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Tusamitamab Ravtansine in Patients with Advanced Solid Tumors: Phase I Study of Safety, Pharmacokinetics, and
Josep Tabernero1, Philippe L Bedard2, Yung-Jue Bang3
1Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), UVic-UCC, IOB-Quirón, Barcelona, Spain.
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 maximum tolerated dose (MTD) was 100 mg/m2 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 express CEACAM5 received intravenous tusamitamab ravtansine 120-170 mg/m2 [loading dose (LD)], then 100 mg/m2 Q2W (Q2W-LD, n = 28), or 120-190 mg/m2 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/m2 in Q2W-LD and in 2 of 3 patients (grade 2 keratopathy; grade 3 transaminase elevation) with 190 mg/m2 in Q3W. Nineteen (67.9%) patients in Q2W-LD and 13 (86.7%) patients in Q3W experienced 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/m2 (LD) followed by 100 mg/m2 Q2W, and 170 mg/m2 Q3W as a fixed dose. (NCT02187848).
Significance:
The collective results of this phase I dose-escalation study will inform further studies of tusamitamab ravtansine in patients with solid tumors with CEACAM5 expression, including patients with non-small cell lung cancer.
Insights
Tusamitamab ravtansine showed a favorable safety profile in patients with solid tumors expressing CEACAM5. Alternative dosing schedules established new maximum tolerated doses, informing future clinical trials.
Area of Science:
- Oncology
- Pharmacology
Background:
- Tusamitamab ravtansine is an antibody-drug conjugate targeting CEACAM5 with a cytotoxic payload.
- A prior Phase I study established a maximum tolerated dose (MTD) of 100 mg/m² every 2 weeks (Q2W).
Purpose of the Study:
- To evaluate alternative dosing schedules for tusamitamab ravtansine in patients with advanced solid tumors.
- To determine dose-limiting toxicities (DLTs) and safety profiles of new schedules.
Main Methods:
- Adult patients (N=43) with CEACAM5-expressing solid tumors received tusamitamab ravtansine at alternative schedules: loading dose (LD) then 100 mg/m² Q2W (n=28) or fixed dose Q3W (n=15).
- Primary endpoint was DLTs during early cycles.
Main Results:
- Reversible DLTs were observed at higher doses in both schedules.
- Treatment-related adverse events (AEs) occurred in 67.9% (Q2W-LD) and 86.7% (Q3W) of patients; 3 patients discontinued due to AEs.
- Most common AEs included asthenia, GI complaints, keratopathy, keratitis, and peripheral neuropathy. Stable disease was observed in 35.7% (Q2W-LD) and 40.0% (Q3W).
Conclusions:
- Tusamitamab ravtansine demonstrated a favorable safety profile on both tested alternative schedules.
- The MTDs were determined as 170 mg/m² (LD) followed by 100 mg/m² Q2W, and 170 mg/m² Q3W (fixed dose).
- These findings will guide further investigations of tusamitamab ravtansine in CEACAM5-expressing solid tumors, including non-small cell lung cancer.
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