Biliary tract cancersĀ (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree and are classified into cholangiocarcinoma (CCA) and gallbladder cancer. BTC is an aggressive and rare epithelial malignancy that is usually diagnosed at an advanced stage with few effective therapeutic options.1Ā CCA is divided into extrahepaticĀ and intrahepaticĀ cholangiocarcinoma,Ā withĀ the extrahepatic type furtherĀ classified into perihilar and distalĀ based on relation to the hilum. Incidence rates have recently increased worldwide;Ā 5–yearĀ survival isĀ 5ā10%Ā for non-resectable advanced disease and approximatelyĀ 30%Ā for those treated with curative surgical intent.2,3Ā The only potentially curative treatment option is surgery;Ā however,Ā only approximatelyĀ 35%Ā of tumours at diagnosis are amenable to resection.4
Advancements in genomic profiling haveĀ revealedĀ critical pathophysiologicalĀ featuresĀ of BTCs, leading to theĀ discoveryĀ of various actionable molecular targets,Ā including alterations inĀ fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH),Ā B-Raf proto-oncogene serine/threonine-protein kinaseĀ (BRAF),Ā neurotrophic tropomyosin receptor kinaseĀ (NTRK)Ā andĀ human epidermal growth factor receptor 2Ā (HER-2),Ā with development of multiple targeted therapies.5Ā Over the past few years,Ā the USĀ Food and DrugĀ AdministrationĀ (FDA) has approved multiple targeted therapies for patients with BTCĀ that hasĀ progressedĀ on first–line chemotherapy,Ā including pemigatinib, infigratinib, futibatinib and ivosidenib. However, these targeted agents benefit onlyĀ aĀ small subset of patients with BTCsĀ thatĀ harbour specific actionable alterations. ForĀ theĀ majority of patients,Ā chemotherapy remains the only viable option.
In patients with BTCs who have unresectable or metastatic disease,Ā theĀ combination of gemcitabine and cisplatin chemotherapy serves as first–line therapy based onĀ theĀ ABC-02 trial published inĀ 2010.6Ā TheĀ ABC-02 trial demonstrated the efficacy of cisplatin plus gemcitabine with an improvedĀ overall survivalĀ (OS) compared withĀ single-agentĀ gemcitabine (median OS 11.7Ā monthsĀ versusĀ 8.1Ā months).6Ā However,Ā progressĀ to improve theĀ first–line therapyĀ optionsĀ for BTCs remains slow,Ā with gemcitabine plus cisplatin being the standard of care for more than a decade.Ā Only one recently published phase III trial has demonstrated improved outcomesĀ by theĀ addition of durvalumab to gemcitabine plus cisplatin in patients with advanced BTCsĀ (TOPAZ-1,Ā see below).Ā This article reviews theĀ immunotherapeutic options for patients with BTCs, describes the studies that led to the TOPAZ-1 trial, and summarizes key areas of research that are necessary to inform future drug development and improve patient outcomes.
Immune checkpoint inhibitor physiologyImmune Checkpoint Inhibitors Physiology
In addition to small molecule inhibitors, immune checkpoint inhibitorsĀ (ICIs)Ā have emerged as a potential option for patients with BTCs.Ā Preclinical studies demonstrated a promising immune microenvironment forĀ ICIĀ usage.7Ā Initial data demonstrated extensive immune cell involvement in CCA,Ā with improved survival, decreased rates of metastasis and betterĀ Tumour-Node-MetastasisĀ staging correlating with the presence ofĀ CD4Ā and CD8 T cells,Ā and poor prognosis associated with macrophage and neutrophil involvement.8,9Ā Programmed death-ligand 1 (PD-L1)Ā expression is seen inĀ moreĀ thanĀ 45%Ā of tumours and has been associated with a worse prognosis and poor survival.10,11Ā Additionally, in a study by NakamuraĀ et al.,Ā 40%Ā of the CCA tumours assessed were determined to have a high mutationalĀ load andĀ highĀ immune checkpointĀ expression.12Ā Furthermore, a pathological study of occupational–associated CCA demonstrated higher levels of PD-L1–expressing lymphocytes and infiltrating CD-8 cells,Ā and hypothesized that these tumours demonstrated immune escape via their expression of PD-L1.13
Based on work in previous cancers,Ā ICIsĀ are known toĀ produce improved responses with various malignancies, especially in thoseĀ with increasedĀ tumour mutationalĀ burdenĀ (TMB) andĀ highĀ microsatellite instability (MSI-H). Genetic studies of CCA demonstrated a modest prevalence of MSI-H and high TMB.Ā In one large–scale genetic analysis,Ā 2ā3.5%Ā of CCA was classified as high TMB withĀ >17Ā somatic missense mutations per mega baseĀ (Mb) analysed.14Ā In several additional studies, CCA was associated with a moderate burden of MSI-H and deficiency in mismatch repair proteinsĀ with a prevalence aroundĀ 5%.[14″>15,16
Single–agent immunotherapy
Multiple trials have evaluated the use of single–agent immunotherapy in patients with CCA following progression on chemotherapy (Table 1).17ā26Ā Pembrolizumab, a monoclonal antibody that binds to the programmed death 1 (PD-1) receptor has recently been studied in CCA in two trials, KEYNOTE-158 and KEYNOTE-028.17Ā These were phaseĀ IIĀ and phaseĀ Ib trials that used pembrolizumab in patients with incurable CCA that progressed after standard treatment regimens. The KEYNOTE-028 trial required patients to have PD-L1–positive tumours,Ā whereasĀ the KEYNOTE-158 trial was open to patients regardless of PD-L1 status.Ā The objective response rate (ORR)Ā wasĀ 5.8%Ā in KEYNOTE-158 andĀ 13.0%Ā inĀ KEYNOTE-028.Ā TheĀ median OS and PFS were 7.4 months andĀ 2.0Ā months,Ā respectively,Ā in KEYNOTE-158Ā comparedĀ withĀ 5.7Ā monthsĀ andĀ 1.8Ā months, respectively, inĀ KEYNOTE-028. InĀ aĀ subgroup analysis of KEYNOTE-158,Ā theĀ ORR wasĀ 6.6%Ā in PD-L1 expressors comparedĀ withĀ 2.9%Ā in non–expressors.17
Table 1: Key clinical trials with checkpoint inhibitors
ORRĀ =Ā objective response rate; OSĀ =Ā overall survival; PFSĀ =Ā progression-free survival.
Another PD-1 inhibitor, nivolumab,Ā has been studied as a second–line treatment in patients with CCA. An early phaseĀ IĀ trial comparing nivolumab aloneĀ versusĀ inĀ combinationĀ withĀ gemcitabine plus cisplatin demonstrated improved medianĀ OSĀ associated with PD-L1 expression;Ā the single patient with a partial response was found to haveĀ deficiency in mismatch repair proteins.19Ā KimĀ et al.Ā evaluated single–agent nivolumab in a phase II trial ofĀ 54Ā patientsĀ with advanced, refractory BTCs.18Ā The trial demonstrated medianĀ progression-free survival (PFS)Ā and OS ofĀ 3.7Ā monthsĀ (95% confidence interval [CI]:Ā 2.3ā5.7)Ā and 14.2Ā monthsĀ (95% CI:Ā 5.9ānot reached),Ā respectively,Ā with an ORR ofĀ 22%. In patients with PD-L1 expression, there was a superior median PFS comparedĀ withĀ PD-L1–negative tumours (10.4Ā monthsĀ versusĀ 2.3Ā months;Ā p<0.001).18Ā In another phase I trial ofĀ 42Ā patients, treatment with durvalumab, a PD-L1 inhibitor, was associated with median PFS and OS of 2Ā monthsĀ andĀ 8.1Ā months,Ā respectively.20
The above studies suggest that single–agentĀ ICIsĀ have modest activity in patients with BTCs who have progressed on prior chemotherapy. Response ratesĀ ofĀ 5ā20%Ā are noted,Ā with median PFSĀ of aboutĀ 2Ā months. Currently, there is no good biomarker to predict the efficacy of single–agent immunotherapy. In one retrospective study of 47Ā patients with BTCs treated with immunotherapy, patients withĀ TMBĀ >5Ā mutations/MbĀ hadĀ improved PFS and OSĀ comparedĀ withĀ patients with TMB <5 mutations/Mb.27
Dual–agent immunotherapy
Treatment with dualĀ ICIsĀ has been attempted following at least one line of systemic therapy, but thus far has not demonstrated effective responses comparedĀ withĀ single–agentĀ ICIsĀ (Table 1).20,21Ā In a study by IokaĀ etĀ al., durvalumab and tremelimumab, a CTLA-4 inhibitor, were used as single agentsĀ or in combination,Ā and demonstrated no significant differences between the single agent or combination therapy,Ā with median OS ofĀ 8.1Ā versusĀ 10.1Ā months,Ā respectively,Ā and duration of response ofĀ 9.7Ā versusĀ 8.5Ā months,Ā respectively.20Ā TheĀ ORRĀ with single–agent durvalumabĀ andĀ theĀ combination of durvalumab plus tremelimumab wasĀ 4.8%Ā andĀ 10.8%,Ā respectively. Nivolumab plus ipilimumab combination in a phase II trial demonstrated anĀ ORRĀ ofĀ 23%Ā andĀ a disease control rate ofĀ 44%.21Ā Interestingly, there was no evidence of MSI-H in the responding patients and all the responses were seen in patients with intrahepatic CCA, with no response in patientsĀ with extrahepatic CCA.21
Chemotherapy plusĀ immunotherapy
As onlyĀ modest activity was observed with single–agent and dual–agentĀ ICIsĀ in advanced BTCs,Ā theĀ combination of immunotherapy and standard–of–care chemotherapy was evaluatedĀ (Table 1).22ā26Ā An initial phase II study examining nivolumab in combination with gemcitabine plus cisplatin demonstrated aĀ PFSĀ ofĀ 6.1Ā monthsĀ (95%Ā CI:Ā 3.4ā8.2)Ā andĀ ORR ofĀ 55.6%.22Ā Treatment–related adverse events were manageable,Ā with onlyĀ oneĀ patient experiencing immune–related adverse events.Ā A phaseĀ Ib/II trial evaluated the addition of nivolumab to 5-fluorouracil and liposomal-irinotecan as second–line therapy.28Ā MedianĀ PFS and OS wereĀ 4.2Ā monthsĀ (95% CI:Ā 1.9-10.2) andĀ 7.5Ā monthsĀ (95% CI:Ā 5.8ā21.4),Ā respectively,Ā and, according to the authors’ conclusions, this study failed to reject the null hypothesis (H0=PFS of 2.9 months) due to overlapping confidence intervals.
In a phaseĀ IIĀ trial assessing nivolumab, cisplatin, plus gemcitabine comparedĀ withĀ nivolumab plus ipilimumab as first–line treatment for advanced BTCs, there was no statistically significant difference in outcomes between theĀ twoĀ arms.26Ā The medianĀ PFS and OS wereĀ 6.6Ā monthsĀ (95% CI:Ā 3.4ā7.7)Ā andĀ 10.6Ā monthsĀ (95% CI:Ā 6.4ā24.5), respectively,Ā with chemoimmunotherapy comparedĀ withĀ 3.9Ā (95% CI:Ā 2.3ā4.5)Ā andĀ 8.2Ā monthsĀ (95% CI:Ā 5.8ā16.9), respectively,Ā with dualĀ ICIs.26Ā A large single–centre, phase II trial conducted in Asia, enrolledĀ 128Ā patientsĀ to receive durvalumab or combination of durvalumb plus tremelimumab in addition to gemcitabine plus cisplatin.23Ā Initially, patients received immunotherapy followingĀ theĀ first cycle of chemotherapy but after protocol amendment, all patients received immunotherapy concurrent withĀ theĀ first cycle of chemotherapy. Impressive ORRsĀ were observed,Ā withĀ 72%Ā inĀ theĀ chemotherapy plus durvalumab arm andĀ 70%Ā inĀ theĀ chemotherapy plus durvalumab and tremelimumab arm. The most common adverse events were cytopenias,Ā with no unexpected safety events. The impressive results of this study formed the basis for development ofĀ theĀ TOPAZ-1 trial.
TOPAZ-1 trial
TheĀ TOPAZ-1 trial evaluated the addition of durvalumab to the standard chemotherapy regimen of gemcitabine and cisplatin asĀ aĀ first–line systemic treatment option for patients with advanced or recurrent BTCs.25,29Ā TOPAZ-1 was a phase III, double-blind, randomized and placebo-controlled studyĀ in whichĀ patients were assigned to receive either durvalumab or placebo with gemcitabine and cisplatin. The primary outcomeĀ was OSĀ andĀ secondary outcomesĀ includedĀ PFS, response rates and safety. Inclusion criteria required patients to have previously untreated BTC that was either unresectable or metastatic or who developed recurrence more thanĀ 6Ā monthsĀ after curative intent surgery andĀ completion ofĀ adjuvant therapy. Patients with ampullary carcinoma or those with exposure to prior immunotherapy were excluded. In the trial, patients could receive up toĀ eightĀ cycles of chemotherapy and if they had stable disease or better response, they were switched to maintenance durvalumab everyĀ 4Ā weeksĀ or placebo,Ā which they continuedĀ until progression or unacceptable toxicity.
A total ofĀ 685Ā patientsĀ were enrolled,Ā with 341 receiving durvalumab with standard chemotherapy and 344 receiving placebo with standard chemotherapy. Baseline characteristics were similar in both groups.Ā The majority of patients were Asian (56%) andĀ hadĀ intrahepatic CCA subtype (56%). OnlyĀ 1%Ā of the patients had MSI-HĀ tumours. The study met its primary endpoint,Ā with median OS ofĀ 12.8Ā monthsĀ (95%Ā CI:Ā 11.1ā14.0)Ā in the durvalumab group and 11.5Ā monthsĀ (95%Ā CI:Ā 10.1ā12.5)Ā in the placebo group (p=0.021).Ā OS rates at 12, 18 andĀ 24Ā monthsĀ wereĀ 54.1%, 35.1%Ā andĀ 24.9%%, respectively,Ā comparedĀ withĀ 48.0%, 25.6% andĀ 10.4%,Ā respectively, for placebo.Ā Median PFS wasĀ 7.2Ā monthsĀ (95%Ā CI:Ā 6.7ā7.4)Ā in patients who received durvalumab andĀ 5.7Ā monthsĀ (95%Ā CI:Ā 5.6ā6.7)Ā in those who received placebo (p=0.001).Ā Multiple subgroup analyses for OS and PFSĀ were conducted toĀ examineĀ the effect ofĀ featuresĀ such asĀ sex, age, PD-L1Ā expression, cancer subtype, race andĀ Eastern Cooperative Oncology Group Performance Status.Ā In all subgroup analyses,Ā there was a trend favouring the durvalumab arm in both OS and PFS. When patients were stratified by PD-L1 positivity, there was no difference in outcomes between thoseĀ whoĀ received durvalumab or placebo,Ā suggesting that PD-L1 status may have limited value in predicting clinical benefit. Finally, ORR wasĀ 26.7%Ā in the durvalumab arm andĀ 18.7%Ā in the placebo arm. Treatment–related adverse event rates were similar between the two groups. The incidences of gradeĀ 3Ā orĀ 4 adverse events were 75.7%Ā andĀ 77.8% inĀ theĀ durvalumab and placebo arms,Ā respectively. OnlyĀ 6%Ā of the patients discontinued durvalumab due to adverse events.
The updated results presented atĀ theĀ 2022Ā European Society for Medical Oncology congress, withĀ anĀ additionalĀ 6.5Ā monthsĀ of follow–up,Ā continued to demonstrate OS benefit with durvalumab plus chemotherapy comparedĀ withĀ placebo plus chemotherapyĀ (median OSĀ 12.9Ā monthsĀ [95%Ā CI:Ā 11.6ā14.1]Ā versusĀ 11.3Ā monthsĀ [95%Ā CI:Ā 10.1ā12.5], respectively;Ā hazard ratio 0.76).30Ā TheĀ 2–yearĀ OS rate wasĀ 40.6%Ā among patients achieving response to treatment with chemoimmunotherapy comparedĀ withĀ onlyĀ 20.7%Ā in patientsĀ who achieved stable disease. All patient subgroups continued to benefit inĀ theĀ updated analyses as well. Subgroup analysis by genomic alterations could not identify any particular alteration includingĀ KRAS, TP53, CDKN2A, ARID1A, IDH1Ā andĀ FGFRĀ that would predict response or lack of benefit to durvalumab treatment.
This study is the first phase III trial to include chemoimmunotherapy in the treatment of BTC.Ā The addition of durvalumab to chemotherapy led to median OS improvement ofĀ 1.3Ā months. More importantly, there was an improvement inĀ theĀ 2–yearĀ OS rate fromĀ 10%Ā toĀ 25%Ā with durvalumab,Ā suggestingĀ theĀ possibility ofĀ more durableĀ long–term survivalĀ inĀ aĀ minority of BTC patients representedĀ in theĀ tail of the survival curve.Ā Given the above findings, the US FDA approved durvalumab in combination with gemcitabine and cisplatin for adult patients with locally advanced or metastatic biliary tract cancer.31
One of the major criticisms of the trial design was that patients receivedĀ aĀ maximum ofĀ eightĀ cycles of chemotherapy followed by durvalumab or placebo as maintenance therapy until progression. This trial design was based onĀ theĀ ABC-02 trial,Ā which established gemcitabine plus cisplatin asĀ theĀ standard of care. However, in typical clinical practice in the USA, treatment with gemcitabine plus cisplatin is continued until unacceptable toxicity or progression of disease, especially in patients responding to treatment. Cisplatin is sometimes difficult to continue beyondĀ eightĀ cycles due to nephrotoxicity and ototoxicity,Ā but gemcitabine is typically continued until progression. The separation in survival curves between theĀ twoĀ arms started atĀ 6Ā months,Ā coinciding with cessation of chemotherapy. Following the results of this trial, it remains unknownĀ whetherĀ the current clinical practice should be changed orĀ whetherĀ chemotherapy plus immunotherapy could be continued beyondĀ eightĀ cycles. This trial demonstratedĀ anĀ OS benefit of durvalumab in both Asian andĀ Western populations, although the improvement was more pronounced in Asian population. Nonetheless, this was a global study including both Asian andĀ Western populations,Ā suggesting general applicability of trial findings.
The KEYNOTE-966 randomized clinical trial, comparing pembrolizumabĀ withĀ placebo in addition to gemcitabine plus cisplatin in first–line therapy for advanced, non-resectable CCA has finished accrual and is expected to read out in the near future.32Ā One key difference fromĀ theĀ TOPAZ-1 trial is that gemcitabine can be continued until progression or unacceptable toxicity along with immunotherapy as part of maintenance therapy. The KEYNOTE-966Ā trial is expected to further address the question of whether immunotherapy adds benefit to chemotherapy as first–line treatment. Hopefully, this trial willĀ alsoĀ identify markers that could help in selecting patientsĀ who would derive maximum benefitĀ fromĀ immunotherapy. It remains unknownĀ whetherĀ theĀ addition of anti-CTLA-4 would have any incremental benefit to chemotherapy plus anti-PD-1/PD-L1 blockade. In the previous phase II trial, the ORRsĀ were similar when durvalumab or durvalumab plus tremelimumab wereĀ added to chemotherapy.23
Conclusions
Despite recent advances in the treatment of CCA, survival remains poor. Durvalumab in combination with gemcitabine and cisplatinĀ chemotherapyĀ should be considered as first–line standard–of–care therapy for patients with newly diagnosed locally advanced or metastatic CCA. However, the use of biomarkers including PD-L1 expression and TMB as a marker of response to immunotherapy in patients with CCA remains unclear. Several ongoing trials would further refine the role of immunotherapy in CCA (Table 228,32ā42).Ā FGFR2, NTRK, IDH, BRAFĀ andĀ HER2Ā alterations are now recognized as therapeutic targets. Further studies with biomarker–guided treatment strategies assessing novel therapeutic options are fundamental to improving survival in this population. The combination of immunotherapy and targeted therapy remains an active area of research.
Table 2: List of selected on–going clinical trials inĀ biliary tract cancersĀ utilizing immunotherapy
Trial |
Regimen |
Phase |
Line of therapy |
NCT0325027333 |
NivolumabĀ +Ā Entinostat |
II |
2ndĀ or later |
NCT0421116834 |
ToripalimabĀ +Ā lenvatinib |
II |
2ndĀ or later |
NCT0429800835 |
AZD6738+Ā durvalumab |
II |
2ndĀ or later |
NCT0505209936 |
FOLFOXĀ +Ā bevacizumabĀ +Ā atezolizumab |
Ib/II |
2ndĀ or later |
NCT0545104337 |
Gemcitabine+Ā cisplatinĀ +Ā durvalumab+Ā tremelimumabĀ +Ā propranolol |
II |
1st |
NCT0494128738 |
AtezolizumabĀ +Ā varlilumabĀ +Ā cobimetiib |
I/II |
2ndĀ or later |
NCT0532758239 |
DurvalumabĀ +Ā lenvatinibĀ +Ā nab-paclitaxel |
I/II |
2ndĀ or later |
NCT0466092940 |
CT-0508+Ā pembrolizumab |
I |
2ndĀ or later |
NCT0427814441 |
BDC-1001+Ā nivolumab |
I/II |
2ndĀ or later |
NCT0523916942 |
DurvaluabĀ +Ā tremelimumabĀ +Ā capecitabine |
II |
Adjuvant |
NCT0400363632 |
Gemcitabine+Ā cisplatinĀ +Ā /- pembrolizumab |
III |
1st |
Sahai28 |
Nivolumab to 5-fluorouracil + liposomal-irinotecan |
I/II |
2nd |