Abstract 4146919: Delta-like Ligand 4 Inhibitors Induce Pulmonary Arterial Hypertension in Clinical Trials

Background: Delta-Like Ligand 4 (DLL-4) blockade with therapeutic monoclonal antibodies is an emerging cancer treatment targeting tumor angiogenesis. Inhibition of DLL-4 within the pulmonary vasculature allows for unopposed JAG-1-NOTCH3 signaling, leading to pulmonary vascular smooth muscle (vSMC) cell proliferation and the development of pulmonary arterial hypertension (PAH). Hypothesis: Clinical trials using DLL-4 inhibitors may show an increased incidence of PAH as a side effect of the drugs tested. Aims: Review the PAH incidence as an adverse outcome in DLL-4 inhibitor clinical trials. Methods: Clinicaltrials.gov was queried for studies on DLL-4 inhibition. Patient demographics, medication regimens, trial methodology, and outcomes were recorded. Adverse events were categorized according to National Cancer Institute Common Terminology Criteria for Adverse Events. PAH grades were defined as ranging from mild dyspnea (Grade 1) to life-threatening airway consequences or death (Grade 4-5). Degree of PAH was determined by the clinical trial investigators. Echocardiography and cardiac catheterization were most widely used as PAH diagnostic modalities. Results: Thirteen clinical trials (Phase: 1[n=3], 1a[n=1], 1b[n=6], 2[n=3]) from 2011-2023 investigating DLL-4 or DLL-4/VEGF inhibitors were included. The most common antibody used was Demcizumab(6), followed by Navicixizumab(2), Dilpacimab(2), ABL001(2), and Enoticumab(1). A total of 672 patients (median age 60, 52.5% female) underwent treatment. There were 74 new PAH cases reported (average incidence of 11.7%[± 5.8%]). Four of seventy-four PAH patients also manifested LHF. PAH grades 1-2 represented 81% (n=60) of cases, and 19% (n=14) were grades 3-5. PAH incidence was higher in combination DLL-4-VEGF inhibitor trials versus sole DLL-4 inhibitor trials (16.2% vs 7.9%). Phase 1 and 2 trials displayed similar PAH incidences (11.4% vs 13.0%). Resolution of PAH after drug cessation was reported in 46% of the studies. Conclusions: DLL-4 inhibition treatment for malignancies has demonstrated PAH as a side effect. These results are in accordance with our previous observation that unopposed JAG-1-NOTCH3 signaling, induces pulmonary vascular SMC proliferation and PAH. Discontinuation of DLL-4 inhibitors leads to resolution of disease. Further studies are needed to minimize PAH risk while optimizing oncological benefits of DLL-4 inhibitors before widespread utilization.