FDA Approves Durvalumab Plus Gemcitabine/Cisplatin for Locally Advanced or Metastatic Biliary Tract Cancers

The FDA has approved durvalumab (Imfinzi) in combination with gemcitabine and cisplatin in adult patients with locally advanced or metastatic biliary tract cancers.

The FDA has approved durvalumab (Imfinzi) in combination with gemcitabine and cisplatin in adult patients with locally advanced or metastatic biliary tract cancers.1

The regulatory decision was supported by findings from the phase 2 TOPAZ-1 trial (NCT03875235), in which durvalumab plus chemotherapy significantly improved median overall survival (OS) compared with chemotherapy alone, at 12.8 months (95% CI, 11.1-14.0) and 11.5 months (95% CI, 10.1-12.5), respectively (HR, 0.80; 95% CI, 0.66-0.97; P =.021).

The median progression-free survival experienced in those who received durvalumab plus chemotherapy was 7.2 months (95% CI, 6.7-7.4) vs 5.7 months (95% CI, 5.6-6.7) with chemotherapy alone (HR, 0.75; 95% CI, 0.63-0.89; P = .001).

Moreover, the addition of durvalumab to gemcitabine/cisplatin resulted in an objective response rate (ORR) of 26.7% (95% CI, 22%-32%) per investigator assessment vs 18.7% (95% CI, 15%-23%) with gemcitabine/cisplatin alone (odds ratio, 1.60; 95% CI, 1.11-2.31).

The most common toxicities experienced by 20% or more of patients included fatigue, nausea, constipation, decreased appetite, abdominal pain, rash, and pyrexia.


The randomized, double-blind, placebo-controlled, multiregional trial enrolled a total of 685 patients with histologically confirmed, locally advanced unresectable or metastatic biliary tract cancer who had not received prior systemic therapy for advanced disease.

To be eligible for enrollment, patients needed to be at least 18 years of age, an ECOG performance status of 0 or 1, and 1 or more measurable lesions per RECIST v1.1 criteria. They could not have previously been exposed to immune-mediated therapy.2

Those with ampullary carcinoma, active or previous documented autoimmune or inflammatory disorders, or a known allergy or hypersensitivity to any study treatment, were excluded.

Study participants were randomly assigned 1:1 to receive durvalumab at 1500 mg on day 1+ in combination with gemcitabine at 1000 mg/m2 and cisplatin at 25 mg/m2 on days 1 and 8 of each 21-day cycle for up to 8 cycles, followed by durvalumab at 1500 mg every 4 weeks (n = 341) or placebo on day 1+ plus the same chemotherapy regimen followed by placebo every 4 weeks (n = 344).

Patients were stratified by disease status (initially resectable vs recurrent) and primary tumor location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer).

The primary objective of the trial was OS, and secondary end points comprised PFS, ORR, duration of response, disease control rate, and efficacy by PD-L1 expression per RECIST v1.1 criteria and investigator assessment.

The median age of participants was 64 years (range, 20-85), with 47% of patients aged 65 years and older. Regarding trial demographics, 56% of patients were Asian, 37% were White, 2% were Black, and 4% were other races; 7% of patients were Hispanic or Latino. Moreover, 50% of patients were male and 50% were female. Fifty-six percent of patients had cholangiocarcinoma, 25% had gallbladder cancer, and 19% had extrahepatic cholangiocarcinoma.

At a data cutoff of August 11, 2021, the median duration of follow-up was 16.8 months (95% CI, 14.8-17.7) in the investigative arm and 15.9 months (95% CI, 14.9-16.9) in the control arm.

Additional data published in NEJM Evidence showed that the OS Kaplan-Meier curve separated at about 6 months of treatment; thereafter, there was a clear and sustained separation of the curves in favor of the durvalumab arm. After 6 months, the hazard ratio for OS was 0.91 (95% CI, 0.66-1.26); after 6 months, the hazard ratio was 0.74 (95% CI, 0.58-0.94).

The OS and PFS benefits reported with durvalumab plus chemotherapy were generally consistent across the clinically relevant subgroups examined. In the subset of patients with a PD-L1 tumor area positivity (TAP) score of 1% or higher, the hazard ratio for OS with durvalumab/chemotherapy vs chemotherapy alone was 0.79 (95% CI, 0.61-1.00). In t he subset of those with a PD-L1 TAP score of less than 1%, the hazard ratio for OS with durvalumab/chemotherapy vs chemotherapy alone was 0.86 (95% CI, 0.60-1.23).

The safety analysis set was comprised of 338 patients in the investigative arm and 342 patients in the control arm who received 1 or more doses of treatment. The median duration of treatment was 7.3 months (range, 0.1-24.5) with durvalumab/chemotherapy and 5.8 months (range, 0.2-21.5) with chemotherapy alone.

Any-grade adverse effects (AEs) were reported in 99.4% of those who received durvalumab/chemotherapy vs 98.8% of those who received chemotherapy alone; grade 3 or 4 AEs were experienced by 75.7% and 77.8% of patients, respectively.

The most common AEs experienced in the durvalumab/chemotherapy arm, included anemia (48.2%), nausea (40.2%), constipation (32.0%), and neutropenia (31.7%); in the chemotherapy-alone arm, the most frequently experienced AEs were anemia (44.7%), nausea (34.2%), and decreased neutrophil count (31.0%).

Moreover, 12.7% of those in the investigative arm experienced immune-mediated toxicities vs 4.7% of those in the control arm; grade 3 or 4 immune-mediated effects occurred in 2.4% and 1.5% of patients, respectively.

The rates of discontinuation of any treatment component because of AEs were 13.0% and 15.2% in the durvalumab/chemotherapy and chemotherapy-alone arms, respectively.


  1. FDA approves durvalumab for locally advanced or metastatic biliary tract cancer. News release. FDA. September 2, 2022. Accessed September 2, 2022. https://bit.ly/3TOU798
  2. Oh D, He AR, Qin S, et al. Durvalumab plus gemcitabine and cisplain in advanced biliary tract cancer. NEJM Evid. 2022;1(8). doi:10.1056/EVIDoa2200015