Gastrointestinal Cancers
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Durvalumab: A PD-L1 Blocking Antibody for the Treatment of Adult Patients with Locally Advanced or Metastatic Biliary Tract Cancer

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Published Online: Mar 24th 2023 touchREVIEWS in Oncology & Haematology. 2023;19(1):22-26 DOI:
Authors: Amit Mahipal, Mathias Palmer, Jennifer Gile, Richard Kim
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Biliary tract cancers (BTCs), comprising intrahepatic, hilar and extrahepatic cholangiocarcinoma and gallbladder cancers, are associated with poor prognoses. The majority of patients present with advancedstage disease, and systemic treatment remains the mainstay of treatment. Recently, multiple targeted therapies have been approved by the US Food and Drug Administration (FDA), including pemigatinib, infigratinib, futibatinib and ivosidenib for patients whose disease has progressed on firstline systemic therapy. However, there has been no improvement othe firstline systemic therapeutic regimen of gemcitabine and cisplatin chemotherapy in more than a decade. Recently, durvalumab in addition to gemcitabine plus cisplatin was approved by the FDA as firstline treatment option for patients with advanced BTC based on the TOPAZ-1 trial. The TOPAZ-1 trial was a phase III doubleblind, placebocontrolled trial that enrolled 685 patients into durvalumab plus gemcitabine plus cisplatin arm or gemcitabine plus cisplatin arm. The trial demonstrated that the addition of durvalumab to standardofcare chemotherapy was associated with improvement in median overall survival (12.8 versu11.5 months), progression-free survival (7.2 versu5.7 months) and response rates (27% versu19%). The incidence and severity of adverse events were similar in both groups. Durvalumab in addition to gemcitabine plus cisplatin has become the new standardofcare treatment for patients with advanced BTCs. This article reviews the 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.


Biliary tract cancers, cholangiocarcinoma, durvalumab, immune checkpoint inhibitors, immunotherapy, programmed death-ligand


Biliary tract cancers (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.1 CCA is divided into extrahepatic and intrahepatic cholangiocarcinoma, with the extrahepatic type further classified into perihilar and distal based on relation to the hilum. Incidence rates have recently increased worldwide; 5year survival is 510% for non-resectable advanced disease and approximately 30% for those treated with curative surgical intent.2,3 The only potentially curative treatment option is surgery; however, only approximately 35% of tumours at diagnosis are amenable to resection.4

Advancements in genomic profiling have revealed critical pathophysiological features of BTCs, leading to the discovery of various actionable molecular targets, including alterations in fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), B-Raf proto-oncogene serine/threonine-protein kinase (BRAF)neurotrophic tropomyosin receptor kinase (NTRK) and human epidermal growth factor receptor 2 (HER-2), with development of multiple targeted therapies.5 Over the past few years, the US Food and Drug Administration (FDA) has approved multiple targeted therapies for patients with BTC that has progressed on firstline chemotherapy, including pemigatinib, infigratinib, futibatinib and ivosidenib. However, these targeted agents benefit only small subset of patients with BTCs that harbour specific actionable alterations. For the majority of patients, chemotherapy remains the only viable option.

In patients with BTCs who have unresectable or metastatic disease, the combination of gemcitabine and cisplatin chemotherapy serves as firstline therapy based on the ABC-02 trial published in 2010.6 The ABC-02 trial demonstrated the efficacy of cisplatin plus gemcitabine with an improved overall survival (OS) compared with single-agent gemcitabine (median OS 11.7 months versu8.1 months).6 However, progress to improve the firstline therapy options for BTCs remains slow, with gemcitabine plus cisplatin being the standard of care for more than a decade. Only one recently published phase III trial has demonstrated improved outcomes by the addition of durvalumab to gemcitabine plus cisplatin in patients with advanced BTCs (TOPAZ-1, see below). This article reviews the 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 physiology

In addition to small molecule inhibitors, immune checkpoint inhibitors (ICIs) have emerged as a potential option for patients with BTCs. Preclinical studies demonstrated a promising immune microenvironment for ICI usage.7 Initial data demonstrated extensive immune cell involvement in CCA, with improved survival, decreased rates of metastasis and better Tumour-Node-Metastasis staging correlating with the presence of CD4 and CD8 T cells, and poor prognosis associated with macrophage and neutrophil involvement.8,9 Programmed death-ligand 1 (PD-L1) expression is seen in more than 45% of tumours and has been associated with a worse prognosis and poor survival.10,11 Additionally, in a study by Nakamura et al.40% of the CCA tumours assessed were determined to have a high mutational load and high immune checkpoint expression.12 Furthermore, a pathological study of occupationalassociated CCA demonstrated higher levels of PD-L1expressing lymphocytes and infiltrating CD-8 cells, and hypothesized that these tumours demonstrated immune escape via their expression of PD-L1.13

Based on work in previous cancers, ICIs are known to produce improved responses with various malignancies, especially in those with increased tumour mutational burden (TMB) and high microsatellite instability (MSI-H). Genetic studies of CCA demonstrated a modest prevalence of MSI-H and high TMB. In one largescale genetic analysis, 23.5% of CCA was classified as high TMB with >17 somatic missense mutations per mega base (Mb) analysed.14 In several additional studies, CCA was associated with a moderate burden of MSI-H and deficiency in mismatch repair proteins with a prevalence around 5%.[14″>15,16

Singleagent immunotherapy

Multiple trials have evaluated the use of singleagent immunotherapy in patients with CCA following progression on chemotherapy (Table 1).17–26 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-028.17 These were phase II and phase 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-L1positive tumourswhereas the KEYNOTE-158 trial was open to patients regardless of PD-L1 status. The objective response rate (ORR) was 5.8% in KEYNOTE-158 and 13.0% in KEYNOTE-028The median OS and PFS were 7.4 months and 2.0 months, respectively, in KEYNOTE-158 compared with 5.7 months and 1.8 months, respectively, in KEYNOTE-028. In a subgroup analysis of KEYNOTE-158, the ORR was 6.6% in PD-L1 expressors compared with 2.9% in nonexpressors.17

Table 1: Key clinical trials with checkpoint inhibitors

ORR = objective response rate; OS = overall survival; PFS = progression-free survival.

Another PD-1 inhibitor, nivolumab, has been studied as a secondline treatment in patients with CCA. An early phase I trial comparing nivolumab alone versus in combination with gemcitabine plus cisplatin demonstrated improved median OS associated with PD-L1 expression; the single patient with a partial response was found to have deficiency in mismatch repair proteins.19 Kim et al. evaluated singleagent nivolumab in a phase II trial of 54 patients with advanced, refractory BTCs.18 The trial demonstrated median progression-free survival (PFS) and OS of 3.7 months (95% confidence interval [CI]: 2.35.7) and 14.2 months (95% CI: 5.9–not reached), respectively, with an ORR of 22%. In patients with PD-L1 expression, there was a superior median PFS compared with PD-L1negative tumours (10.4 months versu2.3 months; p<0.001).18 In another phase I trial of 42 patients, treatment with durvalumab, a PD-L1 inhibitor, was associated with median PFS and OS of 2 months and 8.1 months, respectively.20

The above studies suggest that singleagent ICIs have modest activity in patients with BTCs who have progressed on prior chemotherapy. Response rates of 520% are noted, with median PFS of about 2 months. Currently, there is no good biomarker to predict the efficacy of singleagent immunotherapy. In one retrospective study of 47 patients with BTCs treated with immunotherapy, patients with TMB >5 mutations/Mb had improved PFS and OS compared with patients with TMB <5 mutations/Mb.27

Dualagent immunotherapy

Treatment with dual ICIs has been attempted following at least one line of systemic therapy, but thus far has not demonstrated effective responses compared with singleagent ICIs (Table 1).20,21 In a study by Ioka et al., durvalumab and tremelimumab, a CTLA-4 inhibitor, were used as single agents or in combination, and demonstrated no significant differences between the single agent or combination therapy, with median OS of 8.1 versu10.1 months, respectively, and duration of response of 9.7 versu8.5 months, respectively.20 The ORR with singleagent durvalumab and the combination of durvalumab plus tremelimumab was 4.8% and 10.8%, respectively. Nivolumab plus ipilimumab combination in a phase II trial demonstrated an ORR of 23% and a disease control rate of 44%.21 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 patients with extrahepatic CCA.21

Chemotherapy plus immunotherapy

As only modest activity was observed with singleagent and dualagent ICIs in advanced BTCs, the combination of immunotherapy and standardofcare chemotherapy was evaluated (Table 1).22–26 An initial phase II study examining nivolumab in combination with gemcitabine plus cisplatin demonstrated a PFS of 6.1 months (95% CI3.48.2) and ORR of 55.6%.22 Treatmentrelated adverse events were manageable, with only one patient experiencing immunerelated adverse eventsA phase Ib/II trial evaluated the addition of nivolumab to 5-fluorouracil and liposomal-irinotecan as secondline therapy.28 Median PFS and OS were 4.2 months (95% CI: 1.9-10.2) and 7.5 months (95% CI: 5.821.4), respectively, 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 phase II trial assessing nivolumab, cisplatin, plus gemcitabine compared with nivolumab plus ipilimumab as firstline treatment for advanced BTCs, there was no statistically significant difference in outcomes between the two arms.26 The median PFS and OS were 6.6 months (95% CI: 3.47.7) and 10.6 months (95% CI: 6.424.5), respectively, with chemoimmunotherapy compared with 3.9 (95% CI: 2.34.5) and 8.2 months (95% CI: 5.816.9), respectively, with dual ICIs.26 A large singlecentre, phase II trial conducted in Asia, enrolled 128 patients to receive durvalumab or combination of durvalumb plus tremelimumab in addition to gemcitabine plus cisplatin.23 Initially, patients received immunotherapy following the first cycle of chemotherapy but after protocol amendment, all patients received immunotherapy concurrent with the first cycle of chemotherapy. Impressive ORRs were observed, with 72% in the chemotherapy plus durvalumab arm and 70% in the chemotherapy plus durvalumab and tremelimumab arm. The most common adverse events were cytopenias, with no unexpected safety events. The impressive results of this study formed the basis for development of the TOPAZ-1 trial.

TOPAZ-1 trial

The TOPAZ-1 trial evaluated the addition of durvalumab to the standard chemotherapy regimen of gemcitabine and cisplatin as firstline systemic treatment option for patients with advanced or recurrent BTCs.25,29 TOPAZ-1 was a phase III, double-blind, randomized and placebo-controlled study in which patients were assigned to receive either durvalumab or placebo with gemcitabine and cisplatin. The primary outcome was OS and secondary outcomes included 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 than 6 months after curative intent surgery and completion of adjuvant therapy. Patients with ampullary carcinoma or those with exposure to prior immunotherapy were excluded. In the trial, patients could receive up to eight cycles of chemotherapy and if they had stable disease or better response, they were switched to maintenance durvalumab every 4 weeks or placebo, which they continued until progression or unacceptable toxicity.

A total of 685 patients were enrolled, with 341 receiving durvalumab with standard chemotherapy and 344 receiving placebo with standard chemotherapy. Baseline characteristics were similar in both groups. The majority of patients were Asian (56%) and had intrahepatic CCA subtype (56%). Only 1% of the patients had MSI-H tumours. The study met its primary endpoint, with median OS of 12.8 months (95% CI11.114.0) in the durvalumab group and 11.5 months (95% CI10.112.5) in the placebo group (p=0.021). OS rates at 12, 18 and 24 months were 54.1%, 35.1% and 24.9%%, respectively, compared with 48.0%, 25.6% and 10.4%, respectively, for placeboMedian PFS was 7.2 months (95% CI6.77.4) in patients who received durvalumab and 5.7 months (95% CI5.66.7) in those who received placebo (p=0.001). Multiple subgroup analyses for OS and PFS were conducted to examine the effect of features such as sex, age, PD-L1 expression, cancer subtype, race and Eastern Cooperative Oncology Group Performance Status. In all subgroup analyses, 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 those who received durvalumab or placebo, suggesting that PD-L1 status may have limited value in predicting clinical benefit. Finally, ORR was 26.7% in the durvalumab arm and 18.7% in the placebo arm. Treatmentrelated adverse event rates were similar between the two groups. The incidences of grade 3 or 4 adverse events were 75.7% and 77.8% in the durvalumab and placebo arms, respectively. Only 6% of the patients discontinued durvalumab due to adverse events.

The updated results presented at the 2022 European Society for Medical Oncology congress, with an additional 6.5 months of followup, continued to demonstrate OS benefit with durvalumab plus chemotherapy compared with placebo plus chemotherapy (median OS 12.9 months [95% CI11.614.1] versu11.3 months [95% CI10.112.5], respectively; hazard ratio 0.76).30 The 2year OS rate was 40.6% among patients achieving response to treatment with chemoimmunotherapy compared with only 20.7% in patients who achieved stable disease. All patient subgroups continued to benefit in the updated analyses as well. Subgroup analysis by genomic alterations could not identify any particular alteration including KRAS, TP53, CDKN2A, ARID1A, IDH1 and FGFR 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. The addition of durvalumab to chemotherapy led to median OS improvement of 1.3 months. More importantly, there was an improvement in the 2year OS rate from 10% to 25% with durvalumab, suggesting the possibility of more durable longterm survival in minority of BTC patients represented in the tail of the survival curve. 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 received maximum of eight cycles of chemotherapy followed by durvalumab or placebo as maintenance therapy until progression. This trial design was based on the ABC-02 trial, which established gemcitabine plus cisplatin as the 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 beyond eight cycles due to nephrotoxicity and ototoxicity, but gemcitabine is typically continued until progression. The separation in survival curves between the two arms started at 6 months, coinciding with cessation of chemotherapy. Following the results of this trial, it remains unknown whether the current clinical practice should be changed or whether chemotherapy plus immunotherapy could be continued beyond eight cycles. This trial demonstrated an OS benefit of durvalumab in both Asian and Western populations, although the improvement was more pronounced in Asian population. Nonetheless, this was a global study including both Asian and Western populations, suggesting general applicability of trial findings.

The KEYNOTE-966 randomized clinical trial, comparing pembrolizumab with placebo in addition to gemcitabine plus cisplatin in firstline therapy for advanced, non-resectable CCA has finished accrual and is expected to read out in the near future.32 One key difference from the TOPAZ-1 trial is that gemcitabine can be continued until progression or unacceptable toxicity along with immunotherapy as part of maintenance therapy. The KEYNOTE-966 trial is expected to further address the question of whether immunotherapy adds benefit to chemotherapy as firstline treatment. Hopefully, this trial will also identify markers that could help in selecting patients who would derive maximum benefit from immunotherapy. It remains unknown whether the 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 ORRs were similar when durvalumab or durvalumab plus tremelimumab were added to chemotherapy.23


Despite recent advances in the treatment of CCA, survival remains poor. Durvalumab in combination with gemcitabine and cisplatin chemotherapy should be considered as firstline standardofcare 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 228,32–42). FGFR2, NTRK, IDH, BRAF and HER2 alterations are now recognized as therapeutic targets. Further studies with biomarkerguided 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 ongoing clinical trials in biliary tract cancers utilizing immunotherapy




Line of therapy


Nivolumab Entinostat


2nd or later


Toripalimab + lenvatinib


2nd or later




2nd or later


FOLFOX bevacizumab + atezolizumab


2nd or later


Gemcitabinecisplatin + durvalumabtremelimumab + propranolol




Atezolizumab varlilumab + cobimetiib


2nd or later


Durvalumab lenvatinib + nab-paclitaxel


2nd or later




2nd or later




2nd or later


Durvaluab tremelimumab + capecitabine




Gemcitabinecisplatin + /- pembrolizumab




Nivolumab to 5-fluorouracil + liposomal-irinotecan



Article Information:

Amit Mahipal is a member of the Speakers Bureau at Astrazeneca outside of the submitted work. Richard Kim received honoraria from Incyte, QED, Lilly, BMS, Taiho and Pfizer outside of the submitted work. Mathias Palmer and Jennifer Gile have no financial or non-financial relationships or activities to declare in relation to this article.

Compliance With Ethics

This article involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.

Review Process

Double-blind peer review.


The named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.


Dr Richard KimDepartment of Gastrointestinal OncologyH. Lee Moffitt Cancer Center, 12902 Magnolia Drive FOB-2TampaFL


No funding was received in the publication of this article.


This article is freely accessible at © Touch Medical Media 2023

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the writing of this article.




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37. ClinicalTrials.govDurvalumab and Tremelimumab in Combination with Propranolol and Chemotherapy for Treatment of Advanced Hepatopancreabiliary Tumors (BLOCKED) Identifier: NCT05451043Available at (accessed date 28 February 2023).

38. ClinicalTrials.govTesting a New Combination of Anti-cancer Immune Therapies, Atezolizumab and CDX-1127 (varlilumab) with or Without the Addition of a Third Anti-cancer Drug, Cobimetinib, for Advanced-stage Biliary Tract Identifier: NCT04941287Available at (accessed date 28 February 2023).

39. ClinicalTrials.govAn Open-label, Phase I/II Study of PLENA Regimen in Patients with Unresectable Pancreatic Cancer or Identifier: NCT05327582Available at (accessed date 28 February 2023).

40. ClinicalTrials.govCAR-macrophages for the Treatment of HER2 Overexpressing Solid Identifier: NCT04660929Available at (accessed date 28 February 2023).

41. ClinicalTrials.govA First-in-human Study Using BDC-1001 as a Single Agent and in Combination with Nivolumab in Advanced HER2-expressing Solid Identifier: NCT04278144Available at (accessed date 28 February 2023).

42. ClinicalTrials.govImmunotherapy with Durva and Treme with or Without Capecitabine in Adjuvant Treatment for Biliary Tract Identifier: NCT05239169Available at (accessed date 28 February 2023).

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