Advances in Immunooncology and Precision Medicine in Cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is an uncommon but morbid cancer arising from the intrahepatic or extrahepatic bile ducts. CCA is frequently asymptomatic at early stages and is often unresectable or metastatic at the time of initial diagnosis. While chemotherapy remains the mainstay of treatment for most patients with advanced disease, the addition of immunotherapy to frontline treatment has improved survival and provided an alternative to perpetual chemotherapy. Furthermore, a variety of targeted therapies have demonstrated benefit in patients with specific biomarkers including FGFR2 fusions, IDH1 mutations, HER2 overexpression, and tumor agnostic markers such as NTRK and RET fusions, among others. This review will summarize the established roles of immunotherapy, targeted therapies, and their combinations in CCA as well as treatment strategies that are under development with potential to impact clinical practice in the coming years.

Keywords

cholangiocarcinoma - biliary tract cancer - immunooncology - precision medicine

Cholangiocarcinoma (CCA), a cancer arising from the intrahepatic or extrahepatic bile ducts, is an uncommon cancer whose incidence and mortality have been increasing across the globe over the last several decades, coincident with the increase in specific risk factors for its development.[1] [2] Together with gallbladder cancer, intrahepatic and extrahepatic CCAs (ICC and ECC) are referred to collectively as biliary tract cancers (BTCs).[1] [3] Risk factors for the development of CCA include hepatitis B and C, primary sclerosing cholangitis, liver fluke infection, chronic liver disease, metabolic-associated fatty liver disease, obesity, and diabetes, and the incidence of CCA varies widely across geographic regions.[4] [5] CCA most commonly presents with jaundice, ascending cholangitis, and/or right upper quadrant pain, but CCA confined to the liver is often asymptomatic and is frequently diagnosed incidentally via cross-sectional imaging. Because of its insidious onset, almost half of the patients with CCA present with unresectable or metastatic disease at the time of initial diagnosis.[5] [6] [7] [8]

Prior to the advent of targeted therapies and immunotherapy in BTCs that are highlighted in this review, the treatment of advanced or metastatic disease relied heavily on indefinite cycles of cytotoxic chemotherapy. The publication of the Advanced Biliary Cancer (ABC)-02 Trial in 2010 established the combination of gemcitabine and cisplatin (GemCis) as a standard of care for advanced BTC, with an improvement in overall survival (OS) compared with gemcitabine monotherapy (median OS of 11.7 vs. 8.1 months, hazard ratio [HR] of 0.64, 95% confidence interval [CI] of 0.52–0.80, p < 0.001).[9] The limited benefit of additional chemotherapy was later shown in the ABC-06 trial testing 5-fluorouracil and oxaliplatin (FOLFOX) chemotherapy versus active symptom control (ASC) after progression on gemcitabine-based chemotherapy. The addition of FOLFOX resulted in an improvement of ∼1 month in median OS compared with ASC without chemotherapy (6.2 vs. 5.3 months, HR: 0.69, 95% CI: 0.50–0.97, p = 0.031).[10] Together, these trials established a typical treatment sequence of GemCis followed by FOLFOX for patients with advanced BTC.

In recent years, significant advances in personalized medicine and the adoption of immunotherapy in BTCs have improved outcomes in many patients. While the traditional classification of CCA is based on anatomic origin, systemic therapy trials have combined all anatomic subtypes for the purposes of feasibility despite mounting evidence from molecular profiling that small duct, or cholangiolar, ICC is likely its own distinct entity with a prevalence of actionable molecular alterations approaching 40 to 50%.[11] [12] [13] Furthermore, advancements in our understanding of the biology of CCA and demonstrations of the efficacy of immunotherapy and immunotherapy-based combinations have resulted in additional treatment options for patients for whom targeted therapy may not be appropriate.[14] [15] [16]

As a result, it is now recommended within in the National Comprehensive Cancer Network (NCCN) guidelines that patients with advanced BTC who are being considered for systemic therapy undergo molecular testing for targetable alterations.[17] This testing should include an analysis for microsatellite instability (MSI)/mismatch repair (MMR) proficiency, tumor mutational burden (TMB), HER2 overexpression and/or amplification, IDH1 mutations, FGFR2 fusions or rearrangements, as well as tumor agnostic markers such as RET or NTRK gene fusions or BRAF V600E mutation. Molecular testing of tumor material is preferred when available, but cell-free (cf)DNA testing can act as a substitute if the biopsy yield is insufficient, though the sensitivity of cfDNA is inferior to tissue-based assays, especially for gene fusions.[17]

In this review, we will discuss the role of immunotherapy in CCA and the therapeutic implications for driver mutations. Currently approved as well as promising approaches to immunotherapy, targeted therapy, and personalized therapies are summarized in [Fig. 1].

Fig. 1 Immunotherapy and precision oncology progress in cholangiocarcinoma. Agents that are endorsed in the NCCN guidelines are represented with *. Approaches and progress with other personalized therapies have shown promise in improving outcomes for patients with advanced cholangiocarcinoma. ICI, immune checkpoint inhibitors.

Immunotherapy in Cholangiocarcinoma

Efforts to improve outcomes described in the ABC-02 and ABC-06 trials have been primarily centered on the development of targeted therapy and/or immunotherapy combinations. The tumor microenvironment of CCA is characterized by a desmoplastic and immunosuppressive microenvironment infiltrated by myeloid-derived suppressor cells, tumor-associated macrophages, tumor-associated neutrophils, and T_reg cells.[14] [15] [16] Furthermore, significant intratumoral heterogeneity exists that limits the efficacy of immunotherapy in CCA. Recent work has identified tumor microenvironment-based subtypes that may allow for the identification of patients with CCA who may be more likely to respond to immunotherapy.[18] Although not yet available clinically, the ongoing development of such tools will be critical to improve patient selection for immunotherapy in CCA.

Two pivotal phase III studies have established the benefit of immune checkpoint inhibitors (ICIs) in advanced BTCs. TOPAZ-1 was a randomized phase III trial testing the addition of the PD-L1 inhibitor durvalumab or placebo to GemCis.[19] Chemotherapy was administered for up to eight cycles then stopped in both arms. The intention-to-treat analysis demonstrated an OS benefit (median OS: 12.8 vs. 11.5 months, HR: 0.80 [95% CI: 0.66–0.97] p = 0.021) and progression-free survival (PFS) benefit (median PFS: 7.2 vs. 5.7 months, HR: 0.75 [95% CI: 0.63–0.89] p = 0.001) both favoring the addition of durvalumab to GemCis.[19] This trial established GemCis plus durvalumab as a new frontline standard, but additional questions remained including the role of maintenance chemotherapy and whether all subgroups stood to benefit from ICI therapy. In addition, no candidate biomarker emerged from the study to improve the patient selection for durvalumab.

KEYNOTE-966 further confirmed the benefit of ICI in advanced BTC and showed a survival advantage with the addition of pembrolizumab to GemCis in patients with advanced BTC.[20] The trial was similar in design to TOPAZ-1 but importantly allowed continuation of gemcitabine after the initial eight cycles of GemCis.[19] [20] An improvement in OS was seen with the addition of pembrolizumab compared with placebo (median OS: 12.7 months [95% CI: 11.5–13.6] vs. 10.9 months [95% CI: 9.9–11.6] in the placebo arm, HR death of 0.83 [95% CI: 0.72–0.95] p = 0.0034). Although an improvement in PFS was also observed with the addition of pembrolizumab (HR: 0·86 [95% CI: 0.75–1.00] p = 0·023), this did not meet the predefined significance threshold (p = 0.0125). The benefit of pembrolizumab was seen across subgroups, and, as in TOPAZ, no selective biomarker emerged. As a result of TOPAZ-1 and KEYNOTE-966, GemCis with either durvalumab or pembrolizumab has become the standard initial therapy for patients with advanced BTC.[17] [19] [20]

Dual Immunotherapy Combinations

Prior to the availability of results from TOPAZ-1 and KEYNOTE-966, several trials attempted to improve upon the limited activity observed with single-agent immunotherapy ([Fig. 2]).[21] The combination of the CTLA-4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab in single-arm phase II in patients with refractory-advanced BTC showed an objective response rate (ORR) of 29% and a disease control rate (DCR) of 44%.[22] While the efficacy was encouraging, especially in light of the durability of many of the responses, toxicity was also frequent, with 49% of patients experiencing at least one immune-related adverse event (irAE), highlighting the elevated risk of toxicity with dual ICI therapy.[22]

Fig. 2 Selected immunotherapy combination treatment strategies that have been reported in clinical trials of cholangiocarcinoma.

A randomized phase II trial also tested the combination of ipilimumab and nivolumab against the combination of GemCis plus nivolumab in previously untreated patients with advanced CCA.[23] Although the combination of ipilimumab and nivolumab was well tolerated, with very few grade 3 or higher toxicities, the median PFS in the GemCis plus nivolumab arm was 6.6 months compared with 3.9 months in the ipilimumab and nivolumab arm.[23] OS also favored GemCis plus nivolumab (median OS: 10.6 vs. 8.2 months, p = 0.61).[23] However, the ORR with ipilimumab and nivolumab was only 3.0 versus 22.9% with GemCis plus nivolumab.[23] Interestingly, both arms in this study had long-term survivors, with a 2-year OS of 35.4% with GemCis plus nivolumab and 28.8% with ipilimumab and nivolumab, highlighting the potential long-term efficacy in patients who do experience a response to ICI, a phenomenon also seen in the TOPAZ-1 and KEYNOTE-966 studies.[19] [20] [23]

Durvalumab has also been tested in combination with tremelimumab, an anti-CTLA4 antibody, in patients with refractory BTC. In a phase 1 trial primarily featuring patients from Asia, the combination of durvalumab and tremelimumab resulted in an ORR of 10.8%, compared with 4.8% in patients with BTC treated with durvalumab monotherapy.[24] However, this was accompanied by an increased risk of treatment-related adverse events (any: 81.5 vs. 64.3%, grade 3 or higher: 23.1 vs. 19.0%).[24]

Altogether, dual checkpoint inhibition appears more active than PD-(L)1 inhibitor monotherapy, but also carries a higher risk of irAEs. No published studies have yet evaluated the role of dual ICI therapy after prior ICI treatment. With the current use of ICI in the frontline setting in most patients with advanced disease, the role and future development of dual ICI therapies in BTCs is uncertain.

MSI-High/dMMR and TMB-High

FDA-approved tumor-agnostic indications for immunotherapy (MSI-high, MMR deficiency [dMMR], and/or TMB-high) occur infrequently in CCA, representing only 2 and 3.5% of cases of CCA, but can select for patients more likely to respond to ICIs.[12]

For patients with tumors that are MSI-high or dMMR, single-agent pembrolizumab or dostarlimab-gxly (dostarlimab) is endorsed in the NCCN guidelines.[17] Data in support for tumor-agnostic pembrolizumab for MSI-high and dMMR CCA arose from cohort K of the phase II KEYNOTE-158 trial. Of the 22 enrolled patients with CCA or BTC who had previously had progression to or intolerance of standard first-line therapies, 40.9% (95% CI: 20.7–63.6%) enjoyed an objective response following treatment with pembrolizumab, including three who experienced a complete response. Patients treated with pembrolizumab had a median OS of 19.4 months, median PFS of 4.2 months, and a median duration of response of 30.6 months.[25] [26] Subsequently, pembrolizumab is now supported for initial treatment or as advanced-line treatment in MSI-high or dMMR CCA.[17]

Similarly, dostarlimab was tested in patients with dMMR solid tumors in the GARNET study. Of 327 enrolled patients in the cohorts of dMMR solid tumors, 10 had BTCs, 4 of who experienced an objective response (40%; 95% CI: 12.2–73.8%). Treatment with dostarlimab was overall well-tolerated with only 7.3% of enrolled patients discontinuing due to a treatment-related adverse event.[27] [28]

For patients with MMR-proficient and TMB-high BTCs, combination of nivolumab and ipilimumab or single-agent pembrolizumab is endorsed in the NCCN guidelines, though published clinical data in BTCs remain limited.[17]

Emergence of Actionable Targets

Although the true incidence of targetable molecular alterations is difficult to pinpoint and varies across studies depending on the study population, sequencing platform, and stage of disease, molecular characterization of CCAs has described a prevalence of 40 to 50% of patients with ICC harboring an actionable target, with somewhat lower rates in other anatomic subtypes of BTC.[11] [12] [13] Increasing uptake and utilization of circulating tumor DNA analyses will likely continue to refine our understanding of the prevalence of actionable targets.

The most common actionable mutation in CCA is the IDH1 R132 mutation, found in up to 20% of CCAs, mostly in ICC. This is followed by the FGFR2 fusion, HER2 overexpression or amplification, and BRAF V600E mutation.[11] [12] [13] Other rare but actionable tumor agnostic mutations endorsed by the NCCN guidelines include NTRK fusions and RET fusions.

IDH

Isocitrate dehydrogenase 1 (IDH1) plays a critical role in the Krebs cycle, decarboxylating isocitrate to ɑ-ketoglutarate. However, IDH1 mutated at the R132 residue typically results in the production of the oncometabolite 2-hydroxyglutarate (2HG).[29] 2HG has been long recognized to introduce epigenetic alterations that result in the development of invasive cancers through the inhibition of histone and DNA demethylases. IDH1 mutations are present in 15 to 20% of ICCs and provide an attractive target for therapy.[30]

ClarIDHy was a multicenter randomized phase III clinical trial that compared ivosidenib versus placebo in patients with refractory, advanced IDH1-mutant CCA.[31] Compared with placebo, ivosidenib resulted in an increase in the PFS (median PFS: 2.7 vs. 1.4 months, HR: 0.37; 95% CI: 0.25–0.54, p < 0.0001).[31] Three patients (2%) had a partial response and 63 (51%) had stable disease with ivosidenib, compared with zero patients with a partial response and 17 patients (28%) with stable disease in the placebo arm.[31] Subsequently, ivosidenib was approved by the FDA for the treatment of adult patients with advanced or unresectable CCA following progression on at least one line of therapy.[32] Despite the gain in PFS, an improvement in OS was not apparent on the final intention-to-treat analysis (median OS: 10.3 vs. 7.5 months, HR: 0.79; 95% CI: 0.56–1.12, p = 0.09); however, this was a significant improvement after adjusting for crossover (HR: 0.49; 95% CI: 0.34–0.70, p < 0.001).[33] Toxicity with ivosidenib was generally mild.

Although targeting mutated IDH1 in CCA is endorsed in the NCCN guidelines, further work in optimizing IDH1 inhibition is needed, including combining IDH1 inhibitors with or other agents to improve efficacy. Particularly intriguing are data suggesting mutated IDH1 can alter the tumor microenvironment and may make these cancers more susceptible to the addition of immunotherapy. These tumors with IDH1 mutations demonstrate reduced CD8⁺ T cell infiltration and decreased cytotoxic T cell activity compared with their wild-type counterparts.[18] [34] [35] [36] [37] Mouse models demonstrate that ivosidenib can actively recruit CD8⁺ T cells to tumors with mutant IDH1 while simultaneously restricting tumor growth, an effect abrogated by T cell depletion.[34] Further clinical exploration of ivosidenib and ivosidenib-based combinations for patients with IDH1-mutated CCA is needed.

Isocitrate dehydrogenase 2 (IDH2) is mutated to a far less extent than IDH1 (estimated at 2–5%); however, such mutations could conceivably be targeted with enasidenib, an oral IDH2 inhibitor with demonstrated activity in acute myeloid leukemia. A single report of enasidenib for IDH2-mutated CCA included only four patients, none of who demonstrated a response to enasidenib.[38] While IDH2 is biologically similar to IDH1, further data are needed to support the use of therapies targeting IDH2 in CCA outside of a clinical trial.

FGFR2

The fibroblast growth factor (FGF) pathway is composed of four tyrosine kinase receptors (FGFR1-4) with long-recognized roles in cellular growth, development, and oncogenesis.[39] Fusion mutations of FGFR2 were first reported to be oncogenic in CCA in 2013.[40] These mutations are present in up to 10% of ICC, with rare expression in other BTC subtypes.[41] The FGFR inhibitor pemigatinib was the first therapy of any kind specifically approved by the FDA for CCA and this approval has spurred on a wave of novel FGFR inhibitors currently in clinical development.

Pemigatinib, a reversible FGFR1–3 inhibitor, initially demonstrated efficacy in CCA in the open-label phase II FIGHT202 study. This trial primarily enrolled patients with refractory-advanced BTC harboring FGFR2 fusions (n = 107), as only limited efficacy was seen in patients with other FGFR alterations (n = 20) and in those without FGFR abnormalities.[42] Pemigatinib achieved an ORR of 35.5%, including three complete responses, and a median PFS of 6.9 months (95% CI: 6.2–9.6 months).[42] On the basis of these results, pemigatinib was granted an accelerated approval for patients with previously treated advanced or metastatic CCA with an FGFR2 fusion or rearrangement in April 2020.[43] Pemigatinib is currently undergoing testing versus GemCis in the frontline setting in the randomized phase III FIGHT-302 trial in patients with advanced, FGFR2-rearranged CCA (NCT03656536).[44] [45] Recruitment has been slow and complete enrollment is not expected until 2027.

Futibatinib, an irreversible FGFR inhibitor, was tested in a similar setting of pretreated patients with FGFR2-fusion positive or rearranged CCA in a phase II open-label trial, ultimately demonstrating an ORR of 42%, median PFS of 9.0 months, and median OS of 21.7 months.[46] Futibatinib was subsequently approved by the FDA in September 2022.[47] The reversible FGFR1–3 inhibitor infigratinib also gained accelerated FDA approval based on a single-arm phase II study but was subsequently withdrawn from the market by the manufacturer due to low utilization.[48] Frontline phase III trials of futibatinib and infigratinib compared with GemCis were initiated but later terminated due to poor accrual, highlighting the difficulties of confirmatory studies in uncommon subtypes of a rare cancer.

Next-generation FGFR inhibitors have emerged that seek to improve efficacy and toxicity compared with current agents. One novel agent, RLY-4008, is a highly selective and irreversible inhibitor of FGFR2 only, avoiding the hyperphosphatemia driven by off-target FGFR1 inhibition seen with non-selective agents.[49] RLY-4008 has demonstrated an ORR of 88.2% in the recommended phase II dose level in the phase I/II ReFocus trial in patients with FGFR2-rearranged advanced BTC naive to FGFR inhibitors.[49] [50] Furthermore, RLY-4008 has demonstrated efficacy against common FGFR resistance mutations and has been shown to produce responses in patients who have been previously treated with FGFR inhibitors.[49]

Tinengotinib is another small molecule tyrosine kinase inhibitor with potent FGFR inhibitory activity, with both broad activity against many FGFR resistance mutations and activity at picomolar concentrations.[51] In a recently presented report of a phase I trial of tinengotinib, 20% (3 of 15) of patients with heavily pretreated CCA demonstrated an objective response. This drug was also fairly well-tolerated, with 35.9% experiencing grade 3 toxicities, most commonly hypertension, stomatitis, and diarrhea.[52] A follow-up phase II trial enrolled patients with CCA with primary or acquired resistance to FGFR inhibitors, non-fusion FGFR mutations, and those with wild-type FGFR.[53] At an interim analysis, a DCR of 90% was noted in those with FGFR fusions or mutations and 71% in patients with wild-type FGFR.[53] Furthermore, in those with resistance mutations to FGFR inhibitors, the circulating biomarker analysis revealed loss of the FGFR resistant mutation on liquid biopsy while receiving treatment with tinengotinib.[53] A phase III trial testing tinengotinib versus physician choice FGFR inhibitor in the front-line setting is now active (FIRST-308, NCT05948475). Another trial testing tinengotinib in patients who were previously treated with an FGFR inhibitor and chemotherapy is also underway (NCT06057571).

HER2

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase with no known naturally occurring ligand.[54] Overexpression or amplification of HER2 results in unrestrained cell growth and a variety of agents targeting HER2 have been developed in other cancers. In BTC, gallbladder cancer and ECC frequently overexpress HER2 (15–20%), while overexpression in ICC is uncommon (5%).[54] Several small-molecule inhibitors, antibodies, and antibody–drug conjugates can effectively target cancers overexpressing HER2.

The combination of trastuzumab and pertuzumab, both anti-HER2 antibodies, was first endorsed by NCCN guidelines for use in BTCs following the report of the MyPathway basket trial.[55] In a pretreated population, this combination induced an objective response in 23% and disease control in 51% of enrolled patients.[55] Currently, this is the only HER2-targeting strategy endorsed in the guidelines, though data from novel agents are likely to expand the available armamentarium in the near future.

Trastuzumab deruxtecan (TDXd) is an antibody-drug conjugate targeting HER2 with an enzymatically-cleavable peptide linker and a topoisomerase 1 inhibitor payload with a drug-to-antibody ratio of 8.[56] In a multicenter single-arm phase II study of TDXd, 36.4% of patients with HER2+ BTCs had an objective response. Additionally, activity was seen in patients with HER2-low disease with a 12.5% ORR.[57] [58] The activity across tumor types has subsequently been confirmed in the DESTINY-PanTumor02 phase II basket trial in which 22% of patients with BTCs had a confirmed objective response (all of who had HER2 expression of 3 + ).[59]

Combining trastuzumab with tucatinib, an oral small molecule inhibitor of HER2, has also shown to be a promising approach to the management of advanced HER2-overexpressing BTCs s.[60] Following examples set from HER2Climb in HER2+ breast cancer and MOUNTAINEER in HER2+ metastatic colorectal cancer, SGNTUC-019 was a basket study evaluating the safety and efficacy of the addition of tucatinib to trastuzumab in HER2+ solid tumors. In the HER2-treatment-naive cohort of 30 patients with BTCs who had previously progressed on one or more lines of systemic therapy, preliminary signs of efficacy were observed, with a confirmed ORR of 46.7%, median OS from initiation of treatment of 15.5 months (90% CI: 6.5–16.7), and a median PFS of 5.5 months (90% CI: 3.9–8.1).[60] Of the enrolled patients, 60% experienced grade 3 or higher treatment-emergent adverse events, with nausea, decreased appetite, and cholangitis being the most common (each 10.0%).[60]

Finally, zanidatamab, a bispecific HER2-targeted antibody that targets the HER2 dimerization domain and the extracellular juxtamembrane domain (akin to trastuzumab in combination with pertuzumab) demonstrated acceptable safety in a phase I study of patients with HER2-overexpressed BTCs and produced a confirmed ORR of 47% with a DCR of 65% among 17 enrolled patients.[61] The follow-on phase IIB HERIZON-BTC-01 was recently reported, demonstrating an ORR of 41.3%, DCR of 68.8%, and a duration of response of 12.9 months among 80 patients with HER2-amplified BTCs.[62] Novel therapies targeting HER2 continue to emerge in other disease such as breast cancer, and future trials of these agents as well as combination therapies are likely to further expand the options available for patients with HER2 overexpression or amplification. One large area of unmet needs are those patients with HER2-low disease, which has been successfully targeted in breast cancer but remains an uncertain target in other cancers.[58] [63]

Agnostic Markers

In the past few years, the FDA has granted tumor agnostic approvals for inhibitors of rare driver mutations that appear targetable regardless of tumor origin. These approvals have resulted in the availability of additional targeted therapies for patients with CCA that harbor these mutations. Due to the rarity of some of these mutations and the relative rarity of CCA, limited data exist regarding efficacy in CCA.

NTRK

Fusion mutation in the neurotrophic tyrosine receptor family (NTRK1, NTRK2, and NTRK3) results in constitutive activation of TRK proteins that can lead to activation of cellular growth pathways. These fusions are extremely rare in CCA, detected in only 0.2% of all tumors tested; yet, these mutations can be targeted with the potent small-molecule inhibitors, larotrectinib and entrectinib.[64] Across the two studies that ultimately contributed to the tumor-agnostic approval of these drugs, three patients with CCA were enrolled. One patient receiving entrectinib had a partial response, one receiving larotrectinib had a partial response, and the final patient receiving larotrectinib had progressive disease as the best response to therapy.[65] [66] Subsequently, both drugs have been approved for front-line or subsequent-line therapy for CCA harboring an NTRK fusion.[17]

RET

RET-fusions are an uncommon mutation in BTCs that lead to constitutive activation of the RET pathway.[67] While these mutations are rare, tumors with RET mutations or fusions can exhibit sensitivity to targeted therapies.

Selpercatinib is a highly selective RET inhibitor that currently has a tumor-agnostic approval by the FDA for the treatment of any tumor with a RET mutation. The LIBRETTO-001 trial which led to its approval included two patients with BTCs, one of who was evaluable and had a partial response.[68] Another selective RET inhibitor, pralsetinib, was tested in the phase I/II ARROW basket study for tumor-agnostic safety and efficacy in patients with a RET-fusion positive tumor. Of the 23 patients who enrolled and were evaluated for efficacy, 3 had CCA. Two of those three had a partial response to pralsetinib, while the third had reduction in tumor size but discontinued due to an adverse event.[69] Both pralsetinib and selpercatinib are endorsed in the NCCN guidelines for upfront treatment of patients with CCA harboring a RET fusion.[17]

BRAF

Mutations in BRAF are present in ∼5% of BTCs, although the targetable V600E mutation occurs in ∼1% and is limited to ICC.[70] The NCI-MATCH and the Rare Oncology Agnostic Research (ROAR) basket trials have evaluated dabrafenib and trametinib in patients with BTCs and BRAF mutations.[71] [72] Subprotocol H of NCI-MATCH enrolled patients with solid tumors harboring BRAF V600 mutations to be treated with dabrafenib and trametinib. This trial enrolled a total of 29 patients, of whom 4 had ICC. Three of the four patients with ICC demonstrated a partial response to therapy; the fourth patient had regression in the primary tumor but developed new lesions.[71] ROAR reported the results of a single-arm study of trametinib and dabrafenib in patients with progressive, BRAF V600E mutated BTCs. This trial enrolled 43 patients, of whom 51% enjoyed an objective response, although no complete responses were observed.[72] As a result of these and other studies showing benefit in BRAF V600E mutated cancers, dabrafenib and trametinib received a tumor-agnostic approval from the FDA in June 2022.[73]

A summary of approved and available targeted therapies is available in [Table 1].

Table 1 Summary of approved and currently available targeted therapies for biliary tract cancers

Target	Prevalence	Drug	Response rate	Outcomes
MSI-h, dMMR	2%	Pembrolizumab[25] [26]	40.9%	OS: 19.4 mo PFS: 4.2 mo
		Dostarlimab[27] [28]	40%	–
TMB-high	3.5%	Pembrolizumab[17]	–	–
		Ipilimumab and nivolumab[17]	–	–
IDH1 mutation	15–20%, mostly intrahepatic	Ivosidenib[31] [33]	2%	OS: 10.3 mo PFS: 2.7 mo
FGFR2 fusion	10%, mostly intrahepatic	Pemigatinib[42]	35.5%	PFS: 6.9 mo
		Futibatinib[46]	42.0%	OS: 21.7 mo PFS: 9.0 mo
HER2 amplified	15–20%, mostly extrahepatic or gallbladder	Trastuzumab and pertuzumab[55]	23%	OS: 10.9 mo PFS: 4.0 mo
NTRK fusions	Unknown	Larotrectinib[65]	Unknown	Unknown
		Entrectinib[66]	Unknown	Unknown
RET fusions	Unknown	Selpercatinib[68]	Unknown	Unknown
		Pralsetinib[69]	Unknown	Unknown
BRAF V600E	1%	Dabrafenib and trametinib[72]	51%	OS: 14.0 mo PFS: 9.0 mo

Abbreviations: –, data not yet reported or available; dMMR, deficient mismatch repair; MSI-h, microsatellite instability—high; OS, overall survival; PFS, progression-free survival; TMB-high, tumor mutational burden—high.

Notes: Targeted therapies are generally approved in the second-line setting after progression on cytotoxic chemotherapy combinations. First-line immunotherapy and immunotherapy combinations are approved for microsatellite instability—high, deficient mismatch repair, and tumor mutational burden—high biliary tract cancers. Tumor-agnostic indications for biliary tract cancers are rare and thus there are limited tumor-specific data regarding response rates and outcomes for these patients.

Emerging Targets and Treatment Strategies

KRAS G12C

KRAS activating mutations are frequently observed in BTCs, with higher rates in ECC compared with ICC or gallbladder cancer.[12] [74] G12 allele mutations in KRAS are associated with worse outcomes compared with other KRAS variants.[74] While the G12C mutation in KRAS is uncommon and present only in 1% of all CCAs, it can be effectively targeted with adagrasib.[74] In the phase I/II trial of adagrasib in patients with G12C-mutated KRAS, eight patients with BTCs were enrolled.[75] All eight patients experienced disease control with four patients exhibiting a partial response.[75] Several ongoing studies with existing and novel KRAS G12C inhibitors will provide additional data in the near future.

MDM2 Amplification

Mouse double minute 2 (MDM2) is a negative regulator of TP53, responsible for blocking the transcriptional activation domain and E3 ubiquitin ligase.[76] It is amplified in up to 6% of CCAs and is associated with shorter survival compared with patients with CCA with wild-type MDM2.[76] A recent report of a phase I trial of brigimadlin (formerly BI-097828) included two patients with BTCs and demonstrated acceptable safety, ORR of 11.1%, and a DCR of 74.1%,[77] and accrual continues in the phase II Brightline-2 trial in BTCs (NCT05512377).

Immunotherapy and Targeted Therapy Combinations

With modest activity observed for both immunotherapy and targeted therapies when used as single agents, several trials have been designed to test if combining treatment strategies can result in a synergistic improvement in outcomes while remaining safe and tolerable ([Fig. 2]).

MEK inhibitors are recognized to have immunomodulatory effects in several cancer types. Because of this, a multi-institutional trial sought to test if the addition of cobimetinib to atezolizumab improved PFS compared with atezolizumab monotherapy in pretreated patients with advanced BTCs.[78] While the PFS of the patients in the combination arm was significantly longer (3.65 vs. 1.87 months, HR: 0.58, 90% CI: 0.35–0.93, 1-tail p = 0.027), response rates in both arms were low (3.3 vs. 2.8%) and there was no improvement in OS.[78] Changes in the tumor immune microenvironment were noted in the combination arm (notably an increase in CD8⁺ T cell to FoxP3⁺ T regulator cell ratio, among others) and a follow-up trial is testing the addition of the cobimetinib to atezolizumab and the CD27 agonist varlilumab based on preclinical modeling that MEK inhibition impaired T cell activation could be rescued by CD27 or 4–1BB agonists (NCT04941287).[79]

Lenvatinib is a multikinase inhibitor that primarily exerts its activity through the inhibition of the vascular endothelial growth factor receptors. It has previously demonstrated enhanced anticancer activity in patients with advanced solid tumors when combined with pembrolizumab. In the phase II LEAP-005 study, patients with refractory BTCs after at least one line of treatment received lenvatinib with pembrolizumab.[80] This combination produced an ORR of 10% with a DCR of 68%, encouraging signals in a pretreated population. On the basis of these results, the combination of lenvatinib and pembrolizumab is endorsed in the NCCN guidelines for patients who have progressed on first-line chemotherapy who have not yet been exposed to checkpoint inhibitors.[17]

In an attempt to promote an increase in tumor antigen release and to stimulate an anti-cancer immune response, olaparib has been tested in combination with pembrolizumab in a phase II study.[81] Preliminary data from this study in 12 patients with CCA that had progressed on gemcitabine-based regimens showed one confirmed partial response (8.3%) and four patients with confirmed stable disease (33.3%) for a DCR of 41.7% with good tolerability.[81]

Cancer Vaccination and Adoptive T Cell Therapy

CCAs display a wide range of tumor antigens that can be recognized by T cells and potentially exploited for an anti-tumor effect.[82] Several trials have been completed in attempt to exploit tumor antigens in CCA with cancer vaccines. A phase I trial performed in nine patients with advanced BTC administered weekly vaccination of human leukocyte antigen (HLA)-A*2402-restricted epitope found commonly in CCA.[83] The vaccinations were well tolerated and T cell responses were noted in the majority of patients. Further, six of the enrolled patients exhibited clinical responses in their tumors.[83]

A separate phase II trial attempted to combine low-dose cyclophosphamide to improve antigen-specific immune responses to a peptide-based vaccine in a group of patients with previously treated advanced BTC.[84] Using personalized peptide vaccination, patients received a vaccine that consisted of two to four peptides selected from 31 HLA-matched candidate peptides by levels of IgG titers. Patients were then randomized to low-dose cyclophosphamide or control and T cell responses and IgG titers were measured. Patients who received low-dose cyclophosphamide demonstrated better antigen-specific immune response as well as better PFS (median: 6.1 vs. 2.9 months, HR: 0.427 [95% CI: 0.224–0.813], p = 0.008) and OS (median: 12.1 vs. 5.9 months, HR: 0.376 [95% CI: 0.189–0.747], p = 0.004). Further, antitumor responses were observed in both arms, suggesting potential efficacy in this pretreated population.[84] Another case report demonstrated anti-tumor efficacy in a patient who received a personalized multi-peptide vaccine based on characterization of the patient's tumor.[85] The patient with metastatic CCA received vaccines composed of seven tumor-associated epitopes. During the course of treatment, the patient underwent a pulmonary metastasectomy that demonstrated treatment response. At the time of publication, the patient ultimately experienced a complete response for 41 months; however, following publication, a new liver lesion was noted.[85]

Finally, a single case report exists about the use of adoptive T cell therapy in a patient with widely metastatic CCA who had progressive disease through all known effective therapies.[86] The patient underwent resection of a lung metastasis for whole-exome sequencing and T cell generation. A total of 26 mutations were identified. Of these, a sub-population of CD4⁺ T cells restricted to HLA-DQB1*0601 recognized mutated ERBB2IP. These cells were expanded and the patient ultimately underwent transfer of 42 billion cells. Following this, the patient experienced a 30% reduction in total tumor volume over 7 months post-infusion, followed by disease stabilization for 13 additional months at which point progression was again noted.[86] Altogether, these studies highlight early data supporting a personalized medicine approach to novel immunotherapy approaches in advanced CCA, although more work is needed to bring these approaches to the wider population of patients with CCA.

Conclusions

Although progress in CCA has been slow, significant advancements in immunotherapy and precision oncology have been realized in the past few years. The recent success in CCA has sparked a therapeutic revolution with numerous targeted and immune treatments under active investigation. FGFR remains a paradigmatic example, with several next-generation therapies that appear both more effective and less toxic, and other targets such as HER2 appear poised for similar rapid development. While the addition of ICIs has only modestly improved median OS in patients with advanced CCA, the increase in long-term survivors in both the TOPAZ-1 and KEYNOTE-966 studies provides hope to patients and a foothold for the further development of novel immunotherapies and selective biomarkers. As additional targets and therapies enter the clinic, major questions remain regarding the optimal sequencing of therapies and drug selection within each class of agents, and a substantial investment is needed to more rapidly move these new treatments into earlier stage disease to improve cure rates. However, each new option is one more step toward the end of perpetual cytotoxic chemotherapy and closer to a new era of individualized oncology.

Conflict of Interest

None declared.

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Publication History

Received: 17 January 2024

Accepted: 20 April 2024

Article published online:
15 May 2024