Sacituzumab govitecan (IMMU‐132), an anti‐Trop‐2‐SN‐38 antibody‐drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics

• Published in: Cancer 2017-10, Vol.123 (19), p.3843-3854
• Main Authors: Ocean, Allyson J., Starodub, Alexander N., Bardia, Aditya, Vahdat, Linda T., Isakoff, Steven J., Guarino, Michael, Messersmith, Wells A., Picozzi, Vincent J., Mayer, Ingrid A., Wegener, William A., Maliakal, Pius, Govindan, Serengulam V., Sharkey, Robert M., Goldenberg, David M.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - pharmacokinetics; antibody‐drug conjugate; Antigens; Antigens, Neoplasm - metabolism; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - pharmacokinetics; Breast cancer; Camptothecin; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - blood; Camptothecin - pharmacokinetics; Cancer; Cell Adhesion Molecules - metabolism; Cell surface; clinical trial; Criteria; Drug dosages; epithelial cancers; Female; Glucuronosyltransferase; Glucuronosyltransferase - genetics; Half-Life; Humans; Immunoconjugates - administration & dosage; Immunoconjugates - adverse effects; Immunoconjugates - pharmacokinetics; Immunoglobulin G; Immunoglobulin G - metabolism; IMMU‐132 (sacituzumab govitecan); Irinotecan; Male; Metastases; Metastasis; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Neutropenia; Neutropenia - chemically induced; Oncology; Patients; Pharmacokinetics; Pharmacology; Response Evaluation Criteria in Solid Tumors; Safety; SN‐38; Solid tumors; Time Factors; Toxicity; trophoblastic cell‐surface antigen (Trop‐2); Tumors; Uridine
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.30789

BACKGROUND Sacituzumab govitecan (IMMU‐132), an antitrophoblastic cell‐surface antigen (anti‐Trop‐2) humanized antibody‐SN‐38 conjugate, had encouraging efficacy in the phase 1 clinical trial. This report further examines the pharmacokinetics and safety of multiple cycles of IMMU‐132 at doses of 8 or 10 mg/kg in patients with diverse advanced epithelial cancers. METHODS Patients who had multiple prior therapies received IMMU‐132 on days 1 and 8 of 21‐day treatment cycles. Trop‐2 staining of archived tumor specimens, clearance of IMMU‐132 and its constituents (ie, immunoglobulin G [IgG], SN‐38 [a camptothecin, the active component of irinotecan], and glucuronidated SN‐38 [SN‐38G]), antibody responses, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) levels were determined. Safety was assessed according to Common Terminology Criteria for Adverse Events version 4.0, and responses were assessed using Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS Patients with diverse metastatic cancers who received IMMU‐132 at 8 mg/kg (n = 81) and 10 mg/kg (n = 97) were examined. Trop‐2 was positive in 93% of the available specimens. IMMU‐132 cleared with a half‐life of approximately 11 to 14 hours, reflecting the release of SN‐38 from the conjugate; IgG cleared more slowly (half‐life, approximately 103‐114 hours). Most SN‐38 in the serum (>95%) was bound to IgG. SN‐38G concentrations were lower than SN‐38 concentrations. Dose‐limiting neutropenia after the first cycle was not correlated with SN‐38 in serum or with UGT1A1 genotype. No antibody responses were detected. Objective responses were observed in several indications, including metastatic triple‐negative breast cancer, confirming that 10 mg/kg produced an encouraging overall response. CONCLUSIONS Sacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future development. Cancer 2017;123:3843–3854. © 2017 American Cancer Society Sacituzumab govitecan (IMMU‐132), an antibody‐drug conjugate targeting SN‐38 to Trop‐2 (an antigen identified in many epithelial cancers), is exhibiting promising activity in several indications. The safety and pharmacokinetic properties of this novel conjugate in diverse cancers are presented at 2 dose levels.