Clinical Cancer Research · 17 authors, 16 centres
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This phase I trial established the recommended phase II dose of AGS15E, an antibody-drug conjugate targeting SLITRK6, at 1.00 mg/kg in patients with metastatic urothelial carcinoma. The objective response rate was 35.7% at this dose level, with an overall response rate of 18.3% and a median progression-free survival of 16 weeks. The safety profile was consistent with microtubule-disrupting agents, with common adverse events including fatigue, nausea, and peripheral neuropathy.
**Background:** Metastatic urothelial carcinoma (mUC) has a poor prognosis, with a 5-year overall survival rate of approximately 5%. Antibody-drug conjugates (ADCs) offer targeted therapy. AGS15E is an investigational ADC that delivers monomethyl auristatin E (MMAE) to cells expressing SLITRK6, a tumor antigen highly expressed in urothelial carcinoma (90%) and mUC (100%). This phase I study evaluated the safety, pharmacokinetics, and antitumor activity of AGS15E in patients with mUC.
**Methods:** This multicenter, single-arm, open-label phase I trial (NCT01963052) enrolled 93 patients across 11 centers in North America. The study included a dose-escalation phase (part A) using a continual reassessment method at six dose levels (0.10, 0.25, 0.50, 0.75, 1.00, 1.25 mg/kg) and an expansion phase (parts A, B, C) at the recommended phase II dose (RP2D). Patients received AGS15E intravenously once weekly for 3 weeks of a 4-week cycle. Primary endpoints were safety and pharmacokinetics; secondary endpoints included best overall response per RECIST v1.1. The full analysis set included all patients who received at least one dose.
**Key Results:** The RP2D was determined as 1.00 mg/kg. Among 44 DLT-evaluable patients, 5 (11.4%) experienced dose-limiting toxicities at 0.50 mg/kg (n=1), 0.75 mg/kg (n=2), and 1.25 mg/kg (n=2). The most common treatment-emergent adverse events (TEAEs) were fatigue (54.8%), nausea (37.6%), decreased appetite (35.5%), constipation (31.2%), and diarrhea (30.1%). Grade 3 or higher TEAEs occurred in 35.5% of patients. Peripheral neuropathy and ocular toxicities occurred at doses ≥0.75 mg/kg. Serious TEAEs were reported in 37.6% of patients, with 10.8% considered at least possibly related to the study drug. Six fatal TEAEs occurred, two possibly related (cardiac arrest, acute renal failure). Pharmacokinetics showed dose-proportional increases in AGS15E ADC, MMAE, and total antibody concentrations, with low accumulation (Rac range 1.16–1.79). Antidrug antibodies were confirmed in 6.5% of patients. The objective response rate (ORR) at the RP2D of 1.00 mg/kg was 35.7% (5/14) during dose escalation and 21.7% (13/60) across all patients treated at that dose. In the total population, ORR was 18.3% (17/93), disease control rate was 62.4% (58/93), and median progression-free survival was 16.0 weeks (95% CI, 13.71–23.14). In patients with prior checkpoint inhibitor exposure (n=33), ORR was 27.3% (9/33) and median PFS was 20 weeks (95% CI, 11.43–24.14). Median duration of response was 24.71 weeks overall and 23.86 weeks in CPI-exposed patients. SLITRK6 expression did not correlate with response.
**Clinical Implications:** AGS15E demonstrated manageable safety and encouraging antitumor activity in mUC, particularly at the RP2D of 1.00 mg/kg. The ORR of 35.7% at this dose and activity in CPI-exposed patients (ORR 27.3%) suggest potential as a treatment option. The safety profile aligns with other MMAE-containing ADCs, with peripheral neuropathy and ocular toxicity as notable risks. Further studies are needed to confirm efficacy and explore biomarker-based patient selection.