Tovecimig (CTX-009)

No systemic therapy is approved by the FDA for second-line biliary tract cancer other than biomarker-directed agents, which the sponsor states are appropriate for approximately 10% to 15% of patients. The regimens most commonly used off-label in this setting are reported to produce objective response rates of about 5% or less and a median overall survival of approximately 6 months; FOLFOX, the regimen tested against best supportive care in a randomized study, produced an objective response rate of 4.9%, a median progression-free survival of 4.0 months and a median overall survival of 6.2 months. In COMPANION-002 the objective response rate with tovecimig plus paclitaxel was 18.0% (20 of 111 participants) compared with 5.3% (3 of 57) with paclitaxel alone (p=0.0228) in the final analysis, and median progression-free survival was 4.7 months compared with 2.6 months (hazard ratio 0.44, p<0.0001). No head-to-head study against another agent has been conducted.

Two other bispecific antibodies targeting DLL4 and VEGF have been tested in first-in-human studies. Navicixizumab (OMP-305B83) was given to 66 participants with refractory solid tumors at 0.5 to 12.5 mg/kg every 3 weeks; the maximum tolerated dose was not reached, 7.5 mg/kg was selected for expansion, treatment-related adverse events in at least 15% of participants were hypertension (57.6%), headache (28.8%), fatigue (25.8%) and pulmonary hypertension (18.2%), the half-life was 11.4 days, anti-drug antibodies formed in 29%, and 4 participants had a partial response. Dilpacimab (ABT-165), a dual-variable domain immunoglobulin, was given to 55 participants at 1.25 to 7.5 mg/kg on days 1 and 15 of 28-day cycles; the most common treatment-related adverse events were hypertension (60.0%), headache (30.9%) and fatigue (21.8%), gastrointestinal perforation occurred in 2 participants (3.6%) with one death, the half-life ranged from 4.9 to 9.5 days, the recommended phase 2 dose was 3.75 mg/kg, and 10.9% of participants had a partial response. Neither agent has reported a randomized trial in biliary tract cancer. Tovecimig differs from both in molecular format, being an anti-VEGF IgG backbone with C-terminal anti-DLL4 single-chain variable fragments, and in dose, at 10 mg/kg every 2 weeks. Pulmonary hypertension, reported in 18.2% of participants receiving navicixizumab, was not reported among grade 3 or higher adverse events of special interest in the phase 2 study of tovecimig plus paclitaxel.