google Scholar] [CrossRef]
  111. Zhang, Y.; Esmail, A.; Mazzaferro, V.; Abdelrahim, M. Newest Therapies for Cholangiocarcinoma: An Updated Overview of Approved Treatments with Transplant Oncology Vision. Cancers 2022, 14, 5074. [Google Scholar] [CrossRef] [PubMed]
Life 13 02066 g001
Figure 1. Number of publications indexed on PubMed per year using search terms “targeted” and “cholangiocarcinoma”.
Figure 1. Number of publications indexed on PubMed per year using search terms “targeted” and “cholangiocarcinoma”.
Life 13 02066 g001
Life 13 02066 g002
Figure 2. Depiction of targets of interest in cholangiocarcinoma. Note: Image created using biorender.com.
Figure 2. Depiction of targets of interest in cholangiocarcinoma. Note: Image created using biorender.com.
Life 13 02066 g002
Table 1. Select trials evaluating systemic therapy in the first- and second-line settings for cholangiocarcinoma.
Table 1. Select trials evaluating systemic therapy in the first- and second-line settings for cholangiocarcinoma.
Trial NameStudy ArmControl ArmTrial PhaseLine of TherapyPatient NumberPrimary EndPoint(s)ORRmPFS (Months)HR, 95% CI (mPFS)p (mPFS)mOS (Months)HR, 95% CI (mOS)p (mOS)
TOPAZ-1 [12]Gemcitabine + cisplatin + durvalumabGemcitabine + cisplatin3First685OS26.7%7.2 vs. 5.70.75, 0.64–0.890.00112.8 vs. 11.50.80, 0.66–0.970.021
KEYNOTE-966 [13]Gemcitabine + cisplatin + pembrolizumabGemcitabine + cisplatin3First1069OS29%6.5 vs. 5.60.86, 0.75–1.000.02312.7 vs. 10.90.83, 0.72–0.950.0034
ABC-06 [14]FOLFOXBest supportive care3Second162OS5%4.0 (FOLFOX arm)NRNR6.2 vs. 5.30.69, 0.50–0.970.031
NIFTY [15,16]5-FU + leucovorin + liposomal irinotecan5-FU + leucovorin2Second178PFS12.5%4.2 vs. 1.7 0.61, 0.44–0.860.0048.6 vs. 5.30.68, 0.48–0.950.02
NALIRICC-AIO-HEP-0116 [17]5-FU + leucovorin + liposomal irinotecan5-FU + leucovorin2Second100PFS14.3%2.8 vs. 2.3NRNR6.9 vs. 8.2NRNR
Abbreviations: ORR: objective response rate, mPFS: median progression-free survival, mOS: median overall survival, HR: hazard ratio, 95% CI: 95% confidence interval, NR: not reported.
Table 2. Actionable targets in cholangiocarcinoma and incidence by tumor location.
Table 2. Actionable targets in cholangiocarcinoma and incidence by tumor location.
Incidence
TargetiCCAeCCA
IDH-1 mutation [23,24,25]20–25%<1%
HER2 overexpression/amplification [35]5%17%
FGFR2 fusion or rearrangement [50]15%<1%
BRAF V600E [71,72,73,74,75,76]1–5%<1%
Deficient mismatch repair/high microsatellite instability [81,82,83]2–3%2–3%
High tumor mutation burden [90,91] 3.5%2%
Abbreviations: iCCA: intrahepatic cholangiocarcinoma; eCCA: extrahepatic cholangiocarcinoma.
Table 3. Pertinent clinical trials are evaluating targeted therapy options in cholangiocarcinoma.
Table 3. Pertinent clinical trials are evaluating targeted therapy options in cholangiocarcinoma.
TargetTrial NameStudy ARMControl ArmTrial PhaseCohortPatient NumberPrimary EndPoint(s)ORRmPFS (Months)HR, 95% CI (mPFS)p (mPFS)mOS (MONTHs)HR, 95% CI (mOS)p (mOS)
IDH-1 mutationClarIDHy [29,30]IvosidenibPlacebo3mIDH-1 CCA w/progression on prior therapy230PFS2%2.7 vs. 1.40.37, 0.25-0.54<0.000110.3 vs. 7.50.79, 0.56–1.120.09
HER2 overexpression/amplification MyPathway [39]Pertuzumab plus trastuzumabN/A2aHER2+, previously treated BTC 39ORR23%2.6 (iCCA), 6.8 (eCCA)N/AN/A3.9 (iCCA), 8.0 (eCCA)N/AN/A
HERIZON-BTC-01 [40]ZanidatimabN/A2bHER2 2+/3+ (Cohort 1), previously treated BTC80ORR41.3%5.5N/AN/ANot reportedN/AN/A
DESTINY-PanTumor02 [41]Trastuzumab deruxtecan **N/A2HER2+, previously treated solid malignancies267
(41 w/BTC)		ORR37.1%(22.0% among all BTC)Not reportedN/AN/ANot reportedN/AN/A
FGFR2 fusion/rearrangementFIGHT-202 [57]PemigatinibN/A2FGFR2 fusion/rearrangement107ORR35.5%6.9N/AN/A21.1N/AN/A
FGFR2 mutation2002.16.7
No FGFR2 abnormality1801.74
FOENIX-CCA2 [63,64]FutibatinibN/A2iCCA w/FGFR2 fusion/rearrangement103ORR41.7%8.9N/AN/A20.0N/AN/A
Javle et al. [68]InfigratinibN/A2CCA w/FGFR2 fusion or other alteration61ORR14.80%5.8N/AN/ANot reportedN/AN/A
Javle et al. [69]N/A2CCA w/FGFR2 fusion/rearrangement w/progression on gemcitabine122ORR23.10%7.3N/AN/A12.2N/AN/A
BRAF V600EROAR [78]Dabrafenib plus trametinibN/A2BTC w/BRAF V600E43ORR51%9N/AN/A14N/AN/A
MSI-HKEYNOTE-158 [86,87]PembrolizumabN/A2Advanced non-colorectal dMMR/MSI-H tumors351 (22 w/CCA)ORR30.80%3.5N/AN/A20.1N/AN/A
TMB-HKEYNOTE-158 (subgroup analysis) * [94]PembrolizumabN/A2Advanced non-colorectal TMB-H tumors102ORR29%2.1N/AN/A11.7N/AN/A
Advanced non-colorectal non- TMB-H tumors6886%2.1N/AN/A12.8N/AN/A
CheckMate 848 [95]Ipilimumab plus nivolumabN/A2Advanced, TMB-H solid tumors148ORR22.5-35.3%2.8-4.1N/AN/A8.5-14.5N/AN/A
Abbreviations: ORR: objective response rate, mPFS: median progression-free survival, mOS: median overall survival, HR: hazard ratio, 95% CI: 95% confidence interval, BTC: biliary tract cancer, N/A: not available. * Did not include any patients with cholangiocarcinoma in the TMB-H cohort. ** Currently lacking FDA approval for this indication, although evidence would support its use.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Storandt, M.H.; Kurniali, P.C.; Mahipal, A.; Jin, Z. Targeted Therapies in Advanced Cholangiocarcinoma. Life 2023, 13, 2066. https://doi.org/10.3390/life13102066

AMA Style

Storandt MH, Kurniali PC, Mahipal A, Jin Z. Targeted Therapies in Advanced Cholangiocarcinoma. Life. 2023; 13(10):2066. https://doi.org/10.3390/life13102066

Chicago/Turabian Style

Storandt, Michael H., Peter C. Kurniali, Amit Mahipal, and Zhaohui Jin. 2023. "Targeted Therapies in Advanced Cholangiocarcinoma" Life 13, no. 10: 2066. https://doi.org/10.3390/life13102066

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop