INTRODUCTION — Cholangiocarcinomas are rare malignancies arising from the epithelial cells of the intrahepatic and extrahepatic bile ducts. Systemic therapy for advanced cholangiocarcinoma will be reviewed here. Surgical and other local treatments for cholangiocarcinoma and ampullary cancer; the epidemiology, pathology, classification, clinical presentation, and diagnosis of cholangiocarcinoma and ampullary cancer; and systemic therapy for gallbladder cancer are all discussed elsewhere. (See "Treatment of localized cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis" and "Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma" and "Clinical manifestations and diagnosis of cholangiocarcinoma" and "Epidemiology, pathogenesis, and classification of cholangiocarcinoma" and "Ampullary carcinoma: Epidemiology, clinical manifestations, diagnosis and staging" and "Ampullary carcinoma: Treatment and prognosis" and "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis".)
GENERAL PRINCIPLES OF CHEMOTHERAPY
Benefit — Systemic chemotherapy is increasingly being applied in cases of advanced cholangiocarcinoma. A benefit for first-line chemotherapy over best supportive care alone was suggested in a trial that randomly assigned 90 patients with advanced pancreatic or biliary cancer (37 with bile duct cancer) to fluorouracil-based systemic chemotherapy or best supportive care alone (median survival 6 versus 2.5 months, respectively) [1]. In the second-line setting, the ABC-06 trial of 162 patients with advanced biliary tract cancer demonstrated a significant, albeit modest, survival benefit for oxaliplatin-based combination therapy versus active symptom control alone after failure of an initial cisplatin/gemcitabine regimen (median 6.2 versus 5.3 months) [2]. (See 'FOLFOX' below.)
The literature regarding treatment results with specific regimens is limited because most series are small and many reports consist of a mix of bile duct cancer, gallbladder cancer, ampullary cancer, and either pancreatic or hepatocellular cancer. Although they arise in similar locations, these cancers all have a unique natural history and response to chemotherapy. As an example, patients diagnosed with intrahepatic cholangiocarcinoma have better overall survival compared with other sites [3].
Prognostic factors — Patients with advanced biliary tract cancer are a heterogeneous group, comprising both locally advanced and metastatic disease, as well as a variety of primary disease sites (intrahepatic bile ducts, extrahepatic bile ducts, gallbladder, and ampulla). This heterogeneity complicates assessment of treatment efficacy.
The prognostic influence of these and other factors in patients with advanced biliary tract cancer can be illustrated by a Korean series of 213 patients with advanced biliary tract cancer who were either enrolled in one of two prospective phase II studies or included in a retrospective cohort study of patients receiving first-line chemotherapy [4]. In a multivariate analysis, metastatic disease, an intrahepatic primary site, the presence of liver metastases, a poor Eastern Cooperative Oncology Group (ECOG) performance status (table 1), and an elevated level of serum alkaline phosphatase were significant predictors of overall survival. Using these five variables, the authors developed a prognostic index to stratify patients into low, intermediate, and high risk groups with different median (11.5, 7.3, and 3.6 months, respectively) and one-year survivals (48, 26, and 4 percent, respectively). Although these results are not surprising, they demonstrate the variability of the clinical presentation and outcomes among patients with advanced biliary tract cancer. The broad spectrum of clinical courses and the range of prognostic factors must be kept in mind when assessing the results of investigational studies of new treatments.
Prognostic nomograms based on other factors have also been developed [5]. An important point is that these are prognostic and not predictive models, and they cannot be used to predict which patients are more versus less likely to respond to systemic chemotherapy.
FIRST-LINE CHEMOTHERAPY — Few prospective trials have been undertaken of first-line chemotherapy in advanced biliary tract cancer. Gemcitabine plus cisplatin has been shown to be superior to gemcitabine alone, but this regimen has not been compared head to head with other gemcitabine-based combinations, with the sole exception of gemcitabine plus S-1. (See 'Gemcitabine plus cisplatin' below.)
We prefer that patients enroll in clinical trials whenever possible. If a patient is not a candidate for a clinical trial or one is not available, and if S-1 is not available, we suggest gemcitabine plus cisplatin as a first-line regimen for patients with a good performance status. Another reasonable, possibly better tolerated option is gemcitabine plus oxaliplatin (GEMOX). Clinicians could also consider gemcitabine plus nanoparticle albumin-bound paclitaxel (nabpaclitaxel). (See 'Gemcitabine-based regimens' below and "Treatment protocols for hepatobiliary cancer".)
Where S-1 is available, another alternative to gemcitabine plus cisplatin is gemcitabine plus S-1. (See 'Gemcitabine plus S-1' below.)
Whether or not gemcitabine-based combination regimens are superior to non-gemcitabine-based regimens for advanced biliary tract cancer is not established. In our view, leucovorin (LV)-modulated fluorouracil (FU), capecitabine monotherapy, and S-1 alone (where available) are reasonable options, especially for patients with a borderline performance status. (See 'Borderline performance status' below.)
Good performance status and no hyperbilirubinemia — We prefer that patients enroll in clinical trials whenever possible. Off protocol, the optimal first-line regimen is not established. The following represents our approach:
●For most patients with a good performance status and normal bilirubin levels, we suggest gemcitabine plus cisplatin rather than gemcitabine alone or a non-gemcitabine-based regimen. While gemcitabine plus cisplatin has been shown to be superior to gemcitabine alone [6], this regimen has not been compared head to head with other gemcitabine-based combinations, with the sole exception of gemcitabine plus S-1 [7]. Furthermore, data from randomized trials are insufficient to conclude that gemcitabine-based combinations are superior to non-gemcitabine-based regimens. (See 'Gemcitabine plus cisplatin' below and 'Non-gemcitabine-based regimens' below.)
●Where S-1 is available, another alternative to gemcitabine plus cisplatin is gemcitabine plus S-1. (See 'Gemcitabine plus S-1' below.)
●Another reasonable, possibly better tolerated option is GEMOX. However, one advantage of starting with gemcitabine plus cisplatin or S-1 is that it leaves open the option of short-term infusional FU plus LV and oxaliplatin (FOLFOX) as a second-line regimen, which we would not use if the patient had initially received GEMOX. (See 'Gemcitabine-based regimens' below and "Treatment protocols for hepatobiliary cancer".)
●Clinicians could also consider gemcitabine plus nabpaclitaxel. (See 'Gemcitabine plus nabpaclitaxel' below.)
Gemcitabine-based regimens — Overall, objective response rates with gemcitabine alone range from 7 to 27 percent, but median survival is only rarely longer than eight months [6,8,9]. Although randomized trials have not been carried out, the combination of FU/LV and gemcitabine does not appear to be substantially more active than gemcitabine alone [10-12]. However, a randomized trial (the ABC-02 trial) noted significantly better results when gemcitabine was combined with cisplatin as compared with gemcitabine alone. (See 'Gemcitabine plus cisplatin' below.)
Gemcitabine plus cisplatin — Gemcitabine plus cisplatin is a standard option for treatment of advanced biliary tract cancer, especially for patients without hyperbilirubinemia.
Gemcitabine plus cisplatin is an active regimen and has been well tolerated in most [6,13-15], but not all [16], studies.
The superiority of gemcitabine plus cisplatin over gemcitabine alone was shown in the multicenter ABC-02 trial, in which 410 patients with locally advanced (25 percent) or metastatic bile duct (n = 242), gallbladder (n = 148), or ampullary (n = 20) cancer were randomly assigned to 24 weeks of cisplatin (25 mg/m2) followed by gemcitabine (1000 mg/m2) on days 1 and 8 every 21 days, or gemcitabine alone (1000 mg/m2 on days 1, 8, and 15 every 28 days) (table 2) [17].
At a median follow-up of 8.2 months, median overall survival was significantly greater with combination therapy (11.7 versus 8.1 months), as was median progression-free survival (8 versus 5 months). Toxicity was roughly comparable in both groups, with the exception of significantly higher rates of grade 3 or 4 neutropenia with gemcitabine plus cisplatin (25 versus 17 percent) and of grade 3 or 4 abnormal liver function with gemcitabine alone (27 versus 17 percent). Most quality of life scales showed a trend favoring combined therapy, although the differences were not statistically significant [18]. Of the 21 long-term (>3 years) survivors, 14 had received combination therapy.
The authors concluded that gemcitabine plus cisplatin should be considered the reference regimen for advanced biliary cancer. A similar conclusion was reached in a smaller, identically designed, Japanese randomized trial, which also demonstrated significantly greater overall survival with cisplatin plus gemcitabine compared with gemcitabine alone (11.2 versus 7.7 months) [15].
However, the gemcitabine/cisplatin combination has not been directly compared with other gemcitabine combinations (eg, with capecitabine, irinotecan, or oxaliplatin) in phase III trials, with the exception of gemcitabine plus S-1. (See 'Gemcitabine plus S-1' below.)
A pooled analysis of 104 trials of a variety of chemotherapy regimens in advanced biliary cancer (all but three uncontrolled, only one a phase III randomized trial, not including the ABC trial discussed above) concluded that the gemcitabine/cisplatin combination offered the highest rates of objective response and tumor control (objective response plus stable disease) compared with either gemcitabine-free or cisplatin-free regimens [19]. However, this did not translate into a significant benefit in terms of either time to tumor progression or median overall survival. Thus, in our view, gemcitabine plus cisplatin should be considered a standard option for advanced biliary cancer, but not the definitive reference standard.
Gemcitabine plus cisplatin and durvalumab — Durvalumab plus gemcitabine and cisplatin is an alternative to gemcitabine plus cisplatin, but not necessarily preferred in all patients. The short-term benefits over gemcitabine plus cisplatin alone are modest but long-term benefits may be clinically meaningful for some patients. Unfortunately, there are no predictive biomarkers to select which patients may preferentially benefit. We individualize decision making based on patient preference, insurance coverage, and availability of durvalumab.
The superiority of adding the immune checkpoint inhibitor durvalumab to gemcitabine and cisplatin versus gemcitabine/cisplatin alone was shown in the TOPAZ-1 trial [20]. Patients with previously untreated unresectable locally advanced or metastatic intrahepatic or extrahepatic cholangiocarcinoma or gallbladder cancer (n = 685) were randomly assigned to durvalumab (1500 mg every three weeks) or placebo plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on days 1 and 8 every three weeks for up to eight cycles, followed by durvalumab (1500 mg every four weeks) or placebo until disease progression or unacceptable toxicity. Durvalumab-containing therapy significantly improved overall survival, the primary endpoint (median 12.8 versus 11.5 months, HR 0.8, 95% CI 0.66-0.97), and more than twice as many individuals were still alive at 24 months (24.9 versus 10.4 percent). The addition of durvalumab was also associated with longer progression-free survival and a higher objective response rate (26.7 versus 18.7 percent). Durvalumab did not add additional toxicity that was observed with cisplatin/gemcitabine, and only 13 percent of patients developed immune-mediated side effects, 2.4 percent were grade 3 or 4. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)
Largely based on these results, the US Food and Drug Administration has approved durvalumab, in combination with gemcitabine and cisplatin, for adult patients with locally advanced or metastatic biliary tract cancers [21].
Gemcitabine plus S-1 — S-1 is an oral fluoropyrimidine that includes three different agents: ftorafur (tegafur), gimeracil (5-chloro-2,4-dihydropyridine, a potent inhibitor of the FU-metabolizing enzyme dihydropyridine dehydrogenase [DPD]), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea). It is available in some countries outside of the United States.
Gemcitabine (1000 mg/m2 on days 1 and 8) plus S-1 (60, 80, or 100 mg daily based on body surface area and administered on days 1 to 14 of a 21-day cycle) was directly compared with the same dose and schedule of gemcitabine plus cisplatin (25 mg/m2 intravenously on days 1 and 8) in the Japanese phase III FUGA-BT trial [22]. A total of 354 patients with chemotherapy-naive recurrent or unresectable adenocarcinoma of the gallbladder, biliary tract, or ampulla of Vater were randomized, and the trial was designed to demonstrate noninferiority. Gemcitabine plus S-1 was noninferior in terms of median overall survival (15.1 versus 13.4 months, hazard ratio 0.95, 95% CI 0.78-1.15), median progression-free survival (6.8 versus 5.8 months), and objective response rate (30 versus 32 percent). Both treatments were generally well tolerated, although clinically relevant adverse effects (grade 2 or worse fatigue, anorexia, nausea, vomiting, mucositis, and diarrhea) were slightly more frequent with gemcitabine plus cisplatin (35 versus 31 percent).
Gemcitabine plus oxaliplatin — Others report benefit and good tolerability with GEMOX [23-28].
●In a phase II study of GEMOX, the response rate was 36 percent and median overall survival duration was 15.4 months with every-other-week gemcitabine (1000 mg/m2 as a 10 mg/m2 per minute infusion on day 1) and oxaliplatin (100 mg/m2 on day 2) in a select group of 33 previously untreated patients with advanced biliary cancer, a good performance status, and a serum bilirubin level <2.5 times the upper limit of normal (ULN) [23]. Results were less favorable in 23 other patients receiving second- or third-line therapy who had a poorer performance status or a higher bilirubin level (response rate 22 percent, median survival 7.6 months).
●In a randomized phase III noninferiority trial directly comparing GEMOX versus capecitabine plus oxaliplatin (CAPOX) in 222 patients receiving first-line chemotherapy for advanced biliary tract cancer, there were two complete and 26 partial responses with GEMOX (objective response rate 25 percent), and no complete and 17 partial responses with CAPOX (objective response rate 16 percent). Despite this difference, median overall survival was similar in both groups (10.4 versus 10.6 months), as was the six-month progression-free survival rate (45 versus 47 percent) [28]. The authors concluded that CAPOX was noninferior to first-line GEMOX.
Whether these results with GEMOX are better than those that can be achieved with first-line gemcitabine plus cisplatin will require a randomized trial. However, GEMOX is considered a standard first-line regimen for advanced biliary tract cancer in many parts of the world.
GEMOX plus bevacizumab — Efficacy for the combination of gemcitabine plus oxaliplatin (GEMOX) and bevacizumab was suggested in a phase II trial in which 35 patients (all but three previously untreated) with advanced biliary tract cancer (25 cholangiocarcinoma, 10 gallbladder cancer) received bevacizumab (10 mg/kg on days 1 and 15) followed by gemcitabine (1000 mg/m2 at 10 mg/m2 per minute) and oxaliplatin (85 mg/m2), with cycles repeated every 28 days [29]. Fourteen patients had a confirmed partial response (41 percent). Among the 22 patients with cholangiocarcinoma who were eligible for analysis, the median progression-free and overall survival durations were 7.6 and 14.2 months, respectively. Bevacizumab-related toxicities included grade 3 or 4 hypertension in five, proteinuria in one, thrombosis in two, and cardiac ischemia in one. Whether these results are better than those that can be achieved with GEMOX alone or gemcitabine plus cisplatin will require a randomized trial.
Gemcitabine plus capecitabine — The combination of gemcitabine plus capecitabine is also active for advanced biliary tumors [28,30-34]. As examples:
●In one study of 45 patients (53 percent cholangiocarcinoma, the rest gallbladder cancer), gemcitabine (1000 mg/m2 on days 1 and 8) plus capecitabine (650 mg/m2 twice daily for 14 days of every 21-day cycle) was well tolerated [30]. There were 14 objective responses (two complete), which were seen in both tumor types (objective response rate 31 percent); an additional 42 percent had stable disease. The median progression-free and overall survivals were 6.2 and 12.7 months, respectively.
●A study of 57 patients with advanced biliary tract cancer conducted by the Southwest Oncology Group (SWOG) demonstrated a response rate of 25 percent, but median survival was only seven months [35].
Although gemcitabine plus capecitabine is a reasonable alternative for first-line therapy, randomized trials will be needed to determine if this is a more active regimen than gemcitabine plus cisplatin.
Gemcitabine plus nabpaclitaxel — Antitumor activity was also suggested for first-line therapy with weekly gemcitabine plus nanoparticle albumin-bound paclitaxel (nabpaclitaxel (table 3)) in a phase II trial conducted in 74 patients with advanced or metastatic cholangiocarcinoma [36]. The objective response rate was 30 percent, median progression-free survival was 7.7 months, and median overall survival was 12.4 months. The most common grade 3 or worse treatment-related adverse effects were neutropenia (43 percent) and fatigue (14 percent).
Antitumor efficacy was also shown for the triple combination of gemcitabine, cisplatin, and nabpaclitaxel in a phase II study of 60 patients with locally advanced unresectable or metastatic biliary tract cancer (22 percent gallbladder, the remainder cholangiocarcinoma) [37]. The objective response rate was 45 percent, and the overall disease control rate (partial response plus stable disease) was 84 percent. Median progression-free and overall survival durations were 11.8 and 19.2 months, respectively. Grade 3 or higher adverse events occurred in 58 percent, and nine (16 percent) withdrew because of adverse events. Neutropenia was the most common grade 3 or higher adverse event, occurring in 19 patients (33 percent) overall.
Whether these results are better than those that can be achieved with gemcitabine plus cisplatin or other combinations will require randomized trials.
Non-gemcitabine-based regimens — We consider a gemcitabine-containing regimen to be preferred first-line standard for chemotherapy of advanced cholangiocarcinoma.
At least seven small randomized trials have directly compared gemcitabine-containing with non-gemcitabine-containing chemotherapy or chemoradiotherapy for first-line therapy of advanced biliary tract cancer [38-44]. A Cochrane analysis concluded that the evidence obtained from these low-quality trials was insufficient to prove whether or not gemcitabine-containing combinations are better than non-gemcitabine-containing combinations, and that additional trials were needed [45].
Subsequently, the PRODIGE 38 AMEBICA trial randomly assigned 191 patients with advanced biliary tract cancer (83 percent cholangiocarcinoma) to triplet chemotherapy with modified FOLFIRINOX (table 4) versus cisplatin plus gemcitabine (table 2) [46]. At a median follow-up of 21 months, there were no advantages of triplet therapy in terms of median overall survival (11.7 versus 13.8 months), progression-free survival (6.2 versus 7.4 months), or six-month progression-free survival rate (45 versus 47 percent).
Patients with persistent biliary obstruction — For patients with a good performance status who have hyperbilirubinemia despite stenting, we prefer a non-gemcitabine-based regimen, such as LV-modulated FU (table 5) or a fluoropyrimidine plus oxaliplatin.
In past studies, objective response rates for FU alone or FU-based combination therapies ranged from 0 to 34 percent, and median survival was typically less than six months. Many, but not all, more recent series using either infusional FU in combination regimens or LV-modulated FU report higher response rates and marginally longer survival (but still less than one year) [47-54].
Borderline performance status — For patients with a borderline performance status or extensive comorbidity, LV-modulated FU (table 5), capecitabine monotherapy, and single-agent gemcitabine (table 6) are reasonable options for initial therapy.
Leucovorin-modulated fluorouracil — Objective response rates with FU alone are low, and median survival is typically short (usually less than six months) [49]. Higher response rates are reported in many series using either infusional FU or LV-modulated FU, although whether this translates into better survival is unclear [50-57]. In one report of 28 patients with advanced biliary tract cancer, FU (375 mg/m2 per day by bolus) plus LV (25 mg/m2 per day) was given on days 1 through 5 every three to four weeks [52]. There were nine objective responses (32 percent), two of which were complete and lasted for 14 and 16 months, respectively. However, median survival for the entire group was only six months.
Regimens that combine short-term infusional FU with LV (eg, the de Gramont schedule (table 5)) are better tolerated than bolus regimens, and these are generally preferred, although they require central venous access.
Capecitabine — Capecitabine monotherapy is a reasonable alternative to LV-modulated FU for first-line therapy in patients with a borderline performance status, although for unclear reasons, capecitabine as a single agent appears to be relatively less active for cholangiocarcinoma than for gallbladder cancer [58,59]. (See "Treatment of advanced, unresectable gallbladder cancer", section on 'Borderline performance status'.)
Gemcitabine alone — Although it is better tolerated than combination therapy, gemcitabine alone has been associated with inferior outcomes when compared with gemcitabine-based doublets [15,17,60,61].
Biweekly gemcitabine plus cisplatin — Another option is biweekly cisplatin plus gemcitabine, which is associated with a more favorable toxicity profile than standard cisplatin plus gemcitabine [62].
SECOND-LINE THERAPY AND BEYOND — There are few prospective trials comparing specific chemotherapy regimens in the second-line setting for advanced cholangiocarcinoma, and the selection of candidates for second-line therapy as well as the optimal regimen are not established. Targeted testing of advanced cholangiocarcinomas for mismatch repair deficiency (dMMR)/microsatellite instability (MSI) and for specific molecular alterations for which a targeted treatment might be available is indicated for those who might be eligible for molecularly targeted therapy or immunotherapy, preferably within the context of a clinical trial. (See 'Molecularly targeted therapy' below.)
Prognostic stratification — The optimal selection of candidates for second-line chemotherapy is not established. Three independent studies suggest that patients who have a good performance status (0 or 1 (table 1)), disease control with first-line chemotherapy, a relatively low carbohydrate antigen 19-9 (CA 19-9) level, an absence of peritoneal carcinomatosis, and possibly, previous surgery on their primary tumor have the longest survival with second-line chemotherapy [63-65], but whether these characteristics predict chemotherapy responsiveness or more favorable biologic behavior is not clear. No particular regimen seems superior to any other, and the choice of second-line regimen is empiric [64].
Cytotoxic chemotherapy — Largely based on the ABC-06 trial, for most patients who have disease progression while receiving gemcitabine plus cisplatin and who retain an adequate performance status, in the absence of potentially actionable molecular targets, we suggest treatment with short-term infusional fluorouracil (FU) plus leucovorin (LV) and oxaliplatin (FOLFOX). Other conventional chemotherapy regimens that could be considered in this setting include gemcitabine plus oxaliplatin (GEMOX) with or without bevacizumab, capecitabine plus oxaliplatin (CAPOX), liposomal irinotecan plus leucovorin-modulated FU, or a fluoropyrimidine alone. (See 'Gemcitabine plus oxaliplatin' above.)
After failure of GEMOX, gemcitabine plus capecitabine, capecitabine plus cisplatin, or short-term infusional FU plus LV and irinotecan (FOLFIRI) with or without bevacizumab are appropriate options. For selected patients, second-line molecularly targeted therapy using erlotinib plus bevacizumab may be considered; however, this regimen is highly costly.
Patients initially treated with gemcitabine plus cisplatin
FOLFOX — Short-term infusional FU plus LV and oxaliplatin (FOLFOX, (table 7)) is an active regimen for second-line therapy [61,66,67]. FOLFOX was directly compared with active symptom control alone in the randomized ABC-06 trial, which enrolled 162 patients with disease progression after prior gemcitabine plus cisplatin; there were 117 patients with cholangiocarcinoma, 34 with gallbladder cancer, and 11 with ampullary cancer [2]. FOLFOX was associated with significantly better rates of overall survival at 6 (51 versus 36 percent) and 12 months (26 versus 11 percent), and significantly, albeit modestly, improved median overall survival (6.2 versus 5.3 months, hazard ratio [HR] 0.69, 95% CI 0.50-0.97). Grade 3 or 4 toxic events were reported in 59 percent of the group receiving FOLFOX (versus 37 percent of those undergoing symptom control alone), with fatigue and neutropenia being more frequent in the FOLFOX arm. Notably, the protocol allowed for an initial 20 percent reduction in fluorouracil dose for individuals older than 70, and a reduced initial oxaliplatin dose (65 rather than 85 mg/m2) if the creatinine clearance was 30 to 60 mL/min.
Liposomal irinotecan — A benefit for second-line liposomal irinotecan in combination with leucovorin [LV]-modulated short-term infusional FU (table 8) compared with FU/LV alone after progression on gemcitabine plus cisplatin was addressed in the phase II NIFTY trial [68]. Of the 174 patients who were assessable for response, median progression-free survival (the primary endpoint, as assessed by blinded independent central review) was significantly better in the irinotecan group (7.1 versus 1.4 months) as was median overall survival (8.6 versus 5.5 months) and objective response rate (15 versus 6 percent). The most common grade 3 or worse adverse events in the irinotecan group were neutropenia, fatigue, and nausea.
Capecitabine plus oxaliplatin — All of the data on CAPOX are in the first-line setting:
●Benefit for CAPOX for first-line therapy was also shown in a phase II trial of 65 patients with advanced biliary cancer (38 with intrahepatic or extrahepatic cholangiocarcinoma) [34]. Among the patients with extrahepatic bile duct cholangiocarcinoma, there were two complete and eight partial responses. There were no partial or complete responses among patients with intrahepatic mass-forming cholangiocarcinoma. Treatment was well tolerated, with only mild hematologic toxicity, grade 3 or 4 peripheral neuropathy in 11 patients of the entire cohort, and two hypersensitivity reactions to oxaliplatin.
●Others have demonstrated noninferiority for CAPOX compared with GEMOX in the first-line setting for treatment of advanced biliary tract cancer [28]. (See 'Gemcitabine plus oxaliplatin' above.)
We would not pursue CAPOX for a patient initially treated with GEMOX. However, second-line therapy with this combination may be an appropriate alternative to FOLFOX after failure of gemcitabine plus cisplatin.
GEMOX with or without bevacizumab — The data for front-line therapy with GEMOX with or without bevacizumab are discussed above. (See 'Gemcitabine plus oxaliplatin' above.)
Capecitabine plus irinotecan — Another second-line alternative after failing initial gemcitabine plus cisplatin is XELIRI. However, in our view, given the potential for treatment-related toxicity, other regimens such as liposomal irinotecan plus leucovorin-modulated FU are preferred.
XELIRI (irinotecan 180 mg/m2 on day 1 plus capecitabine 1000 mg/m2 twice daily on days 1 to 10 of every 14-day cycle) was directly compared with irinotecan alone (180 mg/m2 on day 1 of each 14-day cycle) in a randomized phase II trial of 64 patients with advanced biliary tract cancer (12 with gallbladder cancer, the remainder with cholangiocarcinoma) previously treated with gemcitabine plus cisplatin [69]. Median progression-free survival (3.7 versus 2.4 months) and nine-month survival (61 versus 32 percent) were significantly better with combined therapy, although the difference in median overall survival was not significant (10.1 versus 7.3 months, p = 0.107). Rates of severe (grade 3 or 4) toxicity were not much worse with combined therapy, with the exception of palmar-plantar erythrodysesthesia (6.7 versus 0 percent).
Fluoropyrimidine alone — Whether results are better with FOLFOX or CAPOX than a fluoropyrimidine alone is unclear; there are no randomized trials. One retrospective analysis of 321 patients who received a fluoropyrimidine-based second-line regimen after failing gemcitabine plus cisplatin concluded that the objective response rate was higher with a fluoropyrimidine-platinum combination (8 versus 1 percent) but that progression-free and overall survival were not significantly better [70].
Antiangiogenic therapy — Angiogenesis is an important target in biliary tract cancers, as vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) overexpression are reported in 30 to 50 percent of tumors and associated with a poor prognosis [71]. Unfortunately, the benefits in clinical trials have been modest, at best.
●Bevacizumab – The efficacy of bevacizumab, a monoclonal antibody targeting VEGF, in combination with a variety of other drugs has been promising in uncontrolled studies in metastatic biliary tract cancer [29,72-75], but the contribution of this agent remains uncertain due to the lack of controlled trials. Bevacizumab plus erlotinib is discussed below. (See 'Erlotinib plus bevacizumab' below.)
●Regorafenib – Regorafenib is an orally active inhibitor of angiogenic (including the VEGFRs 1 to 3), stromal, and oncogenic receptor tyrosine kinases that targets a variety of kinases implicated in angiogenic and tumor growth-promoting pathways.
A benefit for regorafenib compared with best supportive care after failure of gemcitabine and platinum-based chemotherapy was noted in REACHIN, a randomized double-blind phase II trial [76]. Overall, 66 patients were randomly assigned to regorafenib (160 mg daily) or an identically matched placebo. Median progression-free survival, the primary endpoint, was modestly but significantly higher with regorafenib (3.0 versus 1.5 months), and the disease control rate was also higher (70 versus 33 percent); however, median overall survival was similar (5.3 versus 5.1 months). The most common treatment-related grade 3 or 4 toxicities with regorafenib were fatigue (18 percent), nausea and vomiting (9 percent), and skin toxicity (9 percent).
A similar modest degree of benefit was reported in another open label multi-institutional trial conducted in patients with heavily pretreated advanced biliary tract cancer (median progression-free survival 3.7 months, disease control rate 64 percent [77]).
Given these modest benefits, we would not pursue regorafenib as a second-line strategy but consider it an option for third-line therapy.
●Ramucirumab – Ramucirumab is a fully human IGG1 monoclonal antibody that targets VEGFR2, inhibiting the biding of VEGF. Activity in advanced pretreated biliary tract cancer was shown in a phase II study of 61 patients (62 percent intrahepatic cholangiocarcinoma, 17 percent extrahepatic, and the remainder gallbladder cancer); all had received gemcitabine plus cisplatin frontline, and eight had received four or more prior therapies [78]. One patient achieved a partial response, and the disease control rate overall was 45 percent. median PFS was 3.2 months, and median overall survival 9.5 months. Ramucirumab was well tolerated, and the majority of toxicities were grade 1 or 2.
Whether these results are better than can be achieved with any other salvage regimen in this setting is not clear; there are no comparator trials.
Patients initially treated with gemcitabine plus oxaliplatin
Gemcitabine plus capecitabine — The combination of gemcitabine plus capecitabine is active for advanced biliary tumors. (See 'Gemcitabine plus capecitabine' above.)
Capecitabine plus cisplatin — Capecitabine, as an alternative to infusional FU, has been investigated in combination with cisplatin. A relatively large (although retrospective) study of 176 patients reported a 17 percent response rate and median survival of 7.4 months [79]. Another smaller but prospective study achieved a similar 21 percent response rate and median survival of 9.1 months [80].
FOLFIRI with or without bevacizumab — The efficacy of second-line short-term infusional FU plus LV and irinotecan (FOLFIRI) plus bevacizumab was addressed in a small retrospective analysis of 13 patients who were refractory to first-line GEMOX [72]. There were five objective responders (one complete), and median overall survival was 20 months.
Molecularly targeted therapy — Targeted testing of advanced cholangiocarcinomas for dMMR/MSI and for specific molecular alterations for which a targeted treatment might be available is indicated for those who might be eligible for molecularly targeted therapy or immunotherapy, preferably within the context of a clinical trial [81].
Next-generation sequencing to identify actionable molecular abnormalities — Several ongoing trials (eg, the National Cancer Institute [NCI] Molecular Analysis for Therapy Choice [MATCH] and the ASCO Targeted Agent and Profiling Utilization Registry [TAPUR] trails) are using next-generation sequencing (NGS) of multiple genes (gene panel tests) to identify molecular abnormalities in the tumors of patients with refractory cancers that may potentially match molecularly targeted therapies that are either in clinical trials or approved for treatment of other cancer types. Two such gene panel tests (MSK-IMPACT [Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets] and F1CDx [FoundationOne CDx]) are US Food and Drug Administration (FDA) approved in the United States. These tests can be used on formalin-fixed, paraffin-embedded (FFPE) tissue regardless of the primary organ from which the tumor arose. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Cancer screening and management'.)
Biliary tract carcinomas (particularly intrahepatic cholangiocarcinomas) have multiple molecular alterations, many of which are potential targets for available specific inhibitors [82-89].
The potential impact of this approach in patients with advanced biliary tract cancer can be illustrated by the following reports:
●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 on fresh frozen tissue [88]. Potentially actionable molecular aberrations were identified 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).
Interestingly, all of the patients harboring a fusion transcript involving the fibroblast growth factor receptor 2 (FGFR2) and the single patient with an FGFR2 mutation had dramatic responses with therapeutic FGFR inhibition. Others have reported favorable results from the targeting of FGFR mutations/fusions in advanced cholangiocarcinoma [90-92]. These data are discussed below. (See 'FGFR inhibitors for FGFR fusion-positive tumors' below.)
The two best responders in this series had been treated with human epidermal growth factor 2 (HER2) inhibitors, one of whom had amplification of ERBB2 and the other had a mutation in ERBB3.
Besides these, other promising targets for biliary tract cancers include mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 [82,93], for which specific inhibitors are available (eg, ivosidenib, enasidenib), and the BRAF V600E mutation. (See 'Ivosidenib for IDH-mutated cholangiocarcinoma' below.)
●In a database series of 454 biliary tract cancers, potentially actionable molecular alterations were identified in 30.5 percent, including 39 percent of intrahepatic cholangiocarcinomas, 30 percent of extrahepatic cholangiocarcinomas, and 15 percent of gallbladder cancers [89]. This series used a narrower definition of potentially actionable alterations, and only included those findings for which a tumor-agnostic drug approval existed in the United States in 2022.
An important point is that simply having a potentially targetable mutation does not guarantee that the patient will benefit from a therapy that presumably targets that mutation [94]. If targeted testing identifies a potentially actionable genetic abnormality for which a molecularly targeted treatment is available but not yet approved, we prefer that these patients be enrolled in clinical trials if possible.
Immunotherapy — Immunotherapy with an immune checkpoint inhibitor may be particularly beneficial for patients whose tumors have DNA dMMR/high levels of MSI (MSI-H), programmed cell death 1 ligand 1 (PD-L1) overexpression, or high levels of tumor mutational burden (TMB-high); however, emerging data suggest that durable responses are also possible in patients with intrahepatic cholangiocarcinomas unselected for biomarker status. We would not typically offer second-line immunotherapy to individuals who received frontline durvalumab.
Biomarker-selected patients
●dMMR/MSI-H – It has been hypothesized that tumors that lack the mismatch repair mechanism (ie, mismatch repair deficiency [dMMR]) harbor many more mutations (ie, they are hypermutated) than do tumors of the same type without such mismatch repair defects, and that the neoantigens generated from mutations such as these are more immunogenic than those generated by other mutations. The biologic footprint of dMMR tumors is high levels of MSI (MSI-H).
Several steps are required for the immune system to effectively attack tumor cells. Several immune checkpoints exist to dampen the immune response in order to protect against detrimental inflammation and autoimmunity. In the setting of malignancy, such immune checkpoints can result in immune tolerance of the tumor and subsequent progression of the malignancy. Inhibition of these checkpoints might be expected to halt/reverse disease progression. One well-characterized checkpoint being targeted in several tumor types is programmed cell death 1 (PD-1). PD-1 is upregulated on activated T cells, and upon recognition of tumor via the T cell receptor, PD-1 engagement by PD-L1 expressed by tumor or other immune cells infiltrating the tumor tissue can lead to T cell inactivation and a "brake" on immune-mediated tumor eradication. (See "Principles of cancer immunotherapy".)
Proof of principle that cancers with dMMR might be particularly susceptible to inhibition of the PD-L1/PD-1 interaction was initially provided by a study of pembrolizumab in dMMR colorectal cancer. Subsequently, it was established that immune checkpoint inhibitor immunotherapy appears to benefit a subset of patients with dMMR tumors regardless of anatomic site of origin or tissue histology. As a result, in May 2017, the FDA approved pembrolizumab for treatment of a variety of advanced solid tumors, including cholangiocarcinomas, that had MSI-H or dMMR, that had progressed following prior treatment, and for which there were no satisfactory alternative treatment options, the first such approval of a tissue-agnostic anticancer treatment. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Other tumors with MSI-H/dMMR'.)
Efficacy in dMMR advanced cholangiocarcinoma was shown in the phase II KEYNOTE-158 study, which enrolled 22 patients with cholangiocarcinoma [95]. There were nine objective responses (41 percent), two of which were complete, and the median duration of response ranged from 4.1 to 24.9+ months.
The fraction of cholangiocarcinomas that have dMMR has been addressed in the following reports:
•In one study, approximately 3 percent of cholangiocarcinomas had dMMR or MSI-H [96].
•The frequency of dMMR or MSI-H in other studies has been approximately 5 percent each for gallbladder cancer and extrahepatic cholangiocarcinoma and 10 percent each for intrahepatic cholangiocarcinoma and ampullary carcinoma [97].
•Lower levels of dMMR (1 to 1.3 percent) have been reported for biliary tract cancers when the analysis was limited to individuals with advanced/metastatic disease [96,98].
The approach to testing for dMMR is addressed in detail elsewhere. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Assessing mismatch repair' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Approach to testing dMMR as a predictive marker'.)
●PD-L1 overexpression – Other biomarkers such as overexpression of PD-L1 may also predict response to immune checkpoint inhibitor therapy. As an example, in one phase II trial of nivolumab in 46 patients with advanced refractory biliary tract, 18 of 42 tested tumors (43 percent) had PD-L1 overexpression. Overall, 10 patients achieved an investigator-assessed immune partial response (table 9), all of whom had tumors with proficient mismatch repair (pMMR) [99]; 9 of the 10 overexpressed PD-L1. Four responders achieved durable objective response lasting at least one year.
On the other hand, a combined analysis of data from the KEYNOTE-028 and 158 studies suggest that pembrolizumab monotherapy has limited activity in advanced biliary tract cancer, irrespective of PD-L1 overexpression [100].
Taken together, these limited data suggest that responses appear to be more frequent in patients with PD-L1 positive tumors, although they have also been documented with PD-L1 negative tumors.
Combined immunotherapy approaches may be more beneficial, at least for patients with intrahepatic cholangiocarcinoma, although the predictive value of PD-L1 overexpression remains uncertain. (See 'Biomarker-unselected patients' below.)
●Tumor mutational burden – Biliary tract cancers are generally characterized by low TMB, with only 2.9 to 4.0 percent of cases having high levels of TMB (which has been defined variably) [101-104]. Higher levels of TMB appear to correlate with benefit from immune checkpoint inhibitor immunotherapy in a variety of tumor types [104,105]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumors with high mutational burden'.)
There is scant information on responsiveness of TMB-high cholangiocarcinomas to immune checkpoint inhibitor therapy:
•A single published case report documents durable disease control with treatments targeting the PD-1 pathway in a single patient with TMB-high advanced biliary tract cancer [106].
•The KEYNOTE-158 trial, which assessed the benefit of pembrolizumab monotherapy in a variety of malignancies, including cholangiocarcinoma, reported a correlation between high TMB and objective response to pembrolizumab monotherapy, and responses were seen in anal, cervical, endometrial, salivary, thyroid, or vulvar carcinoma; mesothelioma; a neuroendocrine tumor; and small cell lung cancer [107]. However, none of the cholangiocarcinomas enrolled in the study had TMB-high disease; 2 of 63 patients without high TMB had an objective response.
However, largely based on this study, pembrolizumab is now approved for patients with any solid tumor, including cholangiocarcinoma, that has a TMB ≥10 mut/Mb (as defined by the FDA-approved companion diagnostic test), after progression on standard regimens. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumors with high mutational burden'.)
Although it remains uncertain whether this is the appropriate threshold to define high TMB in biliary tract cancer, as validation studies were conducted mainly in lung and urothelial cancers and thresholds for TMB are likely to vary across tumor types, we suggest using the NGS platform FoundationOne CDx assay to assess TMB, as this was the platform used in the KEYNOTE-158 trial, and the use of a threshold TMB of ≥10 mut/Mb to select patients for immune checkpoint inhibitor immunotherapy. Cutoffs for TMB using other platforms have not been identified or linked to the FoundationOne data. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Approach to testing for high levels of TMB'.)
Biomarker-unselected patients
●Combined immunotherapy for patients with intrahepatic cholangiocarcinoma – Until further information is available regarding the relevance of additional biomarkers on response rates to combined immunotherapy, a trial of nivolumab plus ipilimumab is reasonable in the setting of second-line therapy for patients with intrahepatic cholangiocarcinoma who do not have dMMR, high levels of TMB, or PD-L1 overexpression, and who did not receive frontline durvalumab.
Emerging data suggest that durable responses to immune checkpoint inhibitor immunotherapy are possible even in patients unselected for biomarker status. The multicenter open-label phase II CA209-538 clinical trial of nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) every three weeks for four doses followed by nivolumab 3 mg/kg every two weeks for advanced rare cancers included 39 patients with biliary tract cancers, of whom 26 had cholangiocarcinomas, 16 intrahepatic, 10 extrahepatic, and 13 had gallbladder cancer [108]. Among those with cholangiocarcinoma, there were five objective responses, all in the subgroup with intrahepatic tumors, with all responding patients being treated in the second-line setting, and none had microsatellite-unstable tumors. PD-L1 overexpression status was not addressed. Two other patients with intrahepatic cholangiocarcinoma had stable disease for a disease control rate of 44 percent in this group. Duration of response ranged from 3 to 14.8 months. None of the ten patients with extrahepatic cholangiocarcinoma had an objective response, but one patient had stable disease as the best response. In the entire group of 39 patients, approximately one-half experienced an immune-related adverse event of any grade, and ≥grade 3 toxic effects occurred in six (15 percent).
Until further information is available regarding the relevance of additional biomarkers on response rates to combined immunotherapy, based upon this study, a trial of nivolumab plus ipilimumab is reasonable in the setting of second-line therapy for patients with intrahepatic cholangiocarcinoma who do not have dMMR, high levels of TMB, or PD-L1 overexpression, and who did not receive frontline durvalumab. (See 'Gemcitabine plus cisplatin and durvalumab' above.)
FGFR inhibitors for FGFR fusion-positive tumors — Fibroblast growth factor receptor 2 (FGFR2) gene alterations are involved in the pathogenesis of cholangiocarcinoma, and approximately 9 to 16 percent of patients with cholangiocarcinoma (15 to 20 percent of intrahepatic tumors) harbor FGFR2 alterations [92,109-112].
●Pemigatinib – Pemigatinib is a selective, oral inhibitor of FGFR 1, 2, and 3. Activity of this drug in previously treated advanced cholangiocarcinoma was addressed in the open-label single arm FIGHT-202 trial; there were three cohorts: patients with FGFR2 fusions or rearrangements (n = 107), patients with other FGF/FGFR alterations (n = 20), or patients with no FGF/FGFR alterations (n = 18) [92]. All patients initiated therapy at 13.5 mg once daily for 14 days, followed by seven days off. The primary end point was objective response rate. At a median follow-up of 17.8 months, 38 (36 percent) patients with FGFR2 fusions or rearrangements had an objective response including three complete responses. Disease control (objective response or stable disease) was achieved by 88 (80 percent). The median duration of response was 7.5 months (95% CI 5.7-14.5). No patients with other FGF/FGFR alterations or who lacked FGF/FGFR alterations achieved a response, although stable disease was seen in eight of the 20 patients with other FGF/FGFR alterations, and in four (22 percent) of those with no identifiable FGF/FGFR alterations.
In the entire cohort, treatment was well tolerated overall, with the most frequent adverse event being hyperphosphatemia (60 percent, 12 percent grade 3 or worse (table 10)). Hyperphosphatemia occurred early after treatment initiation (median time to onset 15 days [95% CI 8-47]) and was managed with a low-phosphate diet, concomitant phosphate binders, diuretics, dose reduction, and/or dose interruption. Other grade 3 or worse toxicities included arthralgias, stomatitis, hyponatremia, hypophosphatemia, abdominal pain, and fatigue, all in fewer than 7 percent of patients. Serous retinal detachment due to subretinal fluid accumulation occurred in 6 (4 percent) of 146 patients; all events were grade 1 or 2, except for one grade 3 event. Dry eye occurred in 21 percent overall but was severe in only 1 percent. (See "Ocular side effects of systemically administered chemotherapy", section on 'Fibroblast growth factor receptor (FGFR) inhibitors'.)
Largely based on these data, pemigatinib has been approved by the United States FDA for adult patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement as detected by an FDA-approved test [113]. The approved dose is 13.5 mg once daily for 14 consecutive days followed by seven days off [114].
On the basis of these encouraging results, an international, phase III, randomized, active-controlled trial is currently recruiting patients to compare pemigatinib with gemcitabine plus cisplatin chemotherapy as first-line therapy for unresectable or metastatic cholangiocarcinoma with FGFR2 rearrangements (FIGHT-302; NCT03656536).
●Infigratinib – Infigratinib is another FGFR1-3 selective oral tyrosine kinase inhibitor. Activity in patients with advanced cholangiocarcinoma, progression on one or more lines of systemic therapy, and FGFR2 gene fusions or rearrangements was shown in a preliminary report of a phase II trial, presented at the 2021 ASCO Gastrointestinal Cancers Symposium [115]. Of the 108 patients enrolled, 83 (77 percent) had FGFR2 gene fusions and the remainder had rearrangements; all patients received the drug at 125 mg orally daily for 21 days of each 28 day cycle. At a median follow-up of 10.6 months, there were 25 objective responses (23 percent), one complete, and the median duration of response was five months (range 0.9 to 19.1 months). Responses were more likely in patients treated in the second-line versus the third- or later-line setting (34 versus 13 percent). The most common treatment-emergent adverse effects were hyperphosphatemia (76 percent), eye disorders (68 percent, including one grade 3 central serous retinopathy), stomatitis (55 percent), and fatigue (40 percent). The most common severe adverse events were stomatitis (15 percent), hyponatremia, and hypophosphatemia (13 percent each). (See "Ocular side effects of systemically administered chemotherapy", section on 'Fibroblast growth factor receptor (FGFR) inhibitors'.)
Largely based upon these data, infigratinib was granted accelerated approval by the US FDA for adult patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement as detected by an FDA-approved test [116]. The approved dose of infigratinib is 125 mg orally once daily for 21 consecutive days, followed by 7 days off therapy, in 28-day treatment cycles, until disease progression or unacceptable toxicity.
●Futibatinib – Futibatinib is a highly selective, irreversible FGFR1–4 inhibitor. Efficacy in patients with intrahepatic cholangiocarcinoma harboring FGFR2 fusion/rearrangements with disease progression after one or more prior treatments was shown in the FOENIX-CCA2 phase II study; in the latest analysis (median 25 month follow-up), the confirmed objective response rate was 41.7 percent (43 of 103 patients), the mean duration of response was 9.5 months, and the median overall survival was 20 months, with a 12-month overall survival rate of 73 percent [117]. The most common treatment-related adverse reactions were hyperphosphatemia (85 percent), alopecia (33 percent), dry mouth (30 percent), diarrhea (28 percent), dry skin (27 percent), and fatigue (25 percent).
Largely based on this study, futibatinib was granted an accelerated approval by the US FDA for treatment of locally advanced/metastatic intrahepatic cholangiocarcinoma with an FGFR2 gene rearrangement or fusion [118]. The approved dose is 20 mg orally, once daily, until disease progression or unacceptable toxicity.
Ivosidenib for IDH-mutated cholangiocarcinoma — Mutations in the isocitrate dehydrogenase (IDH) genes are present in up to 25 percent (IDH1) and approximately 3 percent (IDH2) of cholangiocarcinomas; mutations are particularly frequent (up to 20 percent) in intrahepatic cases [82,93,119,120], for which specific inhibitors are available (eg, ivosidenib, enasidenib). As an example, in a combined phase I/II study of ivosidenib in 73 patients with advanced IDH1-mutated cholangiocarcinoma, there were four partial responses, and median progression-free survival was 3.8 months [93]. IDH1 is mutated in up to 25 percent of cholangiocarcinomas, especially intrahepatic [93]; the frequency of IDH2 mutations is lower (3 percent in one study [119]).
Benefit for ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma was further addressed in the placebo-controlled randomized phase III ClarlDHy trial, which enrolled 187 patients with previously treated, progressive advanced (93 percent metastatic) cholangiocarcinoma. The ivosidenib dose was 500 mg once daily in continuous 28-day cycles. In the latest analysis individuals receiving ivosidenib had modestly but significantly better median progression-free survival and a trend toward better overall survival (10.3 versus 7.5 months, HR 0.79, 95% CI 0.56-1.12) [121]. This result was likely influenced by crossover from the placebo to active treatment group; the crossover-adjusted overall survival in the placebo group (as derived using the rank-preserving structural failure time model) was 5.1 months (HR for death with ivosidenib 0.49, 95% CI 0.34-0.70). Notably, in an earlier analysis, 32 percent of the patients receiving ivosidenib had not progressed at six months, and 22 percent were still progression free at 12 months; no patient in the placebo arm lacked disease progression at the six-month point [122]. Common treatment-related adverse effects included nausea, diarrhea, fatigue, cough, abdominal pain, ascites, anorexia, anemia, and vomiting; most were low grade.
Largely based upon these data, ivosidenib has been approved by the US FDA for treatment of adults with previously treated, locally advanced, or metastatic cholangiocarcinoma with an IDH1 mutation, as detected by an FDA-approved test [123]. While this drug may provide modest benefit for a small subset of patients, it may cost as much as USD $1000 per day, a fact that will likely limit general access.
TRK inhibitor therapy for TRK fusion-positive cancers — Another option for treatment at progression for patients who have neurotrophic tyrosine receptor kinase (NTRK) gene rearrangements is larotrectinib or entrectinib. Genomic translocations that lead to the constitutive activation of receptor tyrosine kinases are rare overall in cholangiocarcinoma (3.6 percent for intrahepatic cholangiocarcinoma in one report) [109,124]. However, the potential efficacy of larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor, was shown in a combined analysis of 55 patients with various TRK fusion-positive malignancies enrolled in three trials, two of whom had a primary cholangiocarcinoma [125]. In the entire cohort, the overall response rate by independent review was 75 percent, and responses appeared durable, with 86 percent of responders still on treatment or having undergone surgery that was intended to be curative at a median follow-up of 9.4 months. One of the two cholangiocarcinoma tumors had objective tumor shrinkage. Treatment was well tolerated; no responding patients discontinued larotrectinib due to an adverse event. In a safety analysis of 176 patients enrolled across all three trials, the most common adverse reactions (≥20 percent) included elevations in transaminases, fatigue, nausea, vomiting, dizziness, diarrhea, constipation, and cough [126].
In November 2018, larotrectinib was approved by the FDA for use in adults and children with solid tumors with an NTRK gene fusion and without a known acquired resistance mutation that are either metastatic or where surgical resection is likely to result in severe morbidity who have no satisfactory alternative treatments or whose cancer has progressed following treatment. A similar drug, entrectinib, was approved in Japan for treatment of 10 tumor types with an NTRK gene fusion (including cholangiocarcinoma), and this drug was approved by the FDA for cancers with an NTRK gene fusion in August 2019. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Treatment with TRK inhibitors'.)
BRAF V600E-mutated cancers — Specific mutations in the BRAF gene (BRAF V600E) are reported in approximately 5 percent of biliary tract cancers, especially intrahepatic cholangiocarcinomas [127,128]. Benefit from the combination of the BRAF inhibitor dabrafenib plus trametinib (which reversibly and selectively inhibits mitogen-activated extracellular kinase [MEK], a downstream effector of BRAF) was shown in the phase II open-label ROAR trial (47 percent objective response rate by independent assessment among 43 evaluable patients; and additional 14 percent had stable disease) [129]. The median progression-free survival was nine months. Most of these patients had received two or more lines of prior therapy. Benefit for combined dabrafenib and trametinib was also shown in the NCI-MATCH Trial Subprotocol H, in which three of four advanced cholangiocarcinomas had a partial response, one of which was ongoing at 29 months [130].
Largely based on these data, in June 2022, the combination of dabrafenib and trametinib was granted a tissue-agnostic accelerated approval by the US FDA for the treatment of adult and pediatric patients six years and older with unresectable or metastatic solid tumors harboring mutations in BRAF V600E following progression on previous treatment who have no satisfactory alternative treatment options [131].
RET fusion-positive tumors — RET fusions are rare in cholangiocarcinoma [132]. However, in September 2022, the US FDA granted a tissue-agnostic, accelerated approval to the RET tyrosine kinase inhibitor selpercatinib for adult patients with locally advanced or metastatic solid tumors, including cholangiocarcinomas, with a RET gene fusion and disease progression on or following prior systemic treatment who have no satisfactory alternative treatment options. The phase I/II basket trial (LIBRETTO-001) of selpercatinib for RET fusion positive solid tumors included only one patient with cholangiocarcinoma, but there was a partial response [133].
HER2 overexpression — Up to 20 percent of cholangiocarcinomas (especially distal extrahepatic tumors) have amplification of the human epidermal growth factor receptor 2 (HER2) oncogene or overexpress its protein product, HER2 [82,103,134-136]. Accumulating data provide proof-of-principle support for the potential benefit from HER2-targeted therapies (eg, trastuzumab plus pertuzumab or lapatinib, or trastuzumab deruxtecan) in these patients [137,138]. As an example, in the MyPathway HER2 basket study, combined therapy with pertuzumab plus trastuzumab resulted in an objective antitumor response in 9 of 39 HER2 amplified/overexpressed RAS wild-type biliary tract cancers (23 percent), and the median duration of response was 10.8 months [137].
Targeting the EGFR
Erlotinib — Favorable results have also been seen with blockade of the epidermal growth factor receptor (EGFR) using the oral tyrosine kinase inhibitor erlotinib. In one study, 42 patients with advanced biliary cancer (not stratified according to primary site), 57 percent of whom had received prior chemotherapy, received erlotinib (150 mg daily) [139]. There were three partial responses (two with documented expression of EGFR), and seven additional patients remained progression free at six months.
Additional experience with this drug has been in combination with cytotoxic chemotherapy.
Erlotinib plus bevacizumab — One promising combination is erlotinib plus bevacizumab, which was the subject of a multinational, uncontrolled phase II study [73]. Fifty-three patients with advanced cholangiocarcinoma (n = 43) or gallbladder cancer (n = 10) previously untreated for metastatic disease received erlotinib (150 mg once daily) plus bevacizumab (5 mg/kg every two weeks). Nine patients achieved a partial response, which was sustained beyond four weeks in six (12 percent), with a median response duration of 8.4 months. Stable disease was documented in 51 percent. In the entire group, median time to disease progression was 4.4 months, and median overall survival was 9.9 months. Four patients (8 percent) developed grade 4 toxicity (cerebral ischemia or thrombosis), and the most frequent grade 3 toxicity was skin rash (three patients), although in all, 40 patients developed a rash of any grade during therapy.
Whether results from this biologic-only combination are better than those that can be achieved with conventional cytotoxic therapy will require a randomized trial. Although associated with significant cost (nearly USD $10,000 per month), this regimen could be considered as a salvage regimen after progression on standard cytotoxic therapy for highly selected patients who retain a good performance status and have no other viable treatment options.
Gemcitabine and oxaliplatin plus cetuximab or panitumumab — Cetuximab and panitumumab are two monoclonal antibodies targeting the EGFR. Three phase II trials addressing the efficacy of combined therapy with GEMOX plus either cetuximab or panitumumab have come to differing conclusions, and the role of these agents in advanced biliary tract cancer remains uncertain:
●In an initial phase II study of 30 patients with previously untreated locally advanced or unresectable biliary tract cancer (27 cholangiocarcinoma, 3 gallbladder cancer), 19 had objective responses to GEMOX plus cetuximab (63 percent, three complete) [140]. Nine patients with locally advanced previously unresectable disease had sufficient tumor shrinkage to permit a later potentially curative resection, although long-term outcomes were not reported.
●Unfortunately, benefit for the addition of cetuximab to GEMOX could not be confirmed in a randomized phase II trial in which 150 patients with advanced cholangiocarcinoma (82 percent), gallbladder cancer, or ampullary cancer were randomly assigned to GEMOX with or without cetuximab (500 mg/m2 every two weeks) [141]. Median progression-free survival was modestly (but not significantly) higher with cetuximab (6.1 versus 5.5 months), but median overall survival was shorter (11 versus 12.4 months). Serious adverse events were reported in 51 percent of the cetuximab-treated patients compared with 35 percent of the control group.
●In the setting of advanced colorectal cancer, benefit from monoclonal antibodies that target the EGFR is limited to those patients whose tumors lack mutations in one of the RAS oncogenes. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Agents targeting the EGFR'.)
Unfortunately, a survival benefit for the addition of panitumumab to GEMOX could not be shown in a randomized phase II study of 89 patients with KRAS wild-type advanced biliary tract cancer [142].
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from delaying cancer treatment versus harm from COVID-19, minimizing the number of clinic and hospital visits to reduce exposure whenever possible, mitigating the negative impacts of social distancing on delivery of care, and appropriately and fairly allocating limited health care resources. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SUMMARY AND RECOMMENDATIONS
●First-line therapy – The role of systemic chemotherapy is evolving in patients with advanced cholangiocarcinoma. There is no single standard of care regimen that consistently leads to objective tumor shrinkage, forestalls recurrent biliary obstruction, or extends survival beyond 8 to 15 months. (See 'General principles of chemotherapy' above.)
We prefer that patients enroll in clinical trials whenever possible. Off protocol, the following represents our suggested approach:
•Good performance status and normal bilirubin – For most patients with a good performance status (PS) and a normal bilirubin level, we suggest gemcitabine plus cisplatin (table 2) rather than gemcitabine alone as a first-line regimen (Grade 2B). We also suggest gemcitabine plus cisplatin over a non-gemcitabine-based regimen for most patients (Grade 2C). (See 'Gemcitabine plus cisplatin' above.)
Durvalumab plus gemcitabine and cisplatin is an alternative to gemcitabine plus cisplatin but not necessarily preferred. The short-term benefits over gemcitabine plus cisplatin alone are modest but long-term benefits may be clinically meaningful for some patients. Unfortunately, there are no predictive biomarkers to select which patients may preferentially benefit. We individualize decision making based on patient preference, insurance coverage, and availability of durvalumab. (See 'Gemcitabine plus cisplatin and durvalumab' above.)
Where available, gemcitabine plus S-1 is another option. (See 'Gemcitabine plus S-1' above.)
•Good performance status, persistent hyperbilirubinemia – For patients with a good PS who have hyperbilirubinemia despite stenting, we prefer a non-gemcitabine-based regimen, such as LV-modulated FU (table 5) or a fluoropyrimidine plus oxaliplatin. (See 'Patients with persistent biliary obstruction' above.)
•Borderline performance status or extensive comorbidity – Reasonable first-line therapy options for patients with a borderline PS or extensive comorbidity include LV-modulated FU (table 5), capecitabine monotherapy, gemcitabine monotherapy, or S-1 alone (where available). (See "Treatment protocols for hepatobiliary cancer" and 'Borderline performance status' above.)
●Later lines of therapy
•Prior gemcitabine plus cisplatin – For most patients who have disease progression while receiving gemcitabine plus cisplatin and who retain an adequate performance status and lack potentially actionable molecular targets, we suggest treatment with FOLFOX (table 7) (Grade 2C). Other alternatives include capecitabine plus oxaliplatin (CAPOX (table 11)), liposomal irinotecan plus LV-modulated FU (table 8), a fluoropyrimidine alone, or GEMOX with or without bevacizumab. (See 'Gemcitabine plus oxaliplatin' above and 'Patients initially treated with gemcitabine plus cisplatin' above.)
•Prior gemcitabine plus oxaliplatin – For patients failing GEMOX, appropriate choices for a second-line regimen include capecitabine plus cisplatin or gemcitabine, or short-term infusional FU plus LV and irinotecan (FOLFIRI) with or without bevacizumab (table 12). (See 'Cytotoxic chemotherapy' above and "Treatment protocols for hepatobiliary cancer".)
•Molecularly targeted therapy – As many as 68 percent of advanced cholangiocarcinomas may harbor a molecular alteration for which a targeted treatment might be available. Specific examples include: (see 'Molecularly targeted therapy' above)
-For individuals who did not receive frontline durvalumab, immunotherapy using a checkpoint inhibitor in the setting of deficient DNA mismatch repair (dMMR), overexpression of programmed cell death ligand 1 (PD-L1), or high levels of tumor mutational burden (TMB). (See 'Biomarker-selected patients' above.)
-Pemigatinib, infigratinib, or futibatinib for fibroblast growth factor receptor 2 (FGFR2) gene alterations.
-Ivosidenib for isocitrate dehydrogenase (IDH) mutations.
-A tropomyosin receptor kinase (TRK) inhibitor for those with TRK fusion-positive cancers.
-Selpercatinib for a RET fusion-positive cancer.
-The combination of a BRAF and mitogen-activated extracellular kinase (MEK) inhibitor for those with BRAF V600E mutations.
-HER2-targeted therapy for individuals with HER2 overexpression or amplification.
An important point is that simply having a potentially targetable mutation does not guarantee that the patient will benefit from a therapy that presumably targets that mutation. If targeted testing identifies a potentially actionable genetic abnormality for which a molecularly targeted treatment is available but not yet approved, we prefer that these patients be enrolled in clinical trials if possible. (See 'Next-generation sequencing to identify actionable molecular abnormalities' above.)
•Immunotherapy – For patients with intrahepatic cholangiocarcinoma who do not have dMMR, high levels of TMB, or PD-L1 overexpression, and who did not receive frontline durvalumab, a trial of nivolumab plus ipilimumab is reasonable for second-line therapy or beyond. (See 'Biomarker-unselected patients' above.)
