Results of a phase 2 study of a novel DLL4-VEGF, a bispecific antibody, tovecimig (CTX-009), as a monotherapy in patients with refractory metastatic colorectal cancer (COMPANION-003).

125 Background: Tovecimig is a recombinant bispecific antibody that simultaneously blocks the delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A) signaling pathways. In a Phase 1 study of tovecimig, two patients with metastatic colorectal cancer (CRC) had confirmed partial responses (PRs) prompting the further exploration of tovecimig in patients with CRC treated in the third- or fourth-line setting. Methods: COMPANION-003 (NCT05513742) was a multi-center, single arm Phase 2 study with a Simon Two Stage design. Eligible patients had metastatic CRC with primary tumor resection and had progressed after receiving two or three prior systemic therapies, which must have included oxaliplatin, irinotecan, a fluoropyrimidine, an anti-VEGF therapy, and, if indicated, an anti-EGFR therapy. Patients with both KRAS wild type and KRAS mutated tumors were eligible. Tovecimig was given as a monotherapy intravenously at 10 mg/kg every two weeks, and tumor response was assessed every eight weeks based on RECIST v1.1. DLL4 expression assessed in tumor tissue from archived biopsy specimens was analyzed by immunohistochemistry (IHC) retrospectively. Results: Of the 49 patients enrolled in Stage 1 of the study, there were 40 response evaluable patients. 23 out of the 40 patients (58%) were treated in the fourth-line setting. 16 of the 40 patients (40%) had KRAS mutated tumors. Final analysis shows an objective response rate (ORR) of 5% (2 out of 40 patients), median progression free survival (PFS) of 3.9 months, disease control rate (DCR) of 68% (27 out of 40 patients with a partial response or stable disease as the observed best overall response), and median overall survival (OS) of 10.2 months. Treatment emergent adverse events (TEAEs) were reported in 98.0% of subjects and TEAEs of ≥ Grade 3 were reported in 65.3% of subjects. The most frequently reported TEAEs were hypertension (44.9%), proteinuria (36.7%), nausea (28.6%), and fatigue (26.5%). The most frequently reported TEAEs of ≥ Grade 3 were hypertension (32.7%) and proteinuria (6.1%). Archived biopsy specimens were obtained from 25 patients in the study. IHC analysis suggested a trend toward longer PFS in patients with DLL4 high tumors compared to patients with DLL4 low tumors. Conclusions: The results from the Phase 2 COMPANION-003 study demonstrated clinically meaningful anti-tumor activity with a manageable safety profile, which supports further development of tovecimig in patients with advanced, metastatic CRC. Clinical trial information: NCT05513742 .