Innovative therapeutic concepts for biliary tumors

Cholangiocarcinoma (CC) is a malignant tumor arising from the epithelium of the bile ducts. CC accounts only for about 3% of all gastrointestinal tumors but this cancer is the second most common primary liver tumor. Over 90% of these tumors are adenocarcinomas [1]. Depending on the anatomical location, CC is divided into intrahepatic cholangiocarcinoma (iCC), perihilar cholangiocarcinoma (pCC), and distal cholangiocarcinoma (dCC). pCC and dCC are also defined as extrahepatic (e) cholangiocarcinoma. pCC is the most common type of CC, accounting for 50–60% of cases. In general, the incidence of all forms of CC seems to be increasing [2]. Specifically, the incidence rates of iCC have shown significant increasing trends in high-income countries since 2010, while eCCs have only shown a slight increase [3].

Although these tumors are all called CC, differences in molecular characteristics and cell origin between iCC (hepatic steam cell) and eCC (peribiliary glands) are well described [4]. These circumstances explain why this tumor entity is predestined for biomarker-controlled therapies.

Currently, the poor prognosis of CC is due to difficulties regarding early diagnosis and limited treatment options with patients having a median survival of 24 months after diagnosis. Several risk factors have been identified: primary sclerosing cholangitis (PSC), bile duct cysts, parasitic infections (mainly in Asia), hepatolithiasis, toxins, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Moreover, some evidence has indicated that potential risk factors also include alcohol consumption, smoking, diabetes, nonalcoholic steatohepatitis (NASH), inflammatory bowel disease, and genetic polymorphisms. However, over 70% of patients are diagnosed with CC without any predisposing factors [5]. According to current evidence, surgical resection is the only curative treatment option, which is approved by all guidelines. In very rare and selected cases, a liver transplant can be offered to cure the patient. Unfortunately, there is a high relapse rate in the minority of patients who undergo potentially curative surgery [6]. For this reason, there is a high clinical need for adjuvant therapy.

Similar to other oncologic liver resections, cholangiocarcinoma is considered resectable if the tumor can be fully removed with negative margins while maintaining sufficient functional liver with adequate perfusion and venous and biliary drainage. The patient also must have sufficient physiologic reserve to tolerate surgery.

According to the literature, multiple intrahepatic tumors are present in about 42% of patients on presentation [7]. In one recent study, Buettner et al. compared outcomes between patients undergoing resection for solitary and multiple intrahepatic lesions: the median overall survival in patients with 2 tumors was 21.2 months versus 15.3 months in those ≥ 3 tumors. While not directly comparable and highly susceptible to staging and selection bias, these survival times are longer than the 1‑year median survival usually cited for systemic and locoregional ablative therapies for unresectable iCC [8].

The idea of liver transplantation has been around for a long time. Data on liver transplantation for iCC are mixed, and transplantation is not regularly recommended. However, recent small studies show that after appropriate prior therapy with chemotherapy, transplantation can also bring a certain benefit in selected iCC patients [9].

In hilar cholangiocarcinoma, transplantation preceded by neoadjuvant chemoradiation has demonstrated a survival benefit [10]. However, transplantation does not currently play a major role for this disease. Furthermore, neoadjuvant chemotherapy is not routinely recommended for resectable iCC.

Several adjuvant therapy studies failed to show a benefit versus surveillance [11]. However, more recent data from the phase 3 trial BILCAP changed the current therapeutic approach [11]. A total of 447 patients with biliary tract cancer (BCT) were randomized to capecitabine (n = 223) or observation (n = 224). Sensitivity analyses by intention-to-treat were adjusted to nodal status, grade of disease, and gender (447 patients). This trial demonstrated benefit from capecitabine in terms of overall survival (OS): hazard ratio (HR) 0.71 (95% confidence interval [CI] 0.55–0.92); P < 0.01; median OS 51 months (95% CI 35–59) and 36 months (95% CI 30–45) for capecitabine and observation arms, respectively. There was also benefit from adjuvant capecitabine in terms of relapse-free survival: median 25 months (95% CI 19–37) and 18 months (95% CI 13–28) for capecitabine and observation arms, respectively. Based on these results, adjuvant capecitabine is at the moment standard of care following surgery for biliary tract cancer.

Data from the multicenter phase III study ACTICCA‑1 are eagerly awaited. Here, treatment with cisplatin/gemcitabine is compared after curative resection versus observance. Recently, however, there was a change in the study design: the observation group was exchanged for capecitabine. Recruitment is now complete and data results are expected in 2025.

Around 60–70% of patients will be diagnosed with advanced disease, which is defined as inoperable or metastatic disease. For these patients, palliative treatment is the only choice of treatment at the moment. Unfortunately, survival outcome is historically poor in this patient group.

The phase III ABC-02 trial published in 2010 has established cisplatin plus gemcitabine as the first-line standard in patients with advanced biliary tract cancer [12]. Compared to single-agent gemcitabine, the platinum-based combination improved median overall survival (mOS) by 3.6 months (11.7 vs. 8.1 months), which translated into a 36% mortality reduction (HR 0.64; p < 0.001).

In recent months it has been shown that mOS can be slightly improved by adding immunotherapy to chemotherapy regardless of Microsatellite instability (MSI) status.

The phase III TOPAZ‑1 trial explored the addition of the anti-PD-L1 antibody durvalumab. Patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease were included. In all, 685 patients were randomly assigned to durvalumab (n = 341) or placebo (n = 344) with gemcitabine plus cisplatin for up to eight cycles, followed by durvalumab or placebo monotherapy until disease progression or unacceptable toxicity.

The median survival in the immunotherapy combination group was 12.8 months, which was marginally, but significantly longer. Here the mOS was 11.5 months. The hazard ratio is given as 0.8; the p value is 0.021. The survival curves diverge after 6 months. After 24 months, the OS in the study group was 24.9% and in the placebo group only 10.4% [13].

KEYNOTE-966 was a randomized, double-blind, placebo-controlled, phase 3 trial performed at 175 medical centers globally. Again, patients with previously untreated, unresectable, locally advanced or metastatic biliary tract cancer where included. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m² intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m² intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). There were 1069 patients randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n = 533) or placebo plus gemcitabine and cisplatin (placebo group; n = 536). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p = 0·0034 [significance threshold, p = 0·0200]) [14]. This clearly proves that the combination of chemotherapy with immunotherapy is the new therapeutic standard in the first-line treatment of CC regardless of its origin.

As already mentioned in the introduction in recent years we also have learned CC is a role model for precision medicine in the gastrointestinal (GI) tract. For this reason, the European Society of Medical Oncology (ESMO) guidelines recommend molecular testing using next generation sequencing (NGS).

Experts are still discussing the timing of testing (at the beginning of first-line therapy or after it fails). Aside from that, there is currently no general recommendation about which tests are essential. In any case, all common targets should be recorded and the time of testing should be early enough. At least, if the question of second-line therapy arises.

With the volume of biomarker-informed and -agnostic data, current treatment has changed over the past years. Consequently, this led to numerous new approvals by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), and some new substances are waiting to enter everyday clinical practice.

IDH1-mutant CC occurs in about 15–20% of iCC. Studies estimating prevalence vary greatly across different countries [15].

The FDA and EMA have already approved ivosidenib for the treatment of adults with previously treated locally advanced or metastatic cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. The approval is based on data from the phase III ClarIDHy study [16]. Median OS was 10.3 months ((95% Cl 7.8–12.4 months) with the ivosidenib versus 5.1 months (95% Cl 3.8–7.6 month)); hazard ratio 0.49 (95% Cl 0.34–0.70) with placebo, when adjusted for crossover [17]. As permitted by the study protocol, 57% of patients in the placebo group crossed over to ivosidenib at the time of disease progression. In patients randomized to ivosidenib, progression-free survival (PFS) improved significantly (HR 0.37; p < 0.0001).

Fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements occur in up to 14% of patients with intrahepatic cholangiocarcinoma [18].

Currently, two compounds have been approved by regulatory agencies: pemigatinib (FDA) and (EMA) approved in 2020 and 2021, respectively and infigratinib (FDA) approved in 2021. Responses with these agents have been reported to be 35.5% and 23.1% [19].

Recently, futibatinib, a next-generation, covalently binding FGFR1–4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors [20].

HER2 and/or the ERBB2 gene is mutated, amplified, or overexpressed in 19.1–31.3% of gallbladder cancer, 17.4–18.5% of extrahepatic cholangiocarcinoma, and 3.7–4.8% of intrahepatic cholangiocarcinoma [21].

In recent years, a few small studies targeting HER2 have been presented at major meetings. The data of Destiny02 should be mentioned as an example with trastuzumab–deruxtecan (T-DXd), an antibody–drug conjugate composed of a humanized monoclonal anti-HER2 antibody and a topoisomerase I inhibitor.

There is also data on trastuzumab–pertuzumab [22].

In the current ESMO guidelines trastuzumab-pertuzumab is recommenden for HER-2 status. Nevertheless, at the ASCO 2023 a new substance was presented: zanidatamab.

This targets HER2 via two different antigen binding domains: the HER2 dimerization domain and the extracellular juxtamembrane domain. This biparatopic geometric arrangement results in HER2 binding in trans configuration, which leads to the formation of receptor–antibody clusters, receptor internalization, and HER2 downregulation. In preclinical studies, zanidatamab exhibited antitumor activity in HER2-driven neoplasia that was superior to both trastuzumab monotherapy and trastuzumab combined with pertuzumab [23].

Patients with HER2-amplified (confirmed by in situ hybridization per central testing), unresectable, locally advanced or metastatic biliary tract cancer with progression on a gemcitabine-based therapy were recruited at 32 clinical trial sites in nine countries in North and South America, Asia and Europe. A total of 87 patients were enrolled in the trial. Patients were assigned into cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (IHC 2+ or 3+; HER2-positive) and cohort 2 (IHC 0 or 1+). Patients received zanidatamab 20 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate in cohort 1 as assessed by independent central review.

In all, 80 patients were in cohort 1 (56% were female and 44% were male); 7 patients were included in cohort 2. At the time of the data cutoff (10 October 2022), 18 (21%) patients (17 in cohort 1 and 1 in cohort 2) were continuing to receive zanidatamab. Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41.3%; 95% CI 30.4–52.8). Furthermore, 16 (18%) patients had grade 3 treatment-related adverse events; the most common were diarrhea (4 [5%] patients) and decreased ejection fraction (3 [3%] patients).

The authors of the study concluded from the data collected that zanidatamab demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer.

Further studies with the test substance (HER2-positive bile duct cancer in combination with standard first-line cisplatin–gemcitabine [NCT03929666]) are being planned [24].

However, it is questionable whether there will be phase III studies in this setting due to the small number of patients.

Other targetable alterations include B‑Raf proto-oncogene serine/threonine kinase (BRAF) V600E mutations. The prevalence of BRAFV600 mutations is about 3% [25]. A recent phase II study exploring the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in patients with BRAF V600E-mutated BTC reported an independent reviewer-assessed Overall Response Rate (ORR) of 51% (95% CI 36–67%) [26].

Gene fusions involving one of the three neurotrophic tyrosine receptor kinases (NTRK) have been identified in approximately 1% of solid tumors and inhibitors of TRK (e.g., larotrectinib and entrectinib, which both have FDA and EMA approval) have been shown to have antitumor activity regardless of tumor type. An abstract from the 2020 ASCO showed results from 145 cholangiocarcinoma patients screened by IHC and confirmed by NGS, the percentage of NTRK fusions was 0.75% [27]. ORR of 57–79% with a complete response rate of 7–16% were reported [28].

Since the disease has become more common, this tumor is no longer considered too rare for sufficiently well-founded clinical studies, which ultimately explains why treatment options for biliary tract carcinoma have developed rapidly in recent years.

Not only do the actionable targets make this cancer a role model for precision medicine, but improvements in technology also make molecular characterization less costly. An important key in the treatment of cholangiocarcinoma in the future will be to find the optimal sequence for the individual patient. However, one of the biggest challenges currently is finding a test that finds all potentially treatable targets.