156: Comparable Pharmacokinetics of Sacituzumab Govitecan Between Patients With Metastatic Urothelial Cancer & Metastatic Triple-Negative Breast Cancer

Statement of Purpose, Innovation or Hypothesis: Sacituzumab govitecan (SG) is an antibody‑drug conjugate (ADC) composed of an anti–Trop‑2 antibody coupled to the potent SN‑38 payload via a proprietary, hydrolyzable CL2A linker. It is approved in the US and Europe for patients with metastatic triple-negative breast cancer (mTNBC) who had received at least two prior chemotherapies (≥1 for metastatic disease), pretreated HR+/HER2– metastatic BC, and has accelerated approval in the US for patients with locally advanced or metastatic urothelial cancer (mUC) who had previously received a platinum-containing chemotherapy and immune checkpoint inhibitor.¹ Recognizing patient characteristics differ between mUC and mTNBC, we sought to evaluate pharmacokinetics of SG (ADC), total antibody (hRS7 unconjugated or conjugated with SN-38) and free SN-38 following SG administration in these two patient populations.

Description of Methods & Materials: Pharmacokinetics data from patients who received ≥1 dose of SG and had intensive pharmacokinetic assessments from the phase 2 TROPHY U-01 (mUC)² and the phase 3 ASCENT (mTNBC)³ studies were analyzed using non-compartmental methods (Phoenix^® WinNonlin version 8.2, Pharsight, Cary, NC). All patients received approved starting dose of 10 mg/kg SG on Days 1 and 8, of 21-day cycle. Serum samples for pharmacokinetic analyses were collected at pre-dose, 1-2 minutes prior to the end of the first infusion, and 0.5, 4, 24, 48, 72, and 168 hours after the first infusion in a subset of patients enrolled. Separate validated liquid chromatography-tandem mass spectrometry methods were developed to measure concentrations of free SN-38 and total SN-38 to estimate the bound SN-38. A validated sandwich electrochemiluminescence (ECL) immunoassay was used to quantify total antibody concentrations.⁴ Concentrations of SG were calculated from bound SN-38 concentrations assuming a drug-to-antibody ratio of 8. A total of 11 (of 148) and 48 (of 258) patients were included in these pharmacokinetic analyses for TROPHY U-01 and ASCENT respectively, but the number of patients with enough time points to calculate the different parameters varied. Patients from both studies who received at least one dose of SG and had at least one non-missing reportable ADA test result were analyzed for immunogenicity. An ECL-based immunoassay was utilized to test for anti-SG antibodies using a 3-tier approach: screen, confirm, and titer.

Data & Results: The estimated pharmacokinetic parameters for SG, total antibody, and free SN-38 in patients with mUC and mTNBC are shown in Table 1. The estimated mean CL and Vss for SG were 0.147 L/hr and 2.84 L, respectively, in patients with mUC and closely aligned with 0.134 L/hr and 2.65 L, respectively, in patients with mTNBC. In the mUC and mTNBC studies, 4 (3.7%) of 133 and 4 (1.7%) of 258 patients, respectively, developed antibodies to SG with no discernible impact on SG serum exposures.

Interpretation, Conclusion or Significance: No clinically relevant pharmacokinetic differences were observed between patients with mUC and mTNBC following administration of SG 10 mg/kg on Days 1 and 8, of every 21-day cycle. Population pharmacokinetic analyses across the mUC and mTNBC populations is warranted to further assess impact of covariates on exposure. The incidence of development of antibodies to SG was low with no discernible impact on SG serum exposure.

Disclosures: Y.W., A.D., A.S., K.L., A.O., report employment and stock ownership from Gilead Sciences Inc.

Citations/References: 1. Trodelvy (sacituzumab govitecan-hziy) [prescribing information] Gilead Sciences, Inc., Foster City, CA.; 2023 2. Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: a phase II open label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39(22):2474-2485. DOI: 10.1200/JCO.20.03489 3. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021;384(16):1529-1541. doi: 10.1056/NEJMoa2028489 4. Sathe AG, Singh I, Singh P, et al. Population Pharmacokinetics of Sacituzumab Govitecan in Patients with Metastatic Triple-Negative Breast Cancer and Other Solid Tumors. Clin Pharmacokinet (2024). https://doi.org/10.1007/s40262-024-01366-3

Additional Information/Authors: No additional information.