Novel Pretreatment Autoantibodies Correlate with Enfortumab Vedotin-Related Dermatologic Events in Patients with Advanced Urothelial Cancer.

Enfortumab vedotin (EV) plus pembrolizumab (P) is the first-line treatment for patients with advanced urothelial cancer (aUC). No biomarker for EV toxicity or response has been prospectively validated. EV-related dermatologic events (EVDE) are common and correlate with improved outcomes in retrospective studies. Immune checkpoint inhibitor-related toxicity also correlates with improved outcomes, and the presence of autoantibodies correlates with improved responses. We hypothesized that EV unmasks preexisting subclinical autoimmune responses leading to EVDEs in the setting of EV or EV/P. Our goal was to determine whether novel autoantibodies, if detected, correlate with EVDEs. We screened for novel autoantibodies using an immunoprecipitation-based approach in a pilot retrospective cohort (A) and a prospective longitudinal cohort (B) of patients with aUC who were treated with EV or EV/P and experienced EVDEs. Incidence of EVDEs, radiographic response, and progression-free and overall survival were compared between patients with and without autoantibodies. Two of six cohort A patients had pretreatment autoantibodies [Rho-associated coiled-coil containing protein kinase 2 (one patient) and target of Myb1-like 1 membrane trafficking protein (one patient)]. Pretreatment autoantibodies were also identified in 6/23 cohort B patients [mitochondrial complex 3 - M2 antigen (four patients), NMD3 ribosome export adapter (two patients), and carnitine palmitoyltransferase (one patient)]. All six (100%) cohort B antibody-positive patients developed EVDEs during treatment. To our knowledge, this is the first study correlating EVDEs with novel pretreatment autoantibodies in patients with mUC. Further studies are needed to confirm that they are biomarkers of EV-related skin toxicity and/or response.

Significance: EV is approved alone and with pembrolizumab (EV/P) for aUC. EV-related dermatologic events (EVDEs) have been correlated with improved outcomes. We identified novel pre- and on-treatment autoantibodies in sera of patients with mUC treated with EV or EV/P which correlated with EVDEs.