066: Population Pharmacokinetics & Exposure-Response Analysis of Durvalumab With Gemcitabine & Cisplatin in Patients With Advanced Biliary Tract Cancer

Statement of Purpose: Durvalumab 1,500 mg Q3W in combination with gemcitabine/cisplatin for up to 8 cycles followed by durvalumab 1,500 mg Q4W has demonstrated a favorable benefit-risk profile in the TOPAZ-1 study (Phase III study in patients with first-line advanced biliary tract cancers (BTC)). The current analysis evaluated the population pharmacokinetics (PopPK) of durvalumab, and exposure-response (ER) relationship for efficacy and safety of TOPAZ-1 in patients with advanced BTC.

Description of Methods & Materials: The most recent PopPK model for durvalumab was updated by using data from 3,134 patients with solid tumors, including 314 patients with BTC from TOPAZ-1 who have received durvalumab. Typical population mean parameters and associated inter- and intra-individual variability, as well as the influence of covariates on the PopPK parameters of durvalumab were assessed. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for ER analysis related to efficacy and safety.

Data & Results: A total of 12,805 serum PK samples from 3,134 patients treated with durvalumab were available in the final pooled dataset for analysis. The observed pharmacokinetics of durvalumab in BTC patients was well described by a 2-compartment model with time-dependent clearance. The final population parameters were as follows: CL, 0.298 L/day; V1, 3.42 L; V2, 1.99 L; Q, 0.452 L/day; and the time dependent clearance suggests that the clearance could decrease by a maximum of 39%. There were 111 patients (3.5%) who were treatment-emergent ADA positive in the pooled durvalumab group, and the durvalumab exposure was comparable for treatment emergent ADA positive and negative patients, indicating that durvalumab PK is not impacted by ADA status. All identified covariates including body weight and albumin changed durvalumab PK parameters by less than 20% (except 95^th percentile of body weight which had a 22% impact on V1), thus are regarded of minimal clinical relevance. A total of 314 patients in durvalumab + chemotherapy treatment arm was assessed in the ER analysis. No durvalumab exposure metrics were significantly associated with overall survival (OS), progression-free survival (PFS), or adverse events. Logistic regression analysis indicated no significant (all p >0.01) relationship between the exposure and adverse events (AE) of Grade 3 and above treatment-related AE, Grade 3 and above treatment-related AESI (AEs of special interest), or AE leading to treatment discontinuation in durvalumab treated patients.

Interpretation, Conclusion or Significance: No dose adjustment for durvalumab is needed based on covariates for PopPK or ER analyses. Our findings support the TOPAZ-1 dosing regimen in patients with BTC.

Disclosures: AA, KL, CF, CC, CK, NR, GC, MZ, SR, AP, MG, and DZ are current employees of and shareholders in AstraZeneca.