Precemtabart tocentecan (M9140), an anti-CEACAM5 ADC with exatecan payload, in patients with metastatic colorectal cancer (mCRC): Results from the dose optimization of the phase 1 PROCEADE CRC-01 study.

3038 Background: CEACAM5 is overexpressed in ~90% of CRCs, with limited expression on healthy cells. Precemtabart tocentecan (M9140), the first anti-CEACAM5 ADC with an exatecan payload (topoisomerase 1 inhibitor), showed a predictable, manageable safety profile and promising early clinical activity in the dose escalation of the Phase 1 PROCEADE-CRC-01 study (NCT05464030) in heavily pretreated patients with mCRC. Methods: This global Phase 1 study in 3L adult patients with locally advanced/mCRC (ECOG PS ≤1; previous irinotecan therapy) evaluates clinical activity, safety, and tolerability of precemtabart tocentecan. Here, we report on dose optimization of precemtabart tocentecan tested at 2.8 mg/kg Q3W (Arm A1) or 2.4 mg/kg Q3W (A2; 1:1 randomization) to select the recommended phase 2 dose (RP2D). Results: As of Jan 2025, 60 patients (recruited Apr–Oct 2024) had been treated (A1, n = 29; A2, n = 31). Median age was 60.0 years, and 51.7% were male. In A1, 18 (62.1%) patients remained on treatment and 16 (51.6%) in A2. Treatment-emergent AEs (TEAEs) were reported in all patients; grade ≥3 in 38 (63.3%) patients (A1: n = 19 [65.5%]; A2: n = 19 [61.3%]); anemia and neutropenia (any grade; grade ≥3) were most common. Serious TEAEs were reported in 18 (30.0%) patients (A1: n = 8 [27.6%]; A2: n = 10 [32.3%]). Grade ≥3 hematologic AEs were reported in 32 (53.3%) patients: anemia (A1, n = 9; A2, n = 10), neutropenia (A1, n = 14; A2, n = 12), thrombocytopenia (n = 6 both), leukopenia (A1, n = 7; A2, n = 6), lymphopenia (A1, n = 1; A2, n = 2), febrile neutropenia (n = 3 both), and pancytopenia (A1, n = 0; A2, n = 1). Treatment was discontinued in 26 (43.3%) patients (A1: progressive disease (PD), n = 9, patient withdrawal, n = 1, other, n = 1; A2: PD, n = 14, death, n = 1). No treatment-related deaths were reported. Overall, PK profiles were consistent with previous data, with overlap attributed to high between-subject variability. Partial responses were reported in 7 (24.1%; n = 4 [13.8%] confirmed) patients in A1 and 3 (9.7%; n = 1 [3.2%] confirmed) in A2 (all responders remain on treatment), stable disease in 15 (51.7%) and 21 (67.7%), and PD in 5 (17.2%) and 6 (19.4%) patients, respectively. DCR at 12 weeks was 72.4% in A1 and 67.7% in A2. Conclusions: These preliminary results corroborate the encouraging efficacy and safety data from the dose escalation part of the PROCEADE CRC-01 study, with no new relevant safety findings. ORR was higher at 2.8 mg/kg, with similar tolerability at both doses. The ORR of 24.1% (13.8% confirmed) at 2.8 mg/kg compares favorably with current monotherapy SoCs (ORRs 1-2%) and recent phase 3 data with trifluridine–tipiracil + bevacizumab (ORR 6.1%) in 3L+ mCRC. These results suggest 2.8 mg/kg as the RP2D for further development in CRC, and other solid tumors (NCT06710132). More mature data, including PFS, will be presented at the congress. Clinical trial information: NCT05464030 .