Exposure-Response Analyses of Sacituzumab Govitecan Efficacy and Safety in Patients With Metastatic Triple-Negative Breast Cancer.

Abstract

Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is approved for patients with metastatic triple-negative breast cancer (mTNBC) who received ≥2 prior systemic therapies (≥1 in metastatic setting). Exposure-response (E-R) relationships between SG exposure and efficacy and safety outcomes were characterized in 277 patients with mTNBC using data from the phase I/II IMMU-132-01 and phase III ASCENT (IMMU-132-05) studies. Evaluated endpoints included complete response (CR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety endpoints (individual first worst grade of select adverse events (AEs)). E-R analyses were also conducted for time to first dose reduction or delay. Patients received SG at 8 or 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle. Average SG-related serum exposure over the treatment duration (until the event) was consistently the most significant exposure metric correlated with efficacy and safety endpoints. Higher average concentration over the treatment duration for SG (CAVGSG) was the best predictor of CR and ORR. The model-predicted proportions of patients with CR and ORR at 10 mg/kg were 4.26% and 32.6%, respectively. Higher CAVG for total antibody was the best predictor of OS and PFS. The model-predicted probability of OS at 12 months at median lactate dehydrogenase (227 IU/L) was 53%. The probability of grade ≥1 evaluated AEs and the risk of dose reductions and delays significantly increased with increasing CAVGSG. The model-predicted proportions of patients with any-grade AEs were 35.9%, 67.4%, 64.7%, and 67.1% for vomiting, diarrhea, nausea, and neutropenia, respectively (10 mg/kg dose group). Neutropenia was the only evaluated AE for which CAVGSG was significantly associated with grade ≥3 events. The clinically meaningful efficacy and manageable safety achieved with SG 10 mg/kg on days 1 and 8 of every 21-day cycle dosing regimen supports the appropriateness of this clinical dosage in patients with mTNBC.