Alexander Starodub

Andecaliximab/GS-5745 Alone and Combined with mFOLFOX6 in Advanced Gastric and Gastroesophageal Junction Adenocarcinoma: Results from a Phase I Study

Purpose: Matrix metalloproteinase-9 (MMP9) is implicated in protumorigenic processes. Andecaliximab (GS-5745, a monoclonal antibody targeting MMP9) was evaluated as monotherapy and in combination with mFOLFOX6. Patients and Methods: Three dosages of andecaliximab monotherapy [200, 600, and 1800 mg i.v. every 2 weeks (q2w)] were investigated in patients with advanced solid tumors (n = 13 in a 3+3 design). After determining a recommended dose, patients with advanced HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma (n = 40) received 800 mg andecaliximab + mFOLFOX6 q2w. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed. Results: Andecaliximab monotherapy demonstrated no dose-limiting toxicity (DLT) in any cohort, displaying target-mediated drug disposition at the lowest dose (200 mg) and linear pharmacokinetics at higher doses. Based on target engagement, recommended doses for further study are 800 mg q2w or 1,200 mg q3w. Maximal andecaliximab target binding, defined as undetectable andecaliximab-free MMP9 in plasma, was observed in the gastric/GEJ adenocarcinoma cohort. We observed no unusual toxicity, although there were four deaths on study not attributed to andecaliximab treatment. In first-line patients (n = 36), median progression-free survival (PFS) was 9.9 months [95% confidence interval (CI), 5–13.9 months], and the overall response rate (ORR) was 50%. Among all patients (n = 40), median PFS was 7.8 (90% CI, 5.5–13.9) months, and ORR was 48%, with a median duration of response of 8.4 months. Conclusions: Andecaliximab monotherapy achieved target engagement without DLT. Andecaliximab + mFOLFOX6 showed encouraging clinical activity without additional toxicity in patients with HER2-negative gastric/GEJ adenocarcinoma. A phase III study evaluating mFOLFOX6 ± andecaliximab in this setting is ongoing. Clin Cancer Res; 24(16); 3829–37. ©2018 AACR.

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