Sacituzumab Govitecan Population Pharmacokinetics: Updated Analyses Using HR+/HER2- Metastatic Breast Cancer Data From the Phase 3 TROPiCS-02 Trial

Abstract

Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of a Trop-2-directed antibody coupled to SN-38. SG is approved in multiple countries for pretreated metastatic triple-negative breast cancer (mTNBC) and hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) mBC. Three previously developed population pharmacokinetic (PopPK) models for SG, free SN-38, and total antibody (tAB) in patients with mTNBC or other solid tumors were externally validated using data from 260 patients with HR+/HER2- mBC from TROPiCS-02 (NCT03901339). Pharmacokinetic parameters were re-estimated using data from 789 patients with HR+/HER2- mBC, mTNBC, or other solid tumors from three studies-TROPiCS-02, ASCENT (NCT02574455), and IMMU-132-01 (NCT01631552). Previously developed PopPK models adequately described the data from TROPiCS-02. Typical parameter estimates based on combined dataset for clearance and steady-state volume of distribution were 0.128 L/h and 3.58 L for SG and 0.0155 L/h and 4.29 L for tAB, respectively. The pharmacokinetics of the three analytes (SG, free SN-38, and tAB) in participants with HR+/HER2- mBC were consistent with those observed in mTNBC and other tumor types. The analyses confirmed mild-to-moderate renal impairment, mild hepatic impairment, age, tumor type (based on limited data in non-breast cancer tumor types), baseline albumin level, UGT1A1 genotype, or Trop-2 expression did not have a clinically relevant impact on the exposure of the three analytes across populations. These findings support that the SG dosing regimen of 10 mg/kg on Days 1 and 8 of 21-day cycles is adequate for patients with HR+/HER2- mBC.

Keywords: cancers; clinical trials; metastasis; modeling; phase III; population pharmacokinetics; tumors.

FIGURE 1

Visual predictive check for the final PopPK models for SG, Free SN‐38, and tAB. Prediction‐corrected visual predictive check showing observed and simulated data versus time after last dose for the updated final PopPK models of SG (a), free SN‐38 (b), and tAB (c). Previously developed models were re‐estimated using a combined dataset from the three analyzed studies (number of concentrations across studies, SG, n = 6214; free SN‐38, n = 6118; tAB, n = 6257). Model‐predicted and observed percentiles of concentrations for each specific analyte and time after last dose were plotted. The final models for SG, free SN‐38, and tAB described the observed concentrations across the 3 studies well as shown by the good concordance between the observed and simulated percentiles. PopPK, population pharmacokinetics; SG, sacituzumab govitecan; tAB, total antibody.

FIGURE 2

Impact of statistically significant covariates on exposure. The impact of statistically significant covariates included in the final SG model on predicted AUC (a) and C _max (b) was visualized using tornado plots. First cycle AUC and C _max of SG at the given covariate values were compared with those predicted for a typical patient with a body weight of 70 kg and baseline albumin of 38 g/L at the beginning of the study. Dots and error bars show the predicted relative exposure with 95% CI representing parameter uncertainty. Body weight and serum albumin were the only statistically significant covariates for SG, and the impact of both covariates on AUC and C _max was limited. ALB, albumin; AUC, area under the serum concentration‐time curve; CI, confidence interval; C _max, maximum (peak) serum drug concentration; SG, sacituzumab govitecan.

FIGURE 3

Correlation between all tested covariates and individual predicted exposure for SG. The correlation between continuous (a) and categorical (b) covariates and SG AUC and C _max over the first treatment cycle was evaluated and visualized using forest plots. Gray band shows the 80%–125% range. Dots and error bars show predicted relative exposure and 90% CI, respectively, at the given covariate values versus the reference. Categories with less than five participants (three patients with ECOG score of 2, three participants with missing baseline ECOG, three participants with moderate hepatic impairment and three with missing hepatic impairment status, and four participants with severe renal impairment) were excluded from the plot. Individual exposures were predicted with consideration of the participants' respective covariate values and individual estimated random effects based on an SG dose of 10 mg/kg. Clinically relevant correlations were not observed for SG AUC or C _max for tumor type, mild/moderate renal impairment, mild hepatic impairment, age, sex, baseline albumin level, race, ECOG status, UGT1A1 genotype, use of UGT1A1 inducers or inhibitors, and Trop‐2 expression. ALB, albumin; ALP alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the serum concentration‐time curve; BILI, total bilirubin; CI, confidence interval; CLCr, creatinine clearance; C _max, maximum (peak) serum drug concentration; CPI, checkpoint inhibitor; ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; HR, hormonal receptor; mBC, metastatic breast cancer; mTNBC, metastatic triple‐negative breast cancer; SG, sacituzumab govitecan; Trop‐2, trophoblast cell‐surface antigen‐2; UC, urothelial cancer; UGT1A1, uridine 5′‐diphospho‐glucuronosyltransferase 1A1; ULN, upper limit of normal.