EP-008 - POPULATION PHARMACOKINETICS AND EXPOSURE-RESPONSE ANALYSIS OF TREMELIMUMAB 300 MG SINGLE DOSE COMBINED WITH DURVALUMAB 1500 MG EVERY 4 WEEKS (STRIDE) IN UNRESECTABLE HEPATOCELLULAR CARCINOMA.

K. Lim¹, A. Abegesah¹, X. Song¹, C. Chen², C. Kim¹, A. Negro¹, M. Makowsky¹, C. Gupta¹, A. Khan¹, S. Ren¹, A. Phipps³, D. Zhou⁴; ¹AstraZeneca, Gaithersburg, MD, USA, ²AstraZeneca, South San Francisco, CA, USA, ³AstraZeneca, Cambridge, United Kingdom, ⁴AstraZeneca, Waltham, MA, USA.

Background: A novel regimen of a single dose of tremelimumab (T) 300 mg in combination with durvalumab (D) 1500 mg every 4 weeks (Single Tremelimumab Regular Interval Durvalumab [STRIDE]) showed a favorable benefit-risk profile in the Phase 1/2 Study 22 and the Phase 3 HIMALAYA study in patients with unresectable hepatocellular carcinoma (uHCC).1,2 The current study evaluated the population pharmacokinetics (PopPK) of T and D and exposure-response (ER) relationships for efficacy and safety of STRIDE in patients with uHCC.

Methods: Previous PopPK models for T and D were updated using data from previous studies in various cancers and combined with Study 22 and HIMALAYA. Typical population mean parameters and associated inter- and intra-individual variability, as well as the influence of covariates on the PopPK parameters of T and D, were assessed. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for ER analysis for efficacy and safety.

Results: The observed PK of T in uHCC was well described by a 2-compartment model with both linear and time-dependent elimination. All identified covariates changed PK parameters of T or D by less than 20%, thus are regarded to be of minimal clinical relevance. No T or D exposure metric was significantly associated with overall survival (OS), progression-free survival (PFS), or adverse events in STRIDE, due to plateau of the ER curve at this selected dose level. Baseline aspartate aminotransferase and neutrophil-to-lymphocyte ratio were associated with OS (P < 0.001) by Cox proportional hazards model. No covariate was identified as a significant factor for the PFS hazard.

Conclusion: No dose adjustment for T or D is needed based on PopPK covariate or ER analyses. Our findings support the novel STRIDE dosing regimen for uHCC.

1. Kelley, R.K. et al. Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study J. Clin. Oncol. 39, 2991-3001 (2021).
2. Abou-Alfa, G.K. et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 1(8) (2022).