To appropriately choose targeted therapies for ABTC patients majorly depends on the results of in-depth sequencing or next-generation sequencing. The common genetic mutations vary between IHCC, EHCC and GBC, with
IDH mutation and
FGFR rearrangement in IHCC and
HER2 aberrations in EHCC and GBC [
29]. Currently, the successful clinical trials of targeted therapy in ABTC were mostly biomarker-driven.
3.1. FGFR2 Fusions
In IHCC, the aberrant activation of the FGFR signaling pathway leading to tumor cell migration stands for approximately 15 to 20% of patients, with the most common genetic alternation being
FGFR2 fusion [
30]. A much lower detection rate of 2% was reported in a Chinese report [
31]. Notably, the IHCC patients with
FGFR2 fusions have been frequently associated with several clinical features, such as female, younger age, early stage and better survival [
32]. Co-existing
TP53 mutation and
CDKN2A/B loss were correlated with a shorter median OS [
33]. Recently, multiple pan-FGFR tyrosine kinase inhibitors (TKIs), such as pemigatinib (INCB054828), infigratinib (BGJ398), futibatinib (TAS-120), derazantinib (ARQ087), erdafitinib (JNJ-42756493) and rogoratinib (BAY1163877), have been applied for gemcitabine-refractory IHCC with
FGFR genetic alternations. In this paper, we briefly summarize some of these completed studies.
There are two kinds of FGFR inhibitors divided by the efficacy to inhibit the FGFR4 activity. Some FGFR inhibitors selectively target FGFR1-3 but relatively serve as weak inhibitors to the FGFR4 activity, such as pemigatinib with additional vascular endothelial growth factor receptor 2 (VEGFR2) inhibition, and infigratinib. The others include futibatinib, derazantinib (with additional inhibition to RET, platelet-derived growth factor receptors, KIT and SRC) and erdafitinib with stronger activity to FGFR4 inhibition compared to the former group. Patients with
FGFR2 fusions or translocations had more benefit with a higher ORR (18.8–35.5%) under the treatment of FGFR inhibitors, compared to those with
FGFR2 mutation/amplification or other FGF/FGFR alternations [
17].
In a FIGHT-202 study, patients had treatment-refractory advanced or metastatic cholangiocarcinoma harboring
FGFR2 gene fusion or rearrangement and took oral pemigatinib. Total 107 patients had an ORR of 35.5%, a DCR of 82% and a median PFS of 6.9 months. The median duration of response (DOR) was 9.1 months. The response persisted longer than six months in 24 of the 38 (63%) patients and longer than 12 months in seven (18%) patients. Hyperphosphatemia was the most common all-grade adverse event (AE) up to 60%, followed by arthralgia, stomatitis, diarrhea and fatigue [
34]. Based on the promising result, the Food and Drug Administration (FDA) granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation, Wilmington, DE, USA) for the treatment of patients with previously treated cholangiocarcinoma with
FGFR2 fusion or other rearrangements in April 2020 [
35]. Moreover, FoundationOne
® CDX (Foundation Medicine, Inc., Cambridge, MA, USA) was also approved by the FDA as a companion diagnostic for patient selection.
The other selective-FGFR inhibitor, BGJ398, showed meaningful efficacy in IHCC patients with
FGFR alternations who failed under previous chemotherapy, with 14.8% ORR (18.8% in
FGFR2 fusion group,
n = 48), 75% DCR and a median PFS 5.8 months among 61 patients. The most frequent treatment-related AEs are similar to those of previous items under pemigatinib treatment, except for palmar-plantar erythrodysesthesia [
36]. The update efficacy in the expanded
FGFR2-fusion population (
n = 71) showed a confirmed ORR of 26.9%, a median PFS of 6.8 months and a median OS of 12.5 months [
37]. Derazantinib (ARQ087), a multi-kinase inhibitor with potent activity against FGFR1-3 kinases and an additional inhibition to RET, platelet-derived growth factor receptors (PDGFR), KIT and SRC, was tested in treatment-refractory IHCC patients with
FGFR2 fusions in a phase I/II trial [
38]. In the cohort of 29 patients, the results showed an ORR of 21%, a DCR of 83% and a median PFS of 5.7 months. Among them, two patients were treatment-naïve and others were refractory to at least one prior chemotherapy.
TAS-120 inhibits the kinase activity of FGFR1-4 irreversibly and highly potent, which may overcome some drug resistance from ATP-competitive FGFR inhibitors, such as BGJ398 [
39]. In the dose-escalation phase I TAS120 study (16, 20 and 24 mg QD continuously), 45 IHCC patients harboring FGF/FGFR aberrations who received prior systemic therapies were enrolled. Of the 28 patients with
FGFR2 gene fusions, the ORR and DCR were 25% and 79%, respectively. Of the 13 patients who had received prior FGFR inhibitors, four (three with
FGFR2 gene fusions and one with
FGFR2 amplification) had confirmed PR [
40]. Further trials are currently ongoing in patients with advanced solid tumors harboring FGF/FGFR aberrations, including cholangiocarcinoma (NCT02052778).
There are still many ongoing phase I and II trials on FGFR inhibitors in pretreated
FGFR-fusion IHCC, such as E7090 (NCT04238715), CPL304110 (NCT04149691), EOC317 (NCT03583125) and INCB062079 (NCT03144661). Despite the evidence of the therapeutic efficacy of FGFR inhibitors, almost all patients eventually developed acquired resistance. This result leads to the development of innovative therapeutic strategies to overcome acquired drug resistance [
16]. The common grade 3/4 AEs of FGFR inhibitors include hyperphosphatemia (22–29%), hypophosphatemia (7–14%), hyponatremia (8%), mucositis/stomatitis (7–18%), palmar-plantar erythrodysesthesia (5%), asthenia (6%) and abnormal liver function tests (6%) [
36,
38,
40,
41,
42]. Hyperphosphatemia is an on-target AE related to inhibition of FGF23, which regulates the renal excretion of phosphorus and bone absorption [
43,
44,
45]. On the contrary, hypophosphatemia is possibly related to overcorrection of hyperphosphatemia by dietary restriction and phosphate binders [
37,
42].
3.2. IDH1/2 Mutations and PARP
Somatic point mutations in
IDH1 and
IDH2 result in a gain-of-function for cancer cells, followed by the accumulation and secretion of the oncometabolite, D-2-hydroxyglutarate (2-HG) [
46]. The accumulated 2-HG may inhibit specific α-KG–dependent dioxygenases and participate in tumorigenesis, including signal transduction, extracellular matrix maturation and epigenetic regulation [
47].
IDH1/2 mutations are primarily reported in 19–36% of IHCC [
48]. However, the prognostic implication of
IDH1 mutation remained no conclusion [
49]. Ivosidenib is an IDH1 inhibitor approved in the USA for patients with mutant
IDH1 (
mIDH1) acute myeloid leukaemia. The ClarIDHy trial was a randomized, double-blinded, placebo-controlled phase III study designed to evaluate the efficacy of ivosidenib (500 mg once daily) in previously pre-treated IHCC patients harboring
IDH1 mutations [
50]. The primary endpoint was PFS by independent central review and
p value < 0.05 was considered to be a statistical significance. Patients receiving ivosidenib had a longer PFS (2.7 vs. 1.4 months, HR 0.37,
p < 0.0001) and a comparable OS (10.8 vs. 9.7 months) to those who received the placebo, with 57% of placebo group crossover to ivosidenib when progression. Patients receiving ivosidenib had a favorable safety profile without treatment-related deaths. This study shows the clinical benefit of ivosidenib in advanced,
IDH1-mutant cholangiocarcinoma. There are several clinical trials ongoing to test the efficacy and safety of other IDH inhibitors, such as BYA143602, IDH305, FT21012 and AG-881 (NCT02481154, NCT02746081, NCT02381886 and NCT03684811).
Poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors serve as therapeutic agents, especially for
BRCA-related high-grade serous ovarian cancer and
BRCA-mutation breast cancers [
51], as well as for those with DNA damage repair (
DDR) gene aberrations [
52]. In 28% to 64% of patients with BTCs, the
DDR gene alterations have been identified, including but not limited to, mutations in
BRCA1,
BRCA2,
ATM,
ATR,
BAP1,
BARD1,
BRIP1,
CHEK2,
FAM175A,
GEN1,
MLH1,
MSH2,
MSH6,
MRE11A,
RAD50,
RAD51,
RAD51C,
RAD51D,
NBN,
PALB2,
PMS2,
FANCA,
FANCD2 and
XRCC2 [
53,
54]. Patients with
DDR genetic mutations had a significantly longer PFS and OS among the ABTC patients who received first-line platinum-containing chemotherapies [
53].
BRCA1/2 mutations occur in 1–7% of BTC patients [
55,
56], which frequently come from somatic origin [
57].
BRCA2 mutation carriers have a lifetime risk of around 5% to develop BTC [
55]. There are two ongoing phase II trials of PARP inhibitor associated with BTC: Niraparib for
BAP1 and other DDR pathway deficient neoplasms (NCT03207347) and olaparib for metastatic BTC with somatic or germline
DDR mutations after the failure of platinum (NCT04042831). So far, there are no recommendations to assess
BRCA1/2 or
DDR mutations to routinely in BTC subpopulations. This analysis is very important to determine the real prevalence of
BRCA 1/2 and germline/somatic
DDR mutations in BTCs, as well as the impact of PARP inhibitors on this subpopulation.
Interestingly, a recent study suggested that
IDH1/
2 mutations induce a “BRCAness” phenotype because of an induced defect of homologous recombination [
58]. The oncometabolite, 2-HG, results in a hypermethylated status through inhibiting DNA and protein demethylation. IDH inhibitors in combination with PARP inhibitors or demethylating agents may represent a potential strategy in
IDH-mutated CCA [
58,
59]. There are many ongoing clinical trials on using the PARP inhibitor in refractory,
IDH-mutant CCAs, such as olaparib monotherapy (NCT03212274), olaparib plus durvalumab (NCT03991832) and olaparib plus a small molecule inhibitor targeting ataxia telangiectasia and the Rad3 related protein, ceralasertib (NCT03878095).