Biomarkers predictive of response to enfortumab vedotin (EV) treatment in advanced urothelial cancer (aUC).

Abstract

531 Background: EV is an antibody-drug conjugate which recently received full FDA approval for treatment-refractory aUC. Molecular biomarkers and characteristics of patients (pts) most likely to respond to EV therapy have not been well defined. Methods: We retrospectively identified all aUC pts treated with EV at our institution. Clinicopathologic, treatment and response data were abstracted from pt charts. Pts were considered responders to EV if they had a complete response on initial scans after 2-3 months of treatment, or were treated with EV for ≥ 6 months. Responders and non-responders were compared in terms of their molecular and clinical characteristics using Chi-squared test. Most common somatic alterations present in ≥10 pts ( TERTp, TP53, CDKN2A, CDKN2B) were also used to divide pts with available next-generation sequencing (NGS) results into groups with and without these alterations. Log rank test was used to determine differences in overall survival (OS) and progression free survival (PFS) among these groups. Results: Between 1/2020 and 8/2021 a total of 32 pts received EV and 28 had NGS data available with either FoundationOne (14 pts), UCSF500 (13 pts) or Strata (1). Median age was 69.5 years, 24 (75%) were male, 22 (69%) Caucasian, 22 (69%) had pure urothelial histology and 22 (69%) primary tumor location in the bladder. At EV start, 24 (75%) had visceral metastases (mets), 8 (25%) had liver mets, and 13 (41%) had bone mets. Median follow-up from EV start was 12.5 months (range 0.5-36); 20 (63%) pts received EV monotherapy, and 12 (37%) received EV as part of a combination regimen. Non-responders were more likely to have bone metastases (69% vs 21%, p<0.01), but were otherwise similar in baseline clinical characteristics to responders. TP53 alterations were enriched in responders relative to non-responders, whereas non-responders had more CDKN2B alterations (Table). Similar findings were seen in the subset of pts treated with EV monotherapy. Pts with TP53 alterations had longer OS (NR vs 17.0 months, p=0.06) and PFS (NR vs 6.6 months, p=0.04) relative to wild-type pts. Shorter PFS was seen in pts with CDKN2A (4.4 months vs NR, p=0.05) and CDKN2B (4.3 months vs NR, p=0.02) alterations, but no differences in OS were observed. Conclusions: In this retrospective cohort of aUC pts with available NGS data, presence of TP53 and absence of CDKN2A and CDKN2B alterations were associated with favorable responses and improved clinical outcomes with EV, suggesting they may be biomarkers of response to EV. These preliminary findings should be validated in larger cohorts.[Table: see text]