Abstract
Sacituzumab govitecan (SG), a trophoblast cell-surface antigen-2 (Trop-2)-directed antibody-drug conjugate, is currently approved to treat metastatic triple-negative breast cancer and HR+/HER2- breast cancer and is under clinical investigation for a range of other tumor types. This review describes its mode of action, development, and clinical outcomes. SG is composed of SN-38 (a topoisomerase I inhibitor derived from irinotecan) covalently linked to an anti-Trop-2 mAb (sacituzumab; hRS7) via a hydrolyzable CL2A linker. SN-38 was chosen due to its potent antitumor activity; CL2A occupies the most effective position on SN-38 for maintaining stability during transport, with pH-sensitive payload release in the tumor, and the antigen target (Trop-2) is highly expressed on many solid tumors. SG has an ∼8:1 drug-to-antibody ratio and delivers therapeutic SN-38 concentration to Trop-2+-expressing tumor cells via rapid internalization and efficient payload release. Free SN-38 can subsequently enter the tumor microenvironment and kill adjacent tumor cells with or without Trop-2 expression (bystander effect). SN-38 induces DNA breakage and inhibits nucleic acid synthesis via a drug-induced topoisomerase 1:DNA complex that interferes with cell proliferation, causing apoptosis. Dose-finding studies support SG 10 mg/kg on days 1 and 8 of a 21-day cycle as the monotherapy dose for clinical use; this was determined by therapeutic index improvement based on efficacy and safety. Payload-linker dynamics and SG potency ensure continued tissue penetration. Neutropenia and diarrhea are the most common grade ≥3 treatment-emergent adverse events with SG, but they are manageable. The efficacy of SG has been demonstrated across a broad spectrum of solid tumors.