Abstract 3734: Pharmacokinetics of sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC) targeting Trop-2, in patients with diverse advanced solid tumors
Authors: Sharkey Robert M. , Ocean Allyson J. , Starodub Alexander N. , Bardia Aditya , Guarino Michael , Messersmith Wells A. , Berlin Jordan D. , Picozzi Vincent J. , Moroose Rebecca , Wegener William A. , Maliakal Pius , Govindan Serengulam V. , Goldenberg David M. 
Published: July 2017

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 &lt;2% and ~ 5% of Total SN-38, respectively, indicating most SN-38 in serum is bound to the conjugate. Free SN-38 clears with a half-life of ~20 h, which is consistent with SN-38 clearance in IRI therapy. No correlation was found between Free SN-38 in serum at 30 min and the incidence of severe neutropenia. Total and Free levels of SN-38G were similar, supporting in vitro results indicating that SN-38 is not glucuronidated while bound to the IgG. Free SN-38G levels were lower than Free SN-38 (SN-38G/SN-38 AUC ratio = 0.52), explaining the lower incidence of severe diarrhea. PK parameters for 8 and 10 mg/kg group were similar; no major differences in toxicity. UGT1A1 status showed 43% and 44% with *1*1 and *1*28 haplotype, respectively, and 13% with *28*28 haplotype, which is associated with higher risk of severe neutropenia and diarrhea for IRI therapy. With IMMU-132, 58% of the *28*28 pts had severe neutropenia compared to ~40% of the *1*1 and *1*28 pts, and 16% of the *28*28 pts had grade 3 diarrhea compared to 5-8% of the *1*1 and *1*28. In 3 of 4 cancer indications, objective response rate and clinical benefit ratio favored the 10 mg/kg group.

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