Clinical trialPhase 3Liver cancer

Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer

NEJM Evid · 2022685 patients (341 durvalumab, 344 placebo)

Oh DY, He AR, Qin S, et al. NEJM Evid. 2022. 1:EVIDoa2200015

Study type: Clinical trial
Study name: TOPAZ-1
Phase: Phase 3
Design: Randomised (1:1), double-blind, placebo-controlled trial
Sample size: 685 patients (341 durvalumab, 344 placebo)
Source: NEJM Evid · 2022
Trial registration: NCT03875235

In plain words

Bile duct cancer (cholangiocarcinoma and gallbladder cancer) is usually found late. This study showed that adding the immunotherapy drug durvalumab to standard chemotherapy (gemcitabine and cisplatin) raises the chance of being alive at two years from about 10% to about 25%, without a noticeable increase in severe side effects.

Key results

12.8 vs 11.5 months

Median overall survival

HR 0.80 (95% CI 0.66 to 0.97); P=0.021; medians from the FDA label

24.9% vs 10.4%

24-month overall survival (estimated)

95% CI 17.9 to 32.5 vs 4.7 to 18.8

7.2 vs 5.7 months

Median progression-free survival

HR 0.75 (95% CI 0.63 to 0.89); P=0.001; medians from the FDA label

26.7% vs 18.7%

Objective response rate

Drugs in this study:Cisplatin (Platinol)Gemcitabine (Gemzar)Durvalumab (Imfinzi)

Dose and schedule cards

Gemcitabine + cisplatin + durvalumab (TOPAZ-1)

Unresectable locally advanced or metastatic biliary tract cancer, no prior systemic therapy (recurrence more than 6 months after surgery or adjuvant therapy allowed); ECOG 0–1On the page “Liver cancer” · Advanced biliary tract cancer: first-line

Unresectable locally advanced or metastatic biliary tract cancer, no prior systemic therapy (recurrence more than 6 months after surgery or adjuvant therapy allowed); ECOG 0–1

Drug	Dose	Route	Schedule
Combination phase: up to 8 cycles
Durvalumab	1500 mg (body weight less than 30 kg: 20 mg/kg)	IV, 60-min infusion	Day 1, every 3 weeks
Gemcitabine	1000 mg/m²	IV	Days 1 and 8
Cisplatin	25 mg/m²	IV	Days 1 and 8
Maintenance
Durvalumab	1500 mg (body weight less than 30 kg: 20 mg/kg)	IV, 60-min infusion	Every 4 weeks

Cycle length: 21 days during the combination phase; then 28 days
Duration: Chemotherapy up to 8 cycles; durvalumab until progression or intolerable toxicity

Durvalumab is given before chemotherapy on the same day. Patients with ampullary carcinoma or with active or prior autoimmune disease were excluded from the trial.

On the page “Liver cancer” · Advanced biliary tract cancer: first-line

Gem/Cis + durvalumab

Advanced biliary tract or gallbladder cancer, first lineOn the page “Gemcitabine-cisplatin with durvalumab in biliary tract cancer”

Advanced biliary tract or gallbladder cancer, first line

Drug	Dose	Route	Schedule
Phase 1: up to 8 cycles
Gemcitabine	1000 mg/m²	IV	Days 1 and 8
Cisplatin	25 mg/m²	IV	Days 1 and 8
Durvalumab	1500 mg	IV	Day 1 every 21 days
Phase 2
Durvalumab	1500 mg	IV	Every 28 days

Cycle length: Chemotherapy every 21 days; durvalumab alone every 28 days
Duration: Chemotherapy up to 8 cycles; durvalumab until progression

Doses as in TOPAZ-1; gemcitabine-cisplatin is the same regimen as ABC-02.

Dose source:.

On the page “Gemcitabine-cisplatin with durvalumab in biliary tract cancer”

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Durvalumab + gemcitabine + cisplatin

Durvalumab 1500 mg IV on day 1 + gemcitabine 1000 mg/m² and cisplatin 25 mg/m² IV on days 1 and 8 of each 21-day cycle, for up to 8 cycles; then durvalumab monotherapy 1500 mg IV every 4 weeks until disease progression or unacceptable toxicity (continuation after progression was allowed in clinically stable patients with clinical benefit).

According to the FDA label, for body weight below 30 kg: durvalumab 20 mg/kg every 3 weeks with chemotherapy, then 20 mg/kg every 4 weeks.

2Placebo + gemcitabine + cisplatin

Placebo on day 1 + the same gemcitabine 1000 mg/m² and cisplatin 25 mg/m² IV on days 1 and 8 of each 21-day cycle for up to 8 cycles; then placebo every 4 weeks.

Source of the regimen details: FDA label for Imfinzi (openFDA/DailyMed, dosing and TOPAZ-1 study sections); ClinicalTrials.gov NCT03875235 (description of interventions); abstract of the paper (NEJM Evid 2022)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with histologically confirmed biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma and gallbladder cancer), previously untreated unresectable locally advanced or metastatic, or recurrent more than 6 months after curative surgery or completion of adjuvant therapy; ECOG performance status 0 or 1 and at least one target lesion per RECIST 1.1. According to the FDA label, ampullary carcinoma, active or prior autoimmune or inflammatory disease, HIV, active infection (including tuberculosis or hepatitis C) and immunosuppressive medication within 14 days before the first dose were exclusion criteria.

Endpoints

Primary outcome: overall survival.

Secondary outcomes: progression-free survival, objective response rate and safety.

Safety and side effects

Grade 3 or 4 adverse events occurred in 75.7% with durvalumab and 77.8% with placebo; the safety profile of the two groups was similar.

According to the FDA label (durvalumab + chemotherapy group): serious adverse events 47% (cholangitis 7%, pyrexia 3.8%, anaemia 3.6%, sepsis 3.3%); fatal adverse events 3.6%; durvalumab discontinuation due to an adverse event 6%.

Clinical significance and place in guidelines

Based on this study, the FDA approved durvalumab with gemcitabine and cisplatin for advanced or metastatic biliary tract cancer in 2022. The 2023 ESMO guideline (Vogel et al.) considers adding durvalumab to cisplatin-gemcitabine in the first line [I, A; ESMO-MCBS 4]; at the time that guideline was written, EMA approval had not yet been issued.

Limitations

The absolute gain in median survival is modest, and the curves separate mainly after about one year; patients with ECOG 2 or ampullary carcinoma were not enrolled; the control group was placebo with chemotherapy, and the role of biomarkers for patient selection is unclear.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.