Abstract 3734: Pharmacokinetics of sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC) targeting Trop-2, in patients with diverse advanced solid tumors

BACKGROUND: Sacituzumab govitecan (IMMU-132), an ADC targeting Trop-2, an antigen present in many solid tumors, uses SN-38, a topoisomerase I inhibitor that has nanomolar potency derived from irinotecan (IRI), and a pH sensitive linker that releases SN-38 gradually (in vitro, 50% released per 1 day in serum). Clinical studies in patients (pts) with diverse solid tumors have shown manageable toxicity (dose-limiting neutropenia, diarrhea but lower incidence than IRI) and encouraging efficacy. METHODS: Conjugate and IgG were monitored in pts given 8 (N = 24) or 10 mg/kg (N = 29) by ELISA. SN-38 and glucuronidated SN-38 (SN-38G) were measured by reversed-phase HPLC. SN-38 and SN-38G levels are expressed as the amount of drug dissociated from the conjugate (i.e., Free SN-38) and the amount bound to the IgG (Total SN-38). UGT1A1 status was determined in baseline blood sample from 146 pts. RESULTS: IMMU-132 cleared with a half-life of 11.7-18.9 h, depending on the assay, while the IgG half-life was 4-5 days, which agrees with in vitro drug-release data. Levels of Free SN-38 at 30 min or 1 d after injection were CONCLUSION: IMMU-132 cleared as predicted from in vitro serum stability data, with no difference between the 8 and 10 mg/kg groups. Current data show neutropenia did not correlate with Free SN-38 levels in serum at 30 min, and low SN-38G levels support the lower incidence of severe diarrhea. While pts with the *28*28 haplotype had a somewhat higher incidence of severe neutropenia or diarrhea than *1*1 and *1*28 pts, the overall incidence of each is small, suggesting toxicity management rather than screening is appropriate. With no major difference in safety and PK, but improved responses with 10 mg/kg, 10 mg/kg is selected for future clinical studies. Citation Format: Robert M. Sharkey, Allyson J. Ocean, Alexander N. Starodub, Aditya Bardia, Michael Guarino, Wells A. Messersmith, Jordan D. Berlin, Vincent J. Picozzi, Rebecca Moroose, William A. Wegener, Pius Maliakal, Serengulam V. Govindan, David M. Goldenberg. Pharmacokinetics of sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC) targeting Trop-2, in patients with diverse advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3734. doi:10.1158/1538-7445.AM2017-3734