Abstract 1360: Exposure-response safety analysis of avelumab in patients with locally advanced or metastatic urothelial carcinoma

BACKGROUND: Avelumab is a human IgG1 monoclonal antibody targeting PD-L1 that is approved in the US for second-line locally advanced or metastatic urothelial carcinoma (UC) and first-line maintenance (1LM) treatment of patients with UC that has not progressed with first-line platinum-containing chemotherapy. The current analysis was conducted to evaluate the relationships between avelumab exposure and the probability of experiencing adverse events in 1LM-UC patients. METHODS: Avelumab exposures following 10-mg/kg every-2-weeks (Q2W) dosing in 1LM-UC patients were derived from post hoc parameter estimates from a population pharmacokinetic model. Safety endpoints included grade ≥3 treatment-emergent adverse events (TEAEs), any-grade infusion-related reactions (IRRs), and any-grade immune-related adverse events (irAEs). For each safety endpoint, avelumab exposures were assessed by univariate screen followed by a full model including influence of all potential covariates and a final model that retained statistically significant covariates (α=0.01) after backwards elimination. Safety analyses were performed with R version 3.5.0 by binomial logistic regression. RESULTS: A total of 344 1LM-UC patients treated with avelumab were included in the analyses. Of these patients, 163 (47%), 101 (29%), and 74 (21.5%) experienced grade ≥3 TEAE, any-grade IRR, and any-grade irAE, respectively. Avelumab exposure did not demonstrate statistically significant relationships with grade ≥3 TEAE or any-grade irAE. Any-grade IRR demonstrated a potentially confounded inverse relationship with avelumab exposure (p=0.009), a trend also seen in patients with advanced renal cell carcinoma. In all models, immunogenicity and PD-L1 status were tested as covariates but were not predictors for any safety endpoint. CONCLUSIONS: The exposure range associated with avelumab 10-mg/kg Q2W dosing demonstrated no clinically meaningful relationships with any of the safety endpoints. Given the similarity in avelumab exposures between the flat 800-mg Q2W and weight-based 10-mg/kg dosing, the findings of this analysis support the use of the flat-dosing regimen for 1LM-UC patients. Citation Format: Jerry Li, Carlo Bello, Akash Khandelwal, Yulia Vugmeyster, Dana Nickens, Swan Lin. Exposure-response safety analysis of avelumab in patients with locally advanced or metastatic urothelial carcinoma [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 1360.