The anti-DLL4/VEGF bispecific antibody navicixizumab showed promising clinical activity when used in combination with paclitaxel in heavily pretreated patients with platinum-resistant ovarian cancer.
Siqing Fu, MD, PhD
The anti-DLL4/VEGF bispecific antibody navicixizumab showed promising clinical activity when used in combination with paclitaxel in heavily pretreated patients with platinum-resistant ovarian cancer, according to findings from a phase Ib study.
The data build on positive single-agent phase Ia data previously shared. The phase Ib results showed that the overall response rate per RECIST 1.1 criteria was 43% (n = 19), including 1 (2%) complete response and 18 (41%) partial responses. Fifteen (34%) patients had stable disease as best response for a clinical benefit rate of 77% (n = 34). Progressive disease occurred in 7 (16%) patients and 3 (7%) patients were not evaluable.
“These interim efficacy data in heavily pretreated platinum-resistant ovarian cancer patients are encouraging. The safety profile appears to be manageable with hypertension being the most common adverse event related to navicixizumab,” lead author Siqing Fu, MD, PhD, professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, and coauthors wrote.
Data from the study were made available as part of the virtual platform for the SGO 2020 Annual Meeting that has been implemented due to the shutdown caused by the novel coronavirus (COVID-19).
The ongoing phase Ib study included 44 patients with platinum-resistant ovarian cancer. Patients had received at least 3 prior therapies and/or bevacizumab (Avastin). The median number of prior therapies was 4 (range, 2-12). Across the population, 68% had received bevacizumab, 41% had received a PARP inhibitor, and all (100%) had received prior paclitaxel.
Patients received navicixizumab on days 1 and 15 of every 28-day cycle, and paclitaxel was administered on days 1, 8, and 15. The design of the study was a dose-escalation assessment of navicixizumab at 3 or 4 mg/kg, followed by an expansion cohort. Patients in the expansion cohort received the 3 mg/kg dose, as higher doses resulted in worse toxicity in the phase 1a study, and there was not an accompanying increase in clinical benefit.
At the time of the interim analysis, 5 patients were still being treated. Fu et al wrote that, “Antidrug antibody was detected in 4 of 25 patients who have been evaluated and had at least 1 follow-up ADA sample; drug exposure was affected in 3 patients.”
The most common (>15% of patients) adverse events (AEs) across all grades were hypertension (68%), fatigue (48%), headache (27%), neutropenia (21%), pulmonary hypertension (18%), and diarrhea (16%). The investigators also noted several related AEs of significance: infusion reaction (9%), grade 4 thrombocytopenia (2%), and grade 4 gastrointestinal perforation (2%).
In October 2019, navicixizumab received an FDA Fast Track designation for the treatment of patients with high-grade ovarian, primary peritoneal or fallopian tube cancer who have received at least 3 prior therapies and/or prior bevacizumab.
The designation, which is intended to expedite the development and review of navicixizumab in this setting, was based on data from the first-in-human phase Ia monotherapy trial, which included 66 patients with various solid tumors.2 Ovarian cancer (n = 12) and colorectal cancer (n = 11) were the most common tumor types. The median age of all patients was 60 and 68% of patients were female. Treatment was administered in 1 of 8 dose-escalation cohorts once every 3 weeks. Four patients remained on treatment for more than 300 days, and 2 remained on treatment for more than 500 days.
There were 4 patients who had a partial response, 3 of whom had ovarian cancer. Another 17 patients achieved stable disease. A reduction in tumor size was observed in 19 patients.
Hypertension (57.6%), headache (28.8%), fatigue (25.8%), and pulmonary hypertension (18.2%), were the most common treatment-related AEs reported across all grades.
In a statement at the time of the award of the Fast Track designation, Jill Henrich, senior vice president of Regulatory Affairs at Mereo BioPharma, the company developing navicixizumab said, "We are pleased that the FDA continues to recognize the potential of navicixizumab to become a viable new treatment option for patients with platinum-resistant ovarian cancer who failed multiple other therapies. This designation follows our successful Type B End of phase I meeting with the FDA held in July 2019 regarding a potential pathway for accelerated approval for navicixizumab where the FDA agreed in principle on an outline for a phase II clinical trial that could potentially support accelerated approval of navicixizumab in patients with ovarian cancer who have become resistant to prior therapies."
The median time to progression was 7.3 months and the median duration of response was 5.7 months. Among 36 patients with an elevated CA-125, 75% (n = 24) had a GCIG-defined response.