Navicixizumab plus Paclitaxel Shows Clinical Benefit in Platinum-Resistant Ovarian Cancer

In platinum-resistant ovarian cancer, previous clinical trials have shown improvement to patient outcome when the VEGF inhibitor bevacizumab was added to chemotherapy. However, patients still progress on this regimen. Preclinical studies have indicated that inhibitors of delta-like ligand 4 (DLL4) were active in tumors that progressed on anti-VEGF therapy; therefore, Fu and colleagues conducted a phase Ib, open-label, nonrandomized dose-escalation and dose-expansion study to investigate the safety, tolerability, and efficacy of navicixizumab, a bispecific antibody that inhibits both VEGF and DLL4, in combination with paclitaxel. Determining the maximum tolerated dose (MTD) of navicixizumab was the primary endpoint, with secondary endpoints including the safety profile of the combination, incidence of anti-navicixizumab antibodies, as well as efficacy. Forty-four patients were initially enrolled in the study with five patients in the dose-escalation cohort and the remaining 39 patients in the expansion cohort. The MTD was not determined throughout the course of the study, with no dose-limiting toxicities observed. Grade 3 or higher adverse events (AE) of any cause were seen in 79.5% patients, with one patient (2.3%) experiencing sudden cardiac death. Treatment-related AEs (TRAE) occurred in 90.9% of patients, with the most common being hypertension, fatigue, and headache, and the most common grade 3 or 4 TRAEs were hypertension, neutropenia, and thrombocytopenia. The overall response rate was 43.2% and was higher in bevacizumab-naïve patients, with 36.3% of evaluable patients having a confirmed response as shown on subsequent scans. In the overall population, the median progression-free survival (PFS) was 7.2 months, with the bevacizumab-pretreated group having a median PFS of 5.4 months, while bevacizumab-naïve patients had a median PFS of 7.6 months. Biomarker analysis was also performed, indicating those who were biomarker-positive (angiogenic or immune-suppressed tumor microenvironment) had a higher overall response rate than those who were considered biomarker-negative. Overall, this trial indicated a durable clinical response in patients with heavily pretreated platinum-resistant ovarian cancer and supports further clinical evaluation of navicixizumab in this setting.

Fu S, Corr BR, Culm-Merdek K, Mockbee C, Youssoufian H, Stagg R, et al. Phase Ib study of navicixizumab plus paclitaxel in patients with platinum-resistant ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2022 Apr 19 [Epub ahead of print].

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