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 (CAVG_SG) 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 CAVG_SG. 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 CAVG_SG 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.

Figure 1

Observed proportions and model‐predicted probability of response by CAVG_SG. (a) CR and (b) ORR. Gray circles indicate individual patient data. Closed squares with error bars show observed proportion of patients with efficacy response (95% CI) by exposure quartiles, with dashed vertical lines showing boundaries of exposure quartiles. Solid (dashed and gray area) curves show model‐predicted probability of response event. CAVG_SG, sacituzumab govitecan average concentration; CI, confidence interval; CR, complete response; ORR, objective response rate. Mean CAVG_SG in the 8 and 10 mg/kg groups for the CR endpoint was 12.6 and 16.8 μg/mL, respectively, and for the ORR endpoint was 12.9 and 17.5 μg/mL, respectively.

Figure 2

Survival outcomes stratified by CAVG_tAB. (a) PFS and (b) OS. Vertical dashed lines indicate median survival time (survival probability 0.5) associated with each exposure quartile. CAVG_tAB, average total antibody concentration; CI, confidence interval; OS, overall survival; PFS, progression‐free survival. Mean CAVG_tAB in the 8 and 10 mg/kg groups for the PFS endpoint was 122 and 152 μg/mL, respectively, and for the OS endpoint was 125 and 148 μg/mL, respectively.

Figure 3

Observed proportion and model‐predicted probability of any‐grade AE of diarrhea and neutropenia and for grade ≥3 neutropenia. (a) Grade 1 or worse diarrhea AE, (b) grade 1 or worse neutropenia AE, and (c) grade 3 or worse neutropenia AE are shown. Gray circles indicate data from individual patients. Closed squares (error bars) show the observed proportion of patients with the AE (95% CI) by exposure quartile. Dashed vertical lines show the boundaries of the exposure quartiles. Solid (dashed and gray area) curves show the model‐predicted probability of the AE (95% CI). Mean CAVG_SG in the 8 and 10 mg/kg groups for diarrhea was 19.6 and 29.7 μg/mL, respectively, and neutropenia was 15.9 and 22.1 μg/mL, respectively. AE, adverse event; CAVG_SG, sacituzumab govitecan average concentration; CI, confidence interval.