Biliary tract cancer (BTC) covers a wide variety of malignancies that impact various organs connected by the bile duct, including intrahepatic and extrahepatic cholangiocarcinomas, as well as gall bladder cancer [1]. Usually, BTC is detected at late stages when prognosis is bleak [1]. The standard treatment for advanced disease, gemcitabine and cisplatin chemotherapy, has remained the same for the past decade and is associated with a median overall survival of 11.7 months and an estimated 24 month survival rate of approximately 15% [2], prompting the urgent need for new therapeutics [3, 4]. The TOPAZ-1 trial revealed that incorporating the PD-L1 inhibitor durvalumab into the standard treatment resulted in a substantial and clinically significant enhancement in overall survival (OS, primary endpoint: HR 0.80, p = 0.021) [5], and the OS rate in the durvalumab treatment group showed an advantage over the placebo group at 12 month follow-up (54.3% vs. 47.1%), 18 month follow-up (34.8% vs. 24.1%), and 24 month follow-up (23.6% vs. 11.5%) [6]. The FDA and the EMA has approved the regimen 1500 mg durvalumab every 3 weeks in combination with chemotherapy followed by 1500 mg durvalumab every 4 weeks as a single agent combination as the new standard for first-line treatment of advanced BTC [7].

Durvalumab is a human monoclonal antibody that binds to programmed death ligand 1 (PD-L1) and inhibits its interaction with programmed death protein 1 and cluster of differentiation (CD) 80 (B7.1). This leads to the prevention of the inhibition of T cell activity, which allows the immune system to recognize and attack cancer cells more effectively. Presently it holds approval as monotherapy for unresectable Stage III NSCLC, with or without tremelimumab in combination with platinum based chemotherapy for metastatic NSCLC, in combination with etoposide and carboplatin or cisplatin for extensive-stage small-cell lung cancer (ES-SCLC) in adult patients, in combination with platinum chemotherapy as neoadjuvant therapy, followed by durvalumab as a single agent as adjuvant treatment after surgery in patients with resectable NSCLC, in combination with tremelimumab for unresectable hepatocellular carcinoma (uHCC), in combination with gemcitabine and cisplatin for advanced BTC, and in combination with carboplatin and paclitaxel for endometrial cancer. TOPAZ-1 is a randomized, double-blind, global, phase III trial of durvalumab 1500 mg Q3W in combination with gemcitabine plus cisplatin (Gem/Cis) for up to 8 cycles followed by durvalumab 1500 mg Q4W versus placebo in combination with gemcitabine plus cisplatin as a first-line treatment in patients with advanced BTC [7]. The regimen was approved by the FDA in 09/02/2022 for adult patients with locally advanced or metastatic BTC, and other agencies including but not limited: 12/2022 in the EU, 12 /2022 in Japan, 11/2023 in China, and 05/2023 in Switzerland.

The dosing regimen varies based on indication. Durvalumab is administered via a 1 h infusion, either based on a body weight-based approach or a flat dosing regimen. The recommended doses are 1500 mg every 4 weeks as monotherapy, or 1500 mg or 1120 mg every 3 weeks in combination with chemotherapy, followed by 1500 mg every 4 weeks as monotherapy [8].

The pharmacokinetics of durvalumab as monotherapy were examined in 2837 patients in previous datasets, and 314 patients from TOPAZ-1, at doses ranging from 0.1 mg/kg to 20 mg/kg, administered once every two, three, or four weeks. The studies included in the PopPK analysis were Study 1108, CASPIAN, PACIFIC, ATLANTIC, POSEIDON, and TOPAZ-1. As monotherapy, durvalumab demonstrates nonlinear (dose-dependent) pharmacokinetics, trending toward linearity with a dose ≥ 3 mg/kg, likely attributable to saturable target-mediated clearance. It possesses a half-life of approximately 18 days, with AUC increasing dose proportionally from 3 to 20 mg/kg. Cmax shows dose proportionality across the explored dose range, and steady-state is reached in about 16 weeks [8].

A population pharmacokinetic (PopPK) model for durvalumab monotherapy was initially developed and validated using data from two durvalumab monotherapy studies: Phase 2 clinical trial D4191C00003 (ATLANTIC, data cutoff [DCO]: June 3, 2016) and Phase 1/2 clinical trial CD-ONMEDI4736-1108 (1108, DCO: July 24, 2016). The original two-compartment PopPK model with both linear and nonlinear eliminations was later amended to a two-compartment PopPK model with linear elimination and time-varying clearance (CL) equation at doses ≥ 10 mg/kg every 2 weeks (Q2W) or equivalent intravenous (IV) infusion in a post hoc analysis. This amendment was documented in an addendum to the original PopPK report. The PopPK model of durvalumab is updated with TOPAZ-1 and the 5 previous studies to refine the model and better account for variability when looking at the advanced BTC indication in TOPAZ-1.

The objective of the analysis reported here was to evaluate the population PK (PopPK) of durvalumab by including patients from TOPAZ-1 study into the current PopPK model, and any covariate might impact on PK, and the relationships between durvalumab PK exposure and efficacy and safety in advanced BTC patients treated with the durvalumab 1500 mg Q3W with Gem/Cis then durvalumab 1500 mg Q4W regimen in TOPAZ-1 study.