Abstract 1362: Exposure-response (E-R) analysis of efficacy for avelumab as first-line maintenance therapy for urothelial carcinoma in the JAVELIN Bladder 100 study
Authors: Hibma Jennifer , Li Jerry , Bello Carlo , Khandelwal Akash , Vugmeyster Yulia , Nickens Dana , Li Swan 
Published: July 2021

Abstract
BACKGROUND: Avelumab, a monoclonal antibody targeting PD-L1, was recently approved in the United States for first-line maintenance (1LM) treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. This analysis assessed the potential relationship between covariates, including avelumab exposure, and overall survival (OS) in patients with UC.
METHODS: This analysis included all patients (N=350) who received avelumab 10 mg/kg every 2 weeks (Q2W) + best supportive care (BSC; arm A) in the JAVELIN Bladder 100 study (intention-to-treat population). Exposure metrics were derived based on a separate population pharmacokinetic model. The exposure-response analyses were conducted using parametric time-to-event (TTE) methodology, and the distribution of survival vs time was tested using exponential, Weibull, log-normal, and log-logistic distributions. A stepwise covariate search was conducted to determine the full and final models (forward addition α=0.05; backward elimination α=0.01). Model adequacy and predictability were evaluated using TTE-visual predictive checks and the likelihood ratio test.
RESULTS: The best fit to the hazard distribution was the log-normal distribution. Avelumab exposure (cycle 1 day 15 trough concentration) was associated with a higher probability of longer OS in both univariate and multivariate regression models. Nonvisceral metastatic disease at the time of initiating first-line chemotherapy was associated with higher probability of longer OS compared with visceral metastasis; this was a study stratification factor and a known predictor of OS in this population. Hemoglobin was also identified as a predictor of OS, consistent with previous reports. However, several factors may have confounded the interpretation of the exposure-OS modeling results, including an imbalance of baseline health status across the exposure quartiles, eg, Eastern Cooperative Oncology Group performance status (ECOG PS) and body weight, and that the data were from a single-dose regimen. Covariates that were not identified as predictors of OS were antidrug antibody status, Asian race, age, sex, smoking history, baseline ECOG PS, best response to first-line chemotherapy, and first-line chemotherapy regimen (α=0.01).
CONCLUSION: The E-R analyses were considered exploratory and no definite conclusions could be made on the impact of exposure on OS, as other variables confounded the relationship. Overall, the exposure from avelumab 10 mg/kg IV Q2W + BSC was associated with a manageable safety and tolerability profile and demonstrated superior efficacy compared with BSC alone in terms of OS as 1LM in patients with UC.
Citation Format: Jennifer Hibma, Jerry Li, Carlo Bello, Akash Khandelwal, Yulia Vugmeyster, Dana Nickens, Swan Li. Exposure-response (E-R) analysis of efficacy for avelumab as first-line maintenance therapy for urothelial carcinoma in the JAVELIN Bladder 100 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1362.