In a phase Ib study reported in the Journal of Clinical Oncology, Fu et al found that the combination of navicixizumab (a bispecific antiangiogenic antibody to VEGF and delta-like ligand 4) and paclitaxel showed activity in patients with platinum-resistant ovarian cancer. Delta-like ligand 4 is a Notch ligand with a critical role in angiogenesis that is associated with anti-VEGF resistance.
Study Details
The U.S. multicenter trial enrolled 44 patients between February 2017 and November 2018. Patients received navicixizumab at 3 mg/kg (including 3 in a dose-escalation cohort) or 4 mg/kg (a total of 2 patients in a dose-escalation cohort) once every 2 weeks plus paclitaxel at 80 mg/m2 on days 0, 7, and 14 of 28-day cycles. Navicixizumab at 3 mg/kg was selected as the dose for the expansion cohort (n = 39). No dose-limiting toxicities were observed in the dose-escalation phase.
An RNA-based diagnostic panel was used to test the hypothesis that tumors with high angiogenesis or immune-suppressed tumor microenvironment subtypes (biomarker-positive) would be more likely to respond to navicixizumab than those with immune-active/immune-desert tumor microenvironment subtypes (biomarker-negative).
Responses
Among all 44 patients, objective response was observed in 19 (43.2%, 95% confidence interval [CI] = 28.3%–59.0%), with complete response in 1. Median duration of response was 6 months (95% CI = 5.4 months–not estimable). The disease control rate was 77.3%. Median progression-free survival was 7.2 months (95% CI = 3.9–8.9 months).
Objective response was observed in 10 (33.3%, 95% CI = 17.3%–52.8%) of 30 patients who had received prior treatment with bevacizumab and in 9 (64.3%, 95% CI = 35.1%–87.2%) of 14 who had not received prior bevacizumab. Disease control rates were 66.7% and 100%, respectively. Median response durations were 6.3 months (95% CI = 1.2 months–not estimable) and 5.6 months (95% CI = 1.0 months–not estimable), respectively. Median progression-free survival was 5.4 months (95% CI = 3.3–9.1 months) and 7.6 months (95% CI = 5.3 months–not estimable), respectively.
KEY POINTS
- Navicixizumab plus paclitaxel produced objective response in 43% of patients.
- Outcomes were better in biomarker-positive patients.
Among 33 patients evaluable for retrospective biomarker analysis, objective response was observed in 8 (62%, 95% CI = 31.6%–86.1%) of 13 biomarker-positive patients and in 5 (25%, 95% CI = 8.7%–49.1%) of 20 biomarker-negative patients. Disease control rates were 100% and 65%, respectively. Median progression-free survival was 9.2 vs 3.9 months (hazard ratio = 0.43, 95% CI = 0.188–0.999). Outcomes in patients with prior bevacizumab treatment were consistent with those in the total group.
Adverse Events
The most common treatment-related adverse events of any grade were hypertension (68.2%), fatigue (47.7%), headache (27.3%), and dyspnea (20.5%). The most common treatment-related grade 3 or 4 adverse events were hypertension (40.9%), neutropenia (6.8%), and thrombocytopenia (4.5%). Pulmonary hypertension occurred in 18.2% (all grade 1–2) of patients. Therapy was discontinued due to treatment-related adverse events in three patients (6.8%). No treatment-related deaths were observed.
The investigators concluded, “Navicixizumab plus paclitaxel demonstrated promising clinical activity in bevacizumab-treated and -naive patients with platinum-resistant ovarian cancer, with manageable toxicity.”
Kathleen N. Moore, MD, of the Stephenson Cancer Center, University of Oklahoma Health Sciences, Oklahoma City, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by OncXerna Therapeutics Inc and OncoMed Pharmaceuticals Inc. For full disclosures of the study authors, visit ascopubs.org.
