154: Pharmacokinetics of Sacituzumab Govitecan in Japanese Patients With Advanced Solid Tumors

Statement of Purpose, Innovation or Hypothesis: Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to a potent SN-38 payload and is approved globally for the treatment of relapsed/ refractory metastatic triple-negative breast cancer (mTNBC) and metastatic HR+/HER2− breast cancer. In the phase 3 ASCENT study (NCT02574455), SG showed significant clinical benefit vs physician’s choice chemotherapy in patients with locally advanced unresectable or mTNBC. ASCENT-J02 (NCT05101096) is an open-label, sequential dose-escalation, and dose-expansion study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of SG in Japanese patients with advanced solid tumors. Free SN-38 is mainly metabolized by UGT1A1. This work compares the pharmacokinetics of SG in Japanese and non-Japanese patients with advanced solid tumors based on non-compartmental analyses.

Description of Methods & Materials: The Phase 1 of ASCENT-J02 study was conducted using a 3 + 3 dose-escalation design, in which patients received SG doses starting at 6 mg/kg, with subsequent escalation to 10 mg/kg. Patients with UGT1A1 wild-type (UGT1A1-NM) enrolled in Cohort A first, followed by Cohort B consisting of patients who were heterozygous or homozygous for UGT1A1*28 or UGT1A1*6 (UGT1A1-PM). All patients received SG via intravenous infusion on Days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. Serum samples for intensive pharmacokinetic analyses were collected during Phase 1 at pre-dose, end of infusion, 9, 24, 48, 72, and 168 hours relative to the start of the first infusion. Pharmacokinetic parameters were calculated using a noncompartmental model with Phoenix WinNonlin®.

Data & Results: All patients in Phase 1 who received SG 6 mg/kg (n=6) or 10 mg/kg (n=9) were included in the noncompartmental analyses for SG, total antibody, and free SN-38. At the SG 10 mg/kg dose level, total antibody, SG and free SN-38 had a median serum t1/2 of approximately 112, 23 and 19 hours, respectively. The estimated mean CL and Vss of SG were 0.108 L/h and 2.26 L, respectively. The increase in SG, total antibody, and free SN-38 exposures was dose proportional across the evaluated dose range in Japanese patients with advanced solid tumors.
Overall, SG and total antibody serum exposures in Japanese patients from study ASCENT-J02 were comparable to those previously observed in non-Japanese patients from study ASCENT at the 10 mg/kg dose level. While observed free SN-38 serum exposures in Japanese patients appeared to be lower on average, the individual free SN-38 exposures were mostly within the range of observed free SN-38 exposures in non-Japanese patients from the ASCENT study. In Japanese patients, similar serum exposures of SG as well as free SN-38 were observed between UGT1A1-PM and UGT1A1-NM. In addition, both evaluated dose levels were tolerated, and safety and efficacy were consistent with that in non-Japanese patients.

Interpretation, Conclusion or Significance: Serum SG and total antibody exposures, and pharmacokinetic parameters in Japanese patients were comparable to those in non-Japanese patients with advanced solid tumors with administration of the clinical regimen of 10 mg/kg on Days 1 and 8 of 21-day cycles. Furthermore, the safety and efficacy profiles were consistent between the two populations. Therefore, no dose adjustments are warranted based on ethnicity.

Disclosures: Disclosures: A.D., D.H., D.Z, J.L, C.L, A.O., are employees of, and may own stocks in, Gilead Sciences, Inc.

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