Case–control matching‐guided exposure‐efficacy relationship for avelumab in patients with urothelial carcinoma

Exposure-response (E-R) analyses are an integral component of understanding the benefit/risk profile of novel oncology therapeutics. These analyses are typically conducted using data from the treatment arm to characterize the relationship between drug exposure (low vs. high) and efficacy or safety outcomes. For example, outcomes of patients with lower exposure in the treatment arm (e.g., Q1) might be compared to outcomes of those with higher drug exposure (Q2, Q3, and Q4). Outcomes from the lowest exposure quartile may be also compared to the control arm to evaluate whether the Q1 subgroup derived clinical benefit. However, the sample size and the distribution of patient baseline characteristics and disease risk factors are not balanced in such a comparison (Q1 vs. control), which may bias the analysis and causal interpretation of clinical benefit in the Q1 subgroup. Herein, we report the use of case-control matching to account for this bias and better understand the E-R relationship for avelumab in urothelial carcinoma, a PD-L1 inhibitor approved for the treatment of several cancers. Data from JAVELIN-100 was utilized which is a phase III study of avelumab in first-line maintenance treatment in patients with urothelial carcinoma; this clinical study demonstrated superiority of avelumab versus best-supportive care leading to approval in the United States, Europe, and other countries. A post hoc case-control matching method was implemented to compare the efficacy outcome between Q1 avelumab subgroup and matched patients extracted from the control arm with similar baseline characteristics, which showed a clinically relevant difference in overall survival in favor of the Q1 avelumab subgroup. This analysis demonstrates the importance of accounting for imbalance in important baseline covariates when comparing efficacy outcomes between subgroups within the treatment arm versus the control arm.