Tusamitamab Ravtansine in Patients with Advanced Solid Tumors: Phase I Study of Safety, Pharmacokinetics, and Antitumor Activity Using Alternative Dosing Regimens

Purpose: Tusamitamab ravtansine is an antibody-drug conjugate that targets carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivers a cytotoxic maytansinoid payload. In a phase I dose-escalation study, the maximumtolerated dose (MTD) was 100mg/m(2) every 2 weeks (Q2W). Here we report results for two alternative schedules. Experimental Design: Adults ages >= 18 years (range, 34-73) with locally advanced/metastatic solid tumors (N = 43; colon/rectum, 29; stomach, 7; pancreas, 4; other, 3) expressing/likely to expressCEACAM5 received intravenous tusamitamab ravtansine 120-170 mg/m(2) [loading dose (LD)], then 100 mg/m(2) Q2W (Q2W-LD, n = 28), or 120d-190 mg/m(2) fixed dose [every 3 weeks (Q3W), n= 15]. The primary endpoint was dose-limiting toxicities (DLTs) during cycles 1-2 (Q2W-LD) and cycle 1 (Q3W). Results: Reversible DLTs were observed in 2 of 9 patients (grade 2 keratopathy; grade 2 keratitis) with 170 mg/m(2) in Q2W-LD and in 2 of 3 patients (grade 2 keratopathy; grade 3 transaminase elevation) with 190 mg/m(2) in Q3W. Nineteen (67.9%) patients in Q2W-LD and 13 (86.7%) patients inQ3Wexperienced treatment-related adverse events (AE); 3 of 43 patients discontinued treatment because of AEs. The most common AEs were asthenia, gastrointestinal complaints, keratopathy, keratitis, and peripheral sensory neuropathy. In this small, heavily pretreated population, no confirmed responses were observed; however, stable disease occurred in 35.7% of patients in Q2W-LD and 40.0% of patients in Q3W. Conclusions: Tusamitamab ravtansine had a favorable safety profile with both alternative administration schedules; MTDs were 170 mg/m(2) (LD) followed by 100 mg/m(2) Q2W, and 170 mg/m(2) Q3W as a fixed dose. (NCT02187848).