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R. C. Sperandio et al.
temic approach until 2018, when the therapeutic arsenal
against HCC was broadened with the approval of lenvatinib
as rst-line, after demonstrating non-inferiority versus
sorafenib in the phase III REFLECT study [10]. Moreover,
since 2017, a plethora of anti-angiogenic agents were
approved in second-line settings, with overall survival
improvements ranging from 1.6 to 2.8months versus placebo; subsequent options include regorafenib [11], ramucirumab [12] and cabozantinib [13]. Nevertheless, the impact
of these agents is modest, and no reliable biomarker for
selection of patients has been identied. Therefore, progress
is needed and effective therapy against HCC remains an
unmet need.
With the recognition of cancer as an immunogenic disease, the role of immune modulation as a part of oncologic
management was explored. In the early 2000s, local and systemic immunotherapy with interferon [14] and cytokines
such as IL-12 [15] were studied, with poor results. More
recently, cancer treatment was revolutionized by the introduction of immune checkpoint inhibitors (ICI) [16]. This
group of agents is composed by immunomodulatory antibodies with the primary function of blocking immune inhibitory pathways and therefore unleashing the body’s response
against malignancies, with particular success in melanoma
[17], renal cell carcinoma [18], and non-small cell lung cancer [19]. Strikingly, ICI has demonstrated potential for longterm disease control and even cure in metastatic
chemotherapy-refractory solid tumors [20]. In light of the
limited treatment options and an improved understanding of
liver immune biology, ICI’s use soon expanded to HCC.In
this chapter, we will review the rationale, efcacy data and
future perspectives regarding the use of ICI for HCC.
21.2 Rationale andtheEvolving Role
ofImmunotherapy inCancer
Treatment
A better understanding of how innate and adaptive immune
surveillance interplay with cancer development has led to
major therapeutic advances across many cancer types [21].
The intricated mechanisms underlying this process initiate
with the immune system’s ability to recognize self and nonself antigens. The interface between the immune and tumor
cells is mediated by antigen-presenting cells (APC) and
components of major histocompatibility complex (MHC)
classes I and II, responsible for recognition and consequent
activation/inhibition of the immune response, comprising the
“immune synapse”. The primary connection between T cells
and APC is through the MHC and the T cell receptor (TCR)
complexes [22]. To ensure meticulous regulation of this process, the initial signal depends on additional costimulatory
and co-inhibitory molecules, collectively known as “immune
checkpoints”. These bindings may produce, respectively,
two opposing effects as a nal result: immune activation
through effector T cells; or immune evasion through
increased participation of regulatory and suppressing cells
[23]. These pathways create a dynamic balance between carcinogenesis and immune destruction, exemplifying a phenomenon called “cancer immunoediting”—a relationship
described in three phases: elimination, equilibrium, and
escape. The latter is characterized by tumor growth that is no
longer blocked by adaptive immunity and is able to cause
clinical manifestations of disease [24]. The most representative and studied negative immune checkpoints to date are
cytotoxic T-lymphocyte associated protein 4 (CTLA-4),
programmed cell-death receptor (PD-1) and its ligand programmed cell-death ligand 1 (PD-L1) (Table 21.1).
CTLA-4 blockade is a hallmark to immunotherapy as it
represents the rst-ever approved drug of ICI class—ipilimumab [25]. CTLA-4 is constitutively expressed in regulatory
T cells, and by activated CD4+ and CD8+ lymphocytes.
CTLA-4 competitively binds to CD80 (also known as B7-1)
and CD86 (B7-2), thus decreasing the costimulatory signal
of CD28 on APCs [26]. Upregulation of CTLA-4 occurs
mediated by pro-effector cytokines IL-12, IFN-gamma and
the degree of TCR activation, which leads to a feedback inhibition loop on effector T cells and, consequently, impairment
of the immune response [27].
PD-1 is expressed in lymphocytes (T cells, B cells and
NK cells) and is paramount for immunomodulation in tumor
microenvironment. PD-1 is a co-inhibitory receptor that
binds to the PDL-1 (also known as B7-H1 or CD274) and
PDL-2 (B7-H2 or CD273), promoting peripheral T effector
cell exhaustion [28]. While PDL-2 is mostly found in hematopoietic cells, PDL-1 is expressed across many tissues,
including tumor cells. PDL-1 expression in the tumor microenvironment is also enhanced by IL-12 and IFN-gamma,
highlighting its role as a physiological brake to effector T
cells and as a mechanism for immune evasion [29, 30].
Chronic presented antigens as seen in chronic viral infections or neoplastic clones may induce feedback inhibition of
effector T cells, in a process called “immune exhaustion”
[23].
Table 21.1 Immune checkpoint inhibitors
Anti-PD1 Anti-PDL-1 Anti-CTLA-4
Pembrolizumab Atezolizumab Ipilimumab
Nivolumab Avelumab Tremelimumab
Cemiplimab Durvalumab
21 Immune-Checkpoint Inhibitors inHepatocellular Carcinoma
179
21.3 The Unique Microenvironment
andImmune System oftheLiver
ICI have yielded better responses when used in solid tumors
with high mutational burden cancers, such as melanoma and
non-small cell lung cancer. In such tumors, there is a predicted higher burden of neoantigens to be recognized by
immune effector cells. Most cases of HCC arise in the background of a chronically inamed liver, with underlying cirrhosis. A correlation between an inamed tumor
microenvironment and more neoantigens leading to higher
IFN-gamma and PD-L1 expression has suggested—in a
broad analysis of over 100,000 cancer genomes, the tumor
mutational burden for HCC was found to be moderate [31].
Due to unique features of the hepatic tissue, such as selftolerance, the immunological landscape of HCC is a key feature to the effectiveness of this class of agents. There is a
myriad of cells found in HCCs, which include malignant
hepatocytes, endothelial cells and inltrating immune cells
such as dendritic cells, lymphocytes, macrophages and
monocytes (Fig. 21.1). The immune microenvironment in
HCC is also characterized by upregulation and overexpression of PD-1 in intrahepatic lymphocytes, PD-L1 and
PD-L2 in Kupffer cells, liver sinusoidal endothelium and
leucocytes [32].
Recent advances in gene proling and identication of
gene signatures and other molecular features allow a phenotype classication that intend to better select subsets of
patients which are more likely to respond. There has been
evidence for classifying microenvironment-based immune
subtypes in distinct phenotype groups. A study found that
25% of HCC samples show features of inammatory
response with overexpression of PD-1 and PD-L1. This socalled “Immune Class” is subdivided in two groups accordingly to immune status: (1) active (~65%, with overexpression
of adaptive immune response genes) or (2) exhaustion of
immunological activity (~35%, with predominance of immunosuppressive features such as TGF-ß expression and M2
macrophages inltration [33].
21.4 Single-Agent Immune Checkpoint
Inhibitors Trials
Efcacy and safety of ICI in treating HCC were initially
assessed in single-arm trials. Published in 2017, the
CheckMate-040 [34] was a phase I/II study that evaluated
nivolumab (an anti-PD1 ICI) after sorafenib failure in 262
patients. Results were promising, with an overall response
rate of 20%, and disease control rate of 64%. The median
Fig. 21.1 The complex and multi-faceted functional interactions guid-
ing cancer immune tolerogenesis in hepatocellular carcinoma. Cellular
and functional heterogeneity of the HCC tumour microenvironment.
Reused with permission from: Pinato DJ, Guerra N, Fessas P, et al.
Immune-based therapies for hepatocellular carcinoma. Oncogene.
2020;39(18):3620–3637. https://doi.org/10.1038/s41388- 020- 1249- 9.
License at: http://creativecommons.org/licenses/by/4.0/
180
R. C. Sperandio et al.
progression-free survival was 4.0months, and the median
duration of response was 9.9months, highlighting the ICI’s
potential for long-term responses. Overall survival at
6months and at 9months were 83% and 74%, respectively,
which compared favorably to published trials in the later line
setting. Moreover, treatment was well tolerated, and only 3%
of subjects had to discontinue treatment due to drug-related
adverse events. A particular safety concern was the risk of
immune-related hepatitis, but this event was rare and mostly
low grade [35].
In 2018, the results of the single-arm phase II
KEYNOTE-224 trial [36] were reported. In this study, 104
patients that had progressed on sorafenib were treated with
pembrolizumab (an anti-PD-1 ICI). Overall response rate
was 17%, and disease control rate 62%. Median time to
response was 2.1months and median duration of response
was not reached, with 77% of patients continuing to respond
for ≥9 months. Median overall survival was 12.9 months.
Similarly to nivolumab, only 3% of patients showed
increased alanine aminotransferase concentration attributable to immune-mediated hepatitis, with no viral ares or
further complications.
Unfortunately, larger conrmatory trials of single-agent
anti-PD-1 ICI yielded disappointing results, both in rst- and
second-line settings. KEYNOTE-240 [37] was a multicenter,
randomized phase III study that assigned 413 patients to
pembrolizumab or placebo as second-line therapy, after progression to sorafenib. The trial was negative for the coprimary endpoints of overall survival and progression-free
survival. Notwithstanding, secondary efcacy data was consistent with prior reports—response rate was 16.9, with
median duration of response of 13.8 months. Regarding
frontline therapy, CheckMate-459 [38] was a phase III trial
comparing nivolumab versus sorafenib for 743 systemictherapy naive patients with advanced HCC. This study has
also failed to meet its primary endpoint of overall survival,
with median overall survival of 16.4 months versus
14.8months for the nivolumab and sorafenib groups, respectively (HR 0.85; p=0.0522 not signicant). At 33months,
overall survival rates were 29% for nivolumab and 21% for
sorafenib. Grade 3–4 treatment-related adverse events were
reported in 82 patients (22.3%) of the nivolumab group and
in 180 patients (49.6%) of the sorafenib group.
There is a strong scientic rationale suggesting that combined VEGF/PD-L1 blockade may be benecial in a number
of solid cancers, including HCC.It is recognized that HCC is
a highly vascularized tumor [39], and the VEGF pathway
plays a crucial role in exerting and maintaining an immunosuppressive tumor microenvironment through several mechanisms [40]. In May 2020, a combination therapy has become
the new standard of care for advanced and unresectable HCC
as the FDA approved atezolizumab (an anti-PD-L1 ICI) and
bevacizumab (an anti-VEGF monoclonal antibody) as rstline therapy. This approval followed results of the phase III
IMbrave150 trial [41], which assessed the aforementioned
combination versus sorafenib as a rst-line treatment in 501
previously untreated patients. Median overall survival was
signicantly better for the combined therapy (NR vs
13months; HR 0.58, p <0.001), translating into an overall
survival benet of 12% at 1year (67% vs 55%). Combination
therapy also yielded longer progression-free survival (6.8 vs
4.3months, HR 0.59; p<0.001). Moreover, the combined
therapy doubled the objective response rate (27% vs 12%).
Importantly, authors also reported a benet in quality of life
and physical/role functioning [42].
Further, a novel ICI combination has been approved in the
later-line setting. In March 2020, the FDA granted accelerated approval to the combination of nivolumab plus ipilimumab (an anti-CTLA-4 ICI) for previously treated advanced
HCC patients, based on a cohort of the CheckMate-040 study
[43]. Overall response rate was 33%, including four complete
responses and 12 partial responses. More than 30% of
responses persist for at least 24months, with median response
duration of 17months. This combination was associated with
higher occurrence of immune-related adverse events, requiring the use of steroids, including grade 3–4 increased levels
of aspartate aminotransferase and lipase [44].
Currently, in 2020, there are multiple ongoing clinical trials assessing different combinatory schemes incorporating
ICI—either in combination with other ICIs or with targetedtherapies—, and more approvals are anticipated in the near
future.
21.6 ICIs Use intheNeoadjuvant
andAdjuvant Settings
inResectableHCC
21.5 Combination Strategies
Despite the initial high expectations and relatively good
response rates, ICI as single agents so far failed to demonstrate improvement in survival endpoints. Consequently,
there has been a growing interest towards diversifying strategies and combining agents in order to improve efcacy
(Fig.21.2).
The approval of ICIs for most malignancies initially took
place in the context of advanced disease. More recently, ICI
have been assessed in the management of earlier stages of
cancer, and are approved for the (neo)adjuvant treatment of
melanoma [45, 46] and non-small cell lung cancer [47].
Incorporating ICI earlier in HCC is of special interest as
tumor recurrence is common and 5-year recurrence rates for
resected HCC have been reported to be >70% [5].
a c
21 Immune-Checkpoint Inhibitors inHepatocellular Carcinoma
b
181
d
e
Fig. 21.2 General overview of immune-based therapies for HCC. (a)
Simultaneous inhibition of CTLA-4 and the PD-1 axis by monoclonal
antibodies (brown and blue respectively). The effect of dual checkpoint
blockade on T-cell immune reconstitution is demonstrated, with
CTLA-4 acting mainly on T-reg cells and antigen-presenting cells, and
PD-1 acting on effector CD8+ CTLs. (b) Schematic representation of
synergy between anti-angiogenic therapy (green antibody) and PD-1/
PD-L1-targeted therapy. (c) Locoregional therapies, such as ablation
and trans-arterial chemoembolisation are loco-regional inducers of
immunogenic cell death and drive CD8+ cell inltration into the tumour
microenvironment, providing a rationale for combined anti-PD-1 ther-
In the neoadjuvant setting, it is hypothesized that blocking immune checkpoints preoperatively increases systemic T
cell response by enhancing neoantigen presentation and T
apy. (d) Autologous T cell transfer involves exvivo activation of mixed
T cell/NK cell populations by cytokines (i.e., CIK cells) and reinfusion
into the patient with the intent of bypassing immune-evasion and eliciting an anti-tumour responses. (e) Anti-tumour vaccines against
immunodominant peptides of oncofoetal proteins, such as AFP, GPC3
and hTERT, have been combined with exvivo activation of dendritic
cells to promote effective antigen presentation. Reused with permission
from: Pinato DJ, Guerra N, Fessas P, etal. Immune-based therapies for
hepatocellular carcinoma. Oncogene. 2020;39(18):3620–3637. https://
doi.org/10.1038/s41388- 020- 1249- 9. License at: http://creativecommons.org/licenses/by/4.0/
NCT03383458) and pembrolizumab (KEYNOTE-937,
NCT03867084), in addition to atezolizumab plus bevaci-
zumab randomized to placebo (Imbrave-050, NCT04102098).
cell priming both at the primary tumor site and draining
lymph nodes [48]. The resulting effect would be the elimination of micrometastatic niches that are deposited far from the
21.7 Future Perspectives
resectable lesion, which is thought to be the cause of relapse.
An interim analysis of an ongoing phase II pilot trial of
preoperative ipilimumab with or without nivolumab has
demonstrated a pathological complete response of 29% (4
out of evaluable 14 patients), highlighting the promise of
early ICI use. As expected, grade 3 or higher toxicities prior
to surgery were more present at the combination arm [49].
Larger conrmatory trials are ongoing. Currently, adjuvant
immunotherapy studies in HCC include ICI alone randomized to placebo, including nivolumab (CheckMate-9DX,
Based on the new standard of care approved in 2020—
atezolizumab plus bevacizumab—, the trend for the near
future is towards evaluating diverse combination strategies,
such as ICI with other ICI, or in conjunction with molecular
targeted therapies such as multi-kinase inhibitors, or locoregional therapies, among others. Despite great excitement
regarding the introduction of a novel modality of treatment
with immunotherapy after a long time with few and modest
options of systemic therapy, there is still a signicant cohort
182
R. C. Sperandio et al.
of patients who do not respond to ICIs or combinations.
Additionally, mechanisms of resistance—tumor intrinsic and
extrinsic factors—are relevant and may play an important
role in long-term follow-up of HCC patients. Moreover,
inducing higher response rate is essential to improving outcome in unresectable HCC since it could downsize tumors to
a resectable or transplantable stages and offer cure.
Notably, reliable predictive biomarkers that allow identication and better selection of patients more likely of
responding to therapy are currently lacking. There is a number of candidates under investigation—both intratumoral and
extratumoral biomarkers; such as PD-L1 expression, Tumor
Mutational Burden (TMB), gene signatures, signaling pathways, tumor microenvironment features such as inltrating
lymphocytes. Circulating soluble factors such as cytokines,
and immune cells, are other possible biomarkers which are
currently under investigation [50]. Imaging predictors are
also being assessed—recently, a signicant correlation
between HCC stiffness at magnetic resonance elastography,
presence of intratumoral T lymphocytes, overall survival and
time to disease progression has been recently reported and
warrants further validation [51].
In summary, the study of immunotherapy for HCC is an
active area of interest and has led to the establishment of a
new frontline standard of care for unresectable disease.
However, survival for patients with advanced HCC is still
suboptimal, and there remains a need for novel treatment
strategies, highlighting that progress is particularly strenuous due to the challenges of treating patients with underlying
cirrhosis.
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Molecularly Targeted Therapy
inCholangiocarcinoma
AakashDesai andMiteshJ.Borad
22
Abstract
Biliary tract cancers (BTCs) are a heterogeneous group of
aggressive malignancies of the liver and biliary tract.
While traditional approaches for advanced disease
patients have comprised cytotoxic therapies such as gemcitabine and cisplatin, next generation sequencing has
revolutioned the eld and has cast growing appreciation
of the molecular underpinnings of the disease. Towards
this end, inhibitors of broblast growth factor receptor 2
(FGFR2) and isocitrate dehydrogenase 1 (IDH1) have
yielded compelling data in pivotal clinical studies and
subsequently garnered regulatory approval across a number of geographies. Enhancing this paradigm are studies
that have yielded promising early data for targets such as
BRAF and HER2 and microsatellite instability. These
trends are expected to continue and the role of precision
medicine deepens in the treatment of BTCs and these
therapies are studies in relevant combinations, earlier disease settings and as next generation therapies towards
these targets are developed.
Biliary tract cancers (BTCs) are a heterogeneous group of
malignancies arising from the epithelial cells of the distinct
anatomical locations of the biliary tree (intrahepatic, perihilar, distal bile ducts or the gallbladder). BTCs are generally
A. Desai
Department of Oncology, Mayo Clinic, Rochester, MN, USA
M. J. Borad (
Mayo Clinic Cancer Center, Phoenix, AZ, USA
Center for Individualized Medicine, Mayo Clinic,
Rochester, MN, USA
Department of Molecular Medicine, Mayo Clinic,
Rochester, MN, USA
Division of Hematology/Oncology, Mayo Clinic,
Phoenix, AZ, USA
e-mail: Borad.Mitesh@mayo.edu
*)
categorized into intrahepatic cholangiocarcinoma (ICCA),
extrahepatic cholangiocarcinoma (ECCA), and gallbladder
carcinoma (GBC). In 2019, in there was an estimated total of
54,390 new cases (liver cancer and BTC), with approximately 35,740 deaths in the United States [1].
The denition of an ICCA is a cholangiocarcinoma
(CCA) detected inside the hepatic parenchyma, whereas
ECCA is a type of tumor located outside the liver parenchyma. These tumors can arise in any portion of the extrahepatic bile duct and can be additionally classied as hilar or
distal CCA [2].
For localized disease, surgery remains the only curative
option. Meanwhile, for advanced inoperable disease, chemotherapy with gemcitabine and cisplatin has emerged as the
standard of care [3]. In recent years, a growing number of
genomic studies have begun to uncover the molecular underpinnings of BTCs and suggest many potential treatments
(Table 22.1). Targeted testing of advanced cholangiocarcinoma for decient mismatch repair (dMMR)/microsatellite
instability (MSI) and for specic molecular alterations
(FGFR, IDH and others), for which a targeted treatment
might be available (Table22.2), is indicated for those who
might be eligible for molecularly targeted therapy or immunotherapy, preferably within the context of a clinical trial.
In the Molecular Screening for Cancer Treatment
Optimization (MOSCATO)-01 trial, 43 of 1035 adults with
advanced cancer had a biliary tract malignancy, 34 of whom
successfully underwent high-throughput molecular screening. Potentially actionable molecular aberrations were identied in 23 patients (68 percent), 18 of whom received
targeted treatment. Median progression-free survival was
5.2 months, and there were six objective responses (33
percent, one complete) [4]. This trial informed on the potential impact of a molecularly targeted approach in patients
with advanced biliary tract cancers. Thus, genomic studies of
BTCs are ushering in a new era of precision therapy, already
playing an emerging role in the treatment and prognostication of BTCs.
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
M. Makuuchi et al. (eds.), The IASGO Textbook of Multi-Disciplinary Management of Hepato-Pancreato-Biliary Diseases,
https://doi.org/10.1007/978-981-19-0063-1_22
185
186
Table 22.1 Therapeutic targets and approach to molecular proling in biliary tract cancers
Molecular target Frequency Targeted agents Molecular test
FGFR pathway ~10–20% of intrahepatic
IDH1 ~15% of intrahepatic
BRAF ~5% of intrahepatic
MSI-high or
MMR deciency
or high TMB
ERRB2 (HER2) ~15–20% gallbladder cancer and
NTRK Rare Entrectinib [31],
Table 22.2 Clinical studies for molecularly targeted therapies in cholangiocarcinoma
Drug
FGFR2 fusions or gene rearrangements
Erdanitib [9] Phase 1 (n=11) ORR: 27% –
Ingratinib [8, 10] Phase 2- cohort 1
Pemigatinib [11] Phase 2 (n=146) ORR: 35.5% (26.5%–45.5%) mPFS: 6.9months
IDH1 mutations
Ivosedinib [16] Phase 3 (n=187) mPFS: 2.7months vs. 1.4months; HR:
BRAF V600E mutations
Dabrafenib/Trametinib
[18]
MSI or dMMR/TMB
Pembrolizumab [20] Phase 2 (n=41) irORR: 40% mPFS, mOS: NR
Pembrolizumab [23] Phase 2 (n=105) ORR: 29% 3-yr PFS: 32%
ERRB2 (HER2) mutations
Neratinib [30] Phase 2 (n=9) PR: 2/9 patients (22.2%) –
ORR overall response rate, irORR immune related ORR, DoR duration of response, mPFS median progression free survival, mOS median overall
survival, NR not reached
cholangiocarcinoma
cholangiocarcinoma
cholangiocarcinoma
~2% of biliary tract cancers Pembrolizumab [34] PCR, immunohistochemistry, or tumor next generation
extrahepatic cholangiocarcinoma
cases
Type of trial
(n=sample size) Primary endpoints (95% CI) Secondary endpoints (95% CI)
(n=108)
Phase 2 (n=43) ORR: 51% (36%–67%) mPFS: 9months
Erdatinib [9] Ingratinib
[10] Pemigatinib [11]
Futibatinib [13]
Ivosedinib [16] Tumor next-generation DNA sequencing or targeted
Dabrafenib plus Trametinib
[18], Vemurafenib [33]
Trastuzumab/Pertuzumab Multiple testing modalities available including
Larotrectinib [32]
ORR: 23.1% (15.6%–32.2%); DoR:
5.0months (0.9–19.1)
0.37 (0.25–0.54)
Tumor next generation DNA sequencing including FGFR2
intronic region, targeted RNAseq, or FISH testing for
FGFR2 translocation
sequencing for hotspot mutations in coding region of
IDH1
Tumor next-generation DNA sequencing or targeted
sequencing for hotspot mutations in coding region of
BRAF
DNA sequencing
immunohistochemistry and FISH for expression and
amplication, tumor next generation DNA sequencing for
mutations
Tumor next-generation DNA sequencing including NTRK
intronic region or targeted
RNAseq, or FISH testing for NTRK translocation
mPFS: 7.3months
mOS: 12.2months
OS: 21.1months
mOS: 10.3months (vs. 7.5months), HR: 0.79;
(95% CI, 0.56–1.12)
mOS: 14months
A. Desai and M. J. Borad
The NCI-MATCH trial data conrmed the richness of
molecular targets in cases of cholangiocarcinoma including:
IDH1 mutations (17%), CDKN2A mutations (10%), BRAF
mutations (7%), ERBB2 alterations (6%), NRAS mutations
(6%), IDH2 mutations (5%), and FGFR2 alterations (3%).
Intrahepatic cholangiocarcinoma had an assignment rate of
29.1% to 12 different NCI-MATCH subprotocols [5].
The genes most frequently associated with genomic alterations are TP53, KRAS, ARID1A, SMAD4, CCND1, MET,
MDM2, CDKN2A, and CDKN2B, and the most common
actionable gene targets are FGFR2 fusions, IDH1 mutations,
and ERBB2 (HER-2) and MET amplications; actionable
targets are commonly observed in ICCA (Fig.22.1) [6].
In this chapter, we discuss evidence for the management
of CCA and molecular insights of personalized approaches,
including broblast growth factor receptor (FGFR) inhibitors, checkpoint inhibitors, and other targets.
22.1 FGFR Alterations
About 13–17% of ICCAs harbor genomic alterations in the
FGFR2 gene, with most being fusions, which predict tumor
sensitivity to anti-FGFR2 tyrosine kinase inhibitors [7].
Translocations that relieve the FGFR2 gene of its upstream
transcriptional regulation result in constitutively active
22 Molecularly Targeted Therapy inCholangiocarcinoma
187
Bile acids
STAT3
PO
4
STAT3
PO
4
STAT3
Transcripts: PD-L1, PD-L2,
SOC53. ↑MCL-1, BCL-XL
FDJ amplicon =
↑PD-L1/L2 &↑JAK2
11q amplicon–
↑FGF19
↑ JAK
ruxolitinib
FXR agonists,
obeticholic acid
FXR. ↑MCL-1
BCL-XL
afatinib,
neratinib,
varilitinib
EGFR∆
ERRFI1∆
vemurafenib,
dabrafenib,
etc.
cobimetinib,
trametinib,
etfc.
BBET protiens:
SWI/SNF∆ (e.g.
ARID2∆). TGFβ.
related (e.g.
SMAD4D)
H3B-6527,
INCB062079
BLU-554
↑ ErbB3/4∆
↑ FGF 19
FGFR4
PO
4
ERK
BMS-986158,
CPI-0610,
MK-8628
PO
4
ERK:
e.g. ↑MYC
RNA Pol 2 transcripts: MYC over-expressionamplification, indirectly MYC-targets (e.g. PD-L1)
trastuzumab,
lapatinib,
pertuzumab
↑ HER2∆
RAS/RAS∆
MEK AKT
ERK
tazemetostat
↑EZH2,
SMARCA/B∆
Histone methylation
DNA methylation
BGJ398,
derazantinib,
INCB054828
FGFR2
fusions
JumonjiDormain
HDMs
BKM120.
taselisib
MK2206
IDH1∆
2-HG
TET
PI3K∆RAF/RAF∆
mTOR
ivosiedenib
DNZ HMAs: azacitidine, decitabine,
guadecitabine, zebularine, etc.
ASG-22CE
↑ Nection -4
α-KG
pembrclizumab,
nivolumab
atezolizumab
palbocidib,
ribicidib,
abemecidib
↑ PD-L1
Mitochondrion
onasidenib
CDKN2A/B∆
CCNE1 amplification,
RB1∆
α-KG
PD-1
MHC-peptide
↑ Necantigens
MCL-1
BCL-XL
T Cell
TCR
olaparib,
niraparib,
rucaparib
BRCA∆ &
ARID1A∆
Cell surface
Nucleus
MMR∆ε
Fig. 22.1 Emerging role of precision medicine in biliary tract cancers.
Yellow boxes highlight US FDA-approved drugs and drugs undergoing
clinical investigation as reviewed, with arrows indicating pathway/target activation and blocked lines indicating pathway/target inhibition.
BTC targets/pathways discussed are shown in color-coded boxes
growth factor pathway signaling, promoting cell proliferation, angiogenesis, and metastasis. Patients with FGFR aberrations may have superior overall survival (OS) with
FGFR-targeted therapy as compared to standard non targeted
regimens [8]. Multiple inhibitors of FGFR isoforms 1–3
have shown activity in advanced cholangiocarcinoma harboring FGFR2 translocations, including several ATPcompetitive, reversible inhibitors (erdatinib, ingratinib,
pemigatinib, and derazantinib) as well as a non-ATP competitive, covalent inhibitor, futibatinib.
Erdatinib was studied in a phase I trial including 187
patients with advanced solid tumors for which standard antineoplastic therapy was no longer effective. All patients with
urothelial carcinoma and cholangiocarcinoma who responded
to erdatinib carried FGFR mutations or fusions. Median
duration of response (DoR) was 5.6months for urothelial
according to subcellular localization, blue = cell surface, orange = cytsolic, red = mitochondrial, and green = nuclear. “Upwards arrow”
denotes over-expression, “Delta” denotes copy number aberrations and/
or point mutation, a lighting bolt symbol denotes a synthetic lethal
interaction between drug(s) and target(s) listed
carcinoma and 11.4months for cholangiocarcinoma, clearly
demonstrating response in cholangiocarcinoma patients [9].
BJG 398 (ingratinib), an ATP-competitive FGFR1–3selective oral tyrosine kinase inhibitor has showed good
response in the second line setting for patients resistant to
frontline gemcitabine-based therapies. This was based on the
an open-label, phase 2 trial enrolled 140 patients with unresectable locally advanced or metastatic cholangiocarcinoma
who had either progressed on or were intolerant to
gemcitabine- based chemotherapy. For eligibility, all participants had to have either FGFR gene fusions or rearrangements. Patients were grouped into three different cohorts:
patients with FGFR2 gene fusions or rearrangements comprised cohort 1 (n= 120), those with FGFR1 and FGFR3
gene fusions or rearrangements and/or FGFR mutations
comprised cohort 2 (n= 20), and those with FGFR2 gene
188
A. Desai and M. J. Borad
fusions who had progressed after previous treatment with a
selective FGFR inhibitor beyond ingratinib were included
in cohort 3 (n=20). Patients received ingratinib 125mg
orally for 21days of each 28-daycycle until unacceptable
toxicity or disease progression.
Among 61 patients (n=48 FGFR2 fusions, n=8 FGFR2
mutations, n = 3 FGFR2 amplications) with >1 type of
FGFR2 aberration detected in three patients the ORR, all
partial responses (PRs), was 15%, with 75% of patients
experiencing some disease control and a median progressionfree survival (PFS) of 5.8months. Four patients who carried
FGFR3 amplications did not respond. Dose modications
were required for many patients, although AEs were mostly
reversible. The most common adverse events (AE) were
hyperphosphatemia (72%), with 25% of patients experiencing grade 3 or 4 hyperphosphatemia [10].
The updated results of the largest cohort of FGFR2 gene
fusions or rearrangements (cohort 1) were reported recently
with median follow up of 10.6 months (range 1.1–
55.9months). Centrally reviewed ORR was 23.1% (95% CI
15.6–32.2) with a median DoR of 5.0months (range 0.9–
19.1months). Among responders, 8 (32.0%) patients had a
DoR of 6 months. Median PFS was 7.3months (95% CI
5.6–7.6 months). Most common adverse events (AEs, any
grade) were hyperphosphatemia (76.9%), eye disorders
(67.6%, excluding central serous retinopathy/retinal pigment
epithelium detachment [CSR/RPED]), stomatitis (54.6%),
and fatigue (39.8%).
Pemigatinib is a selective, potent, oral competitive inhibitor of FGFR1, FGFR2, and FGFR3, which was studied in the
multicenter, open-label phase 2 broblast Growth factor
receptor inhibitor in oncology and Hematology Trial
(FIGHT-202) [11]. This trial evaluated the safety and antitumor activity of pemigatinib in previously treated patients
with locally advanced or metastatic cholangiocarcinoma,
with or without FGF/FGFR alterations. 38 (35.5% [95% CI
26.5–45.4]) patients with FGFR2 fusions or rearrangements
achieved an ORR.Overall, hyperphosphatemia was the most
common all-grade adverse event irrespective of cause (88
[60%] of 146 patients). Overall, 71 (49%) patients died during the study, most frequently because of disease progression
(61 [42%]); no deaths were deemed to be treatment related.
Lastly, activation of FGFR2 kinase domain point mutations occurs as a mechanism of resistance to ATP-competitive
FGFR inhibition; these mutations can be polyclonal and heterogeneous [12]. Futibatinib (non-ATP-competitive) shows
inhibitory activity against most secondary acquired resistance mutations, suggesting a role in FGFR2-translocated
cholangiocarcinoma after progression on ATP-competitive
FGFR inhibitors [13], although it is not active against the
V565F gatekeeper mutation. Selective FGFR2 kinase inhibitors are in development with more potent FGFR2 inhibition
and reduced off-target adverse events.
22.2 IDH Mutations
Gain-of-function mutations in the coding region of IDH1 are
present in about 13% of cases of intrahepatic cholangiocarcinoma (almost never in extrahepatic cholangiocarcinoma)
based upon a systematic review including 5393 cases of
cholangiocarcinoma [14]. The mutant- IDH1 protein catalyzes production of an oncometabolite, D-2-hydroxyglutarate
(2-HG), via NADPH-dependent reduction. Accumulation of
2-HG impairs cellular differentiation through effects on
chromatin structure and DNA methylation, leading to
tumorigenesis.
Ivosidenib is a rst-in-class, oral, selective, and reversible mutant-IDH1 inhibitor. In a phase 1 basket study of
IDH1- mutated solid tumors, 73 patients with advanced
cholangiocarcinoma refractory to standard therapies
received ivosidenib [15]. Although objective responses were
uncommon (5%), the median progression-free survival
(3.8months) and overall survival (13.8months) were longer
than expected for standard chemotherapy in similar populations. The subsequent phase 3 ivosidenib in IDH1-mutant,
chemotherapy- refractory cholangiocarcinoma (ClarIDHy)
trial enrolled 185 patients with advanced IDH1-mutant
cholangiocarcinoma after 1–2 lines of previous, unsuccessful systemic therapy [16]. Patient were randomized 2:1 to
ivosidenib versus placebo and allowance of crossover at
progression for patients in the placebo group Ivosidenib
improved progression- free survival (the primary endpoint):
median 2.7months for ivosidenib versus 1.4months for placebo (HR 0.37, 95% CI 0.25–0.54, p < 0.001), and 32%
treated with ivosidenib were progression-free at six months
(vs none in the placebo group). The updated OS results presented at ASCO GI 2021 showed median OS was
10.3months in patients who received ivosidenib compared
with 7.5months for those who received placebo (HR, 0.79;
95% CI, 0.56–1.12; 1-sided p=0.093). Overall, ivosidenib
was well tolerated with low rates of grade 3 or higher
adverse events and only 8.5% (vs. 6.6%) requiring discontinuation for toxicity attributed to ivosidenib. The most
common grade 3 or higher TEAEs reported in the ivosidenib
and placebo groups, respectively, were ascites (9.0% vs
6.8%, respectively), blood bilirubin increase (5.4% vs
1.7%), and anemia (7.2% vs 0%). Based on these results, a
regulatory approval is anticipated for patients with advanced,
IDH1-mutant cholangiocarcinoma after ineffective standard
therapy.
22.3 BRAF Alterations
Activating serine/threonine-protein kinase B-raf kinase
(BRAF) mutations at the V600E locus are well-known drivers in oncology and an established therapeutic target in