Pathologic response and safety of neoadjuvant pembrolizumab with or without entinostat in muscle-invasive urothelial cancer (MIUC).

4603 Background: Entinostat (Ent) is a selective histone deacetylase 1/3 inhibitor that potentiates immune checkpoint inhibitor activity in immunocompetent mouse models of urothelial cancer through immune editing of tumor neoantigens resulting in tumor immune microenvironment remodeling and associated changes in immune gene signature expression (J Clin Invest. 2021). Pembrolizumab (P), an immune checkpoint inhibitor, has demonstrated activity as neoadjuvant therapy for muscle-invasive urothelial cancer (MIUC) with the potential for combination treatment with Ent to improve outcomes. Methods: LCCC1827 is a window of opportunity trial of P with or without Ent in cisplatin-ineligible patients with T2-4aN0M0 MIUC prior to definitive therapy with radical cystectomy (RC) or trimodality therapy (TMT) with maximal TURBT followed by chemoradiation (NCT03978624). Patients were treated with P 200mg IV on day 1 and day 22 alone (Arm 1) or P 200mg IV on day 1 and 22 in combination with Ent 5mg po on days 1, 8, 15 (Arm 2) followed by definitive treatment within 10 weeks of day 1. The primary endpoint was change in immune gene signature expression in pre- and post-treatment tumors in Arm 2 compared to Arm 1. Here, we report clinical and secondary endpoints of pathologic response rate (pRR, < pT2N0) and pathologic complete response (pCR, pT0N0) for patients with RC, clinical complete response rate (cT0) at repeat TURBT for patients with TMT, and safety. Results: 20 patients (10 P; 10 P-Ent) were enrolled between 09/2020 and 10/2023 (85% male; median age 76 years; 25% black; 75% clinical T2) with all patients completing protocol-defined neoadjuvant therapy. 19 patients underwent definitive therapy (1 refused; 14 RC and 5 TMT). For RC, pRR was 43% and pCR was 29% in each arm. For TMT, cT0 was 100% in Arm 1 (n = 2) and 66% in Arm 2 (n = 3). Most common treatment-related AEs were diarrhea (20% in both arms), nausea (10% Arm 1, 30% Arm 2), and fatigue (10% Arm 1, 20% Arm 2). Grade 3 or higher treatment-related adverse events occurred in two patients (10%) (myalgias and back pain in one patient on Arm 1, hyponatremia in one patient on Arm 2). No patients had RC or TMT delayed due to treatment-related adverse events. All patients completed RC within 10 weeks of study initiation, except for 1 patient who delayed cystectomy for logistical reasons. One patient died after RC due to complications unrelated to study treatment. Conclusions: Neoadjuvant pembrolizumab with or without entinostat is active in MIUC with an acceptable safety profile. Analysis of the primary endpoint and other translational endpoints is ongoing. Clinical trial information: NCT03978624 .