The Mode of Action and Clinical Outcomes of Sacituzumab Govitecan in Solid Tumors

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.

Figure 1.

Mode of action of SG (, –15, 23). TOP I, topoisomerase I.

Figure 2.

Survival outcomes in SG studies in approved indications (–55, 61, 62). CI, confidence interval; LOT, line of therapy; NA, not assessable; NE, not estimable; NR, not reached; OS, overall survival.

Figure 3.

Most common grade ≥3 TRAEs in key SG studies (, –, –60). LA/mUC, locally advanced, unresectable, or metastatic urothelial cancer; WBC, white blood cells. TRAEs include SG-related TRAEs. Patients received SG plus pembrolizumab in TROPHY-U-01 C3.