Targeted Therapies in Advanced Biliary Tract Cancers

A Narrative Review

Michael LaPelusa; Thatcher Heumann; Laura Goff; Rajiv Agarwal

Chin Clin Oncol. 2023;12(2):14

Abstract and Introduction

Abstract

Background and Objective: Biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder cancer, are a relatively rare group of cancers with a poor prognosis. Over the past decade, the utilization of next-generation sequencing has led to the identification of multiple actionable somatic aberrations in BTCs. Subsequently, new therapies have been created to target these molecular alterations and have been incorporated into clinical practice. In this review, we outline therapies that have been previously studied, and those that are under investigation, to target genomic alterations with the goal of improving survival in patients with advanced disease.

Methods: A literature search was performed to identify phase I, II, and III trials of targeted therapies in patients with advanced BTCs published between January 1, 2010 and October 1, 2022. Medline (via PubMed) and ClinicalTrials.gov were searched for relevant studies and 415 trials were identified. The search strategy was performed using keywords including: biliary tract cancer, cholangiocarcinoma, gallbladder cancer, chemotherapy, targeted therapy, randomized trials, controlled trials, phase I, phase II, and phase III. Search results were imported into EndNote X 9.1.

Key Content and Findings: Overall, immune checkpoint inhibitors, fibroblast growth factor receptor (FGFR) inhibitors, isocitrate dehydrogenase (IDH) inhibitors, and human epidermal growth factor receptor 2 (HER2)-directed therapies have all shown promising results with regard to efficacy in patients with advanced BTCs studied in clinical trials. A number of other agents have also been studied in early-phase trials.

Conclusions: Targeted agents can improve survival in patients with advanced BTCs and have substantially increased the number of potential therapeutic options in patients with refractory disease. The therapeutic landscape of targeted therapies for patients with advanced BTCs continues to evolve based on improvements in detection of genomic alterations.

Introduction

Intrahepatic cholangiocarcinoma (IC), distal extrahepatic cholangiocarcinoma (EC), hilar (Klatskin) cholangiocarcinoma, and gallbladder cancer, collectively known as biliary tract cancers (BTCs) arise from the epithelium of the biliary tree and are relatively rare cancers. The global incidence of BTCs is estimated to be between 0.3 to 6 per 100,000 people, with the highest incidence in southeast Asia (age-standardized rate as high as 3.00 in South Korea) and lowest in Western countries (age-standardized rate as low as 0.66 in the United Kingdom).^[1,2] In the United States, the incidence of cholangiocarcinoma, particularly IC, is rising.^[3,4] Risk factors for BTCs include liver fluke infection, primary sclerosing cholangitis, hepatolithiasis, choledochal cysts, alcohol consumption, tobacco use, hepatitis B and hepatitis C infection, and metabolic conditions such as obesity, diabetes, and nonalcoholic fatty liver disease.^[5–9] Although some progress has been made with respect to improving the survival of patients with BTCs over the past decade, historically, these malignancies are associated with a poor prognosis, with 5-year overall survival (OS) rates of less than 15%.^[10–12]

Early detection of BTCs greatly impacts prognosis. Currently, no screening guidelines exist or are recommended for BTCs. When BTC is suspected, contrast-enhanced magnetic resonance cholangiopancreatography (MRCP) or computed tomography (CT) are the imaging modalities of choice to evaluate for vascular anomalies, satellite lesions, lymph node involvement, and metastatic disease.^[13,14] These characteristics are crucial in determining whether a biliary tract tumor is surgically resectable and thereby potentially curable. A tissue diagnosis is often obtained via endoscopic retrograde cholangiopancreatography (ERCP) and via biliary tract brushings. Resectable disease is defined by the absence of multifocal liver disease, lymph node metastasis beyond the porta hepatis, and distant metastasis. Resectability status is ultimately determined by a multidisciplinary team of experienced radiologists and surgeons. In patient's with hilar cholangiocarcinoma, biopsy should not be performed until resectability status and transplant candidacy have been determined because transperitoneal biopsy may preclude transplantation depending on institutions' protocols. In patients with unresectable disease, biopsies should be performed for tissue analysis and molecular profiling, including next-generation sequencing, to identify actionable mutations. In addition, positron emission tomography (PET) and diagnostic laparoscopy can help detect regional lymph node involvement and distant metastasis, although PET scans have a higher propensity for falsely detecting sites of disease that are not actually sites of metastasis.^[15–17]

While chemotherapy has historically been the mainstay of treatment for patients with advanced cholangiocarcinoma, targeted molecular therapies are increasingly utilized in clinical practice due to newly identified alterations and the desire to reduce adverse effects associated with cytotoxic therapy (Figure 1). One analysis postulated that approximately 68% of patients with BTCs have an actionable mutation.^[18] In this review, we examine the evidence supporting the utilization of targeted therapies for patients with advanced BTCs. We present the following article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-22-93/rc).

(Enlarge Image)

Figure 1.

Key targets in biliary tract cancers. Created with BioRender.com. FGFR, fibroblast growth factor receptor; NTRK, neurotrophic tyrosine receptor kinase; RAS, rat sarcoma; BRAF, v-raf murine sarcoma viral oncogene homolog B1; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; IDH1, isocitrate dehydrogenase 1; ERB, epidermal growth factor.

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Table 1. Search strategy
Items	Specification
Date of search	06/01/2022
Databases and other sources searched	PubMed, ClinicalTrials.gov
Search terms used	Biliary tract cancer, cholangiocarcinoma, gallbladder cancer, chemotherapy, targeted therapy, randomized trials, controlled trials, phase I, phase II, phase III
Timeframe	January 1, 2010 and October 1, 2022
Inclusion and exclusion criteria	All clinical trials (phase I, phase II, phase III) for the treatment of biliary tract cancers were included, based on search criteria above. Trials were excluded if they were not completed, closed early, or did not report their outcome in the form of an abstract or manuscript
Selection process	An independent search was conducted by the authors

Table 2. Completed landmark trials utilizing chemotherapy
Investigational arm	Comparison arm	N	Line	Phase	mPFS	mOS
Gemcitabine plus cisplatin, ABC-02 Study (19)	Gemcitabine	410	1L	3	8.0 vs. 5.0 months (P<0.001)	11.7 vs. 8.1 months (HR 0.64; 95% CI: 0.52, 0.80; P<0.001)
FOLFOX plus active symptom control, ABC-06 Study (20)	Active symptom control	162	2L	3	4.0 months (95% CI: 3.2–5.0) vs. not reported	6.2 vs. 5.3 months (HR 0.69; 95% CI: 0.50, 0.97; P=0.031)
Liposomal Irinotecan (nal-IRI) plus 5FU/LV, NIFTY Study (21)	5FU/LV	174	2L	2B	7.1 vs. 1.4 months (P=0.0019)	8.6 vs. 5.3 months (HR 0.68; 95% CI: 0.48, 0.95; P=0.024)

mPFS, median progression-free survival; mOS, median overall survival; CI, confidence interval; HR, hazard ratio; nal-IRI, nanoliposomal irinotecan; 5FU, fluorouracil; LV, leucovorin.

Table 3. Completed landmark trials utilizing first-line immunotherapy
Investigational arm	Comparison arm	N	Line	Phase	mPFS	mOS
Durvalumab plus gemcitabine plus cisplatin, TOPAZ-1 Study (27)	Gemcitabine plus cisplatin	685	1L	3	7.2 vs. 5.8 months (HR 0.75; 95% CI: 0.64–0.89; P=0.001)	12.8 vs. 11.5 months (HR 0.80; 95% CI: 0.66–0.97; P=0.021)

mPFS, median progression-free survival; mOS, median overall survival; CI, confidence interval; HR, hazard ratio.

Table 4. Ongoing trials utilizing immunotherapy in advanced disease
Investigational arm	Comparison arm	n	Line	Phase	NCT number
Pembrolizumab plus gemcitabine plus cisplatin (KEYNOTE-966)	Gemcitabine plus cisplatin	1,048	1L	3	NCT04003636
Durvalumab plus SNDX-6532 after intra-arterial chemoembolization or radioembolization	None	30	Unspecified	2	NCT04301778
Sitravatinib plus tislelizumab	None	43	2L and beyond	2	NCT04727996
Durvalumab plus tremelimumab plus radiation	None	70	2L and beyond	2	NCT03482102
Nivolumab plus rucaparib	None	35	Maintenance following platinum therapy	2	NCT03639935
Nivolumab plus DKN-01	None	30	2L and beyond	2	NCT04057365
Durvalumab plus tremelimumab with or without paclitaxel	None	106	2L	2	NCT03704480
Nivolumab plus nanoliposomal-irinotecan plus 5-FU	None	34	2L	1/2	NCT03785873
XmAb22841	XmAb22841 with pembrolizumab	242*	2L and beyond	1	NCT03849469
Toripalimab plus lenvatinib	None	44	2L	2	NCT04211168
Toripalimab plus S1 plus albumin paclitaxel	None	30	1L	2	NCT04027764
Toripalimab plus gemcitabine plus oxaliplatin	none	20	1L	2	NCT04191343
Avelumab plus regorafenib	None	482*	2L and beyond	1/2	NCT03475953
Camrelizumab plus apatinib	Camrelizumab plus either GEMOX or FOLFOX	157*	Arm A: 2L or beyond; arm B: 1L	2	NCT03092895
Durvalumab plus guadecitabine	None	55*	2L	1	NCT03257761
Envafolimab plus GEMOX	GEMOX	480	1L	3	NCT03478488

*, includes several cancer types. NCT, National Clinical Trial; FOLFOX, leucovorin (folinic acid), fluorouracil, oxaliplatin; GEMOX, gemcitabine, oxaliplatin.

Table 5. Ongoing trials in patients with *FGFR* alterations
Investigational arm	Comparison arm	N	Line	Phase	NCT number
Infigratinib	Gemcitabine plus cisplatin	300	1L	3	NCT03773302
Infigratinib	None	143	2L and beyond	2	NCT02150967
Pemigatinib	Gemcitabine plus cisplatin	434	1L	3	NCT03656536
Futibatinib	Gemcitabine plus cisplatin	216	1L	3	NCT04093362
Erdafitinib	None	35*	2L and beyond	2	NCT02699606
Gunagratinib	None	56*	2L and beyond	1/2	NCT03758664
Pazopanib plus trametinib	None	89*	2L and beyond	1	NCT01438554
Derazantinib	None	148	2L and beyond	2	NCT03230318
E7090	None	60	2L and beyond	2	NCT04238715

*, includes several cancer types. NCT, National Clinical Trial; FGFR, fibroblast growth factor receptor.

Table 6. Ongoing trials in patients with *IDH* mutations
Investigational arm	Comparison arm	N	Line	Phase	NCT number
Olaparib	None	145*	2L and beyond	2	NCT03212274
Olaparib plus durvalumab	None	78*	2L or 3L	2	NCT03991832
Olaparib plus ceralasertib	None	50*	2L and beyond	2	NCT03878095
LY3410738	LY3410738 with gemcitabine plus cisplatin or with durvalumab	200*	Dependent on cohort (e.g., dose expansion cohort limited to 1L)	2	NCT04521686
HMPL-306	None	90*	2L and beyond	1	NCT04762602
Dasatinib	None	8	2L and beyond	2	NCT02428855
FT-2102 plus gemcitabine plus cisplatin	None	93*	2L	1/2	NCT03684811
Ivosidenib plus nivolumab	None	35*	2L and beyond	2	NCT04056910
Ivosidenib or pemigatinib plus gemcitabine plus cisplatin	None	40	Maintenance	1	NCT04088188

*, includes several cancer types. NCT, National Clinical Trial; IDH, isocitrate dehydrogenase.

Table 7. Ongoing trials in patients with *HER2* alterations
Investigational arm	Comparison arm	N	Line	Phase	NCT number
Trastuzumab plus tucatinib	None	12	2L and beyond	2	NCT04579380
Multiple targeted therapies	None	6,452*	2L and beyond	2	NCT02465060
Multiple targeted therapies	None	3,581*	2L and beyond	2	NCT02693535
BDTX-189	None	91*	2L and beyond	1/2	NCT04209465

*, includes several cancer types. NCT, National Clinical Trial; HER2, human epidermal growth factor receptor 2.

Table 8. Ongoing trials of other targeted and novel therapies
Investigational arm (mechanism)	Comparison arm	n	Line	Phase	NCT number
Olaparib (PARP inhibitor)	None	36	Maintenance following platinum therapy	2	NCT04042831
Ramucirumab (monoclonal antibody against VEGFR2	None	61	2L and beyond	2	NCT02520141
Niraparib (PARP inhibitor)	None	35*	2L and beyond	2	NCT03207347
Anlotinib (multikinase inhibitor) and levamisole (T cell activation and proliferation)	Anlotinib	152	2L and beyond	3	NCT03940378
Bortezomib (proteasome inhibitor)	None	50	2L and beyond	3	NCT03345303
CB-103 (diaryl ether against Notch receptors)	None	200*	2L and beyond	1/2	NCT03422679
Opaganib (SK2 inhibitor) with or without hydroxychloroquine	Opaganib	65	1L or 2L	2	NCT03377179
Apatinib (VEGFR2 inhibitor)	None	55	2L and beyond	2	NCT03427242
Apatinib (VEGFR2 inhibitor)	None	30	2L and beyond	2	NCT03521219
Surufatinib (pan-VEGFR and CSF-1R inhibitor)	Capecitabine	298	2L	2/3	NCT03873532
Copanlisib (PI3K inhibitor) plus gemcitabine plus cisplatin	None	24	1L (although patients who received adjuvant therapy more than 6 months prior are also eligible)	2	NCT02631590
RXC004 (porcupine inhibitor) plus denosumab	None	15	2L	2	NCT04907851
Crizotinib (multikinase inhibitor)	None	246*	2L and beyond	2	NCT02034981
Natural killer cells plus pembrolizumab	None	40	2L and beyond		NCT03937895
Tumor infiltrating lymphocytes plus aldesleukin (recombinant interleukin-2)	None	59	2L and beyond	2	NCT03801083
Memory T cells plus chemotherapy	Chemotherapy	20	Resection without recurrence	2	NCT03820310
MUC-1 CAR-T cells plus fludarabine plus cyclophosphamide	None	9	1L	1/2	NCT03633773
Anti-HER2 CAR-macrophages	None	18*	2L and beyond	1	NCT04660929
Gavocabtagene autoleucel (cell therapy) plus fludarabine plus cyclophosphamide with or without nivolumab and ipilimumab	None	175*	2L and beyond (but not more than 5 lines)	1/2	NCT03907852
Oncolytic adenovirus encoding TMZ-CD40L and 4–1BBL plus gemcitabine plus cisplatin	None	50*	1L and beyond	1/2	NCT03225989

*, includes several cancer types. NCT, National Clinical Trial; VEGFR, vascular endothelial growth factor receptor; CSF-1, colony stimulating factor 1; PI3K, phosphoinositide 3-kinase; CAR, chimeric antigen receptor; HER2, human epidermal growth factor receptor 2; PARP, poly adenosine diphosphate-ribose polymerase.

Table 9. Genomic clusters in biliary tract cancers
Cluster 1	Cluster 2	Cluster 3	Cluster 4
TP53, KRAS, HER2, and ATM mutations	CDKN2A/B mutations	IDH1 and chromatin remodeling gene (ARID1A and PBRM1) mutations	FGFR2 fusions and BAP1 mutations

BAP1, BRCA1 associated protein-1; FGFR, fibroblast growth factor receptor; IDH1, isocitrate dehydrogenase 1; CDKN2A/B, cyclin-dependent kinase inhibitor 2A/B; HER2, human epidermal growth factor receptor 2; ARID1A, AT-rich interactive domain-containing protein 1A; PBRM1, polybromo 1; ATM, ataxia telangiectasia mutated.