2360O The double antibody drug conjugate (DAD) phase I trial: Sacituzumab govitecan (SG) plus enfortumab vedotin (EV) as ≥ second-line therapy for metastatic urothelial carcinoma (mUC)

Antibody-drug conjugates are a mainstay in treatment of mUC. Given different targets, payloads with non-overlapping toxicities and preclinical synergy of SG with anti-microtubule agents, we evaluated the safety and efficacy of SG+EV in a phase I trial (NCT04724018). Patients (pts) with mUC and ECOG ≤1 who progressed on platinum and immunotherapy or were cisplatin ineligible and received one line of therapy were enrolled. SG+EV were dosed D1,8 of a 21-day cycle until progression of unacceptable toxicity. To assess the feasibility and safety of combining SG+EV, doses were adjusted based on the incidence of dose-limiting toxicities (DLTs) during cycle(C) 1 and the total number of pts treated at four pre-specified dose levels (DL) using a Bayesian Optimal Interval design (Table). Adverse events (AE) were assessed using CTCAE 5.0. 24 pts were enrolled (9 DL1, 9 DL2, 6 DL3) from 5/2021 to 4/2023. At data cutoff on May 1, 2023, 23 pts were evaluable for DLT assessment; one pt in DL3 never started therapy. Median age was 69 years (range 41-88); 22 received ≥ 2 lines of therapy. After 2 pts in DL1 experienced febrile neutropenia (FN) prophylactic granulocyte stimulating factor (GCSF) was permitted; 18 pts received GCSF. 70% pts experienced ≥ grade 3 AE at any DLs with one grade 5 AE (pneumonitis possibly related to EV) during C2 (pt in DL3.) The table summarizes DLTs at corresponding DLs; DL2 has been selected for future studies. Among 21 pts evaluble for response, objective response rate was 71% (15/21, 90% Confidence interval: 51-87) with 2 complete and 13 partial responses; 2 pts had progressive disease. With median follow-up 11.9 months, 11/15 responses are ongoing from 1.1+ to 21.6+ months.Table: 2360ODLSG dose (mg/kg)EV dose (mg/kg)N enrolledDLT-1610NA18192 (FN)281.2591 (delay C2D1 > 3 wks)3101.256 (1 not evaluable)3 (grade 3 mucositis, delay C2D1 > 3 wks, FN) Open table in a new tab SG+EV was safe with an ORR of 71% in pts with treatment refractory UC. Further DAD expansion cohorts in treatment refractory and naïve setting are in development; triplet therapy with immunotherapy is being explored.