Navicixizumab/Paclitaxel Combo Demonstrates Early Promise in Platinum-Resistant Ovarian Cancer

The addition of navicixizumab (OMP-305B83) to paclitaxel produced encouraging responses with manageable toxicity in patients with platinum-resistant ovarian cancer irrespective of prior treatment with bevacizumab (Avastin), according to findings from a phase 1b trial (NCT03030287) published in the Journal of Clinical Oncology.¹

The combination elicited an overall response rate (ORR) of 43.2% (95% CI, 28.3%-59.0%) in the intent-to-treat (ITT) population (n = 44); 2.3% of patients achieved a complete response and 40.9% experienced partial responses (PRs). Additionally, 34.1% of patients had stable disease, 15.9% experienced disease progression, and 6.8% were not evaluable.

The disease control rate (DCR) with the doublet was 77.3% (95% CI, 62.2%-88.5%). The median duration of response (DOR) was 6 months (95% CI, 5.4–not estimable [NE]). The median progression-free survival (PFS) was 7.2 months (95% CI, 3.9-8.9).

“The efficacy observed with navicixizumab in patients with heavily pretreated platinum-resistant ovarian cancer that had shown limited response to the most recent prior treatments is encouraging,” lead study author Siqing Fu, MD, PhD, a professor in the Department of Investigational Cancer Therapeutics, of the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, and colleagues, wrote in the paper. “Navicixizumab plus paclitaxel demonstrated durable clinical activity in both bevacizumab-naïve and -pretreated patients, with monitorable, manageable toxicity.”

Patients with platinum-resistant ovarian cancer are known to have a poor prognosis, and platinum resistance occurs frequently after primary treatment with cytoreductive surgery and platinum-based chemotherapy.² Although the addition of bevacizumab to chemotherapy has improved outcomes for those with platinum-resistant disease, disease progression is inevitable.³

Navicixizumab is a first-in-class, bispecific, antiangiogenic antibody that inhibits VEGF and DLL4. Since DLL4 is cell-bound, the agent can localize to the tumor microenvironment to block DLL4 and sequester VEGF that is locally secreted.⁴ In a phase 1a trial (NCT02298387), single-agent navicixizumab resulted in a disease control rate of 64% in 11 patients with platinum-resistant ovarian cancer.

The phase 1b trial enrolled patients who were at least 21 years of age who had cytologically or histologically confirmed grade 2 or 3 platinum-resistant ovarian cancer. Those with serous adenocarcinoma, endometroid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, transitional cell carcinoma, malignant Branner’s Tumor, or adenocarcinoma not otherwise specified were eligible.

Patients were required to receive prior bevacizumab and/or 2 or more prior therapies. They also needed to have an ECOG performance status of 0 or 1 and a life expectancy of longer than 3 months.

Those with nonepithelial ovarian carcinoma, hypertension not controlled by less than or equal to 2 medications, a history of cardiac ischemia or heart failure with a peak tricuspid velocity greater than 3.0 m/s on Doppler echocardiography, clinically significant gastrointestinal disease, or known bleeding disorders or coagulopathy, were excluded.

In the dose-escalation portion of the trial, 3 patients were initially enrolled to receive 3 mg/kg of intravenous (IV) navicixizumab once every 2 weeks followed by 80 mg/m2 of IV paclitaxel on days 0, 7, and 14 of each 28-day cycle, preceded by dexamethasone, an antihistamine, and an H-2 blocker.

If no dose-limiting toxicities (DLTs) occurred within the first 28 days, 3 patients would be enrolled in a second dose level cohort to receive navicixizumab at 4 mg/kg once every 2 weeks. Three additional patients would then be treated at the dose selected for expansion, and if no more than 1 patient experienced a DLT, then that dose would be used in the expansion phase of the trial. Notably, navicixizumab dose modifications were not permitted in each dose cohort.

In the dose-expansion phase of the research, dose reductions were allowed in accordance with standard modification criteria to manage toxicity. If paclitaxel or navicixizumab were delayed or discontinued because of toxicity, patients could still receive the other drug as scheduled. Treatment was continued until confirmed CR, disease progression, intolerance, or withdrawal.

The primary end point of the trial was to establish the maximum tolerated dose of navicixizumab, which was defined as the highest dose level at which 1 or fewer patients experienced a DLT. Secondary end points included safety of the combination of navicixizumab and paclitaxel, the incidence of anti-navicixizumab antibodies, and efficacy, which included ORR, DOR, and PFS per RECIST v1.1 criteria, as well as tumor response per Rustin Gynecologic Cancer Intergroup CA-125 criteria.

Exploratory end points included the retrospective analysis of pretreatment tumor tissue for RNA expression utilizing the Xerna TME Panel biomarker panel to identify the dominant angiogenic and immunogenic biology in the patient’s tumor microenvironment.

Among those in the ITT population, the median age was 63.0 years (range, 37-77), and 88.6% of patients were White. Patients had either ovarian cancer (77.3%), primary peritoneal cancer (6.8%), or fallopian tube cancer (15.9%). The median time from diagnosis was 3.21 years (range, 0.8-12.1). Most patients had stage III disease (56.8%) at diagnosis, followed by stage IV disease (38.6%) and stage I disease (2.3%).

Most patients were platinum resistant (97.7%), and 58.1% had a platinum progression-free interval of less than 3 months. Additionally, 4.5% and 97.7% of patients had prior radiotherapy and surgery, respectively. The median number of prior treatment regimens received was 4.0 (range, 2-12); patients previously received paclitaxel (97.7%), bevacizumab (68.2%), immunotherapy (20.5%), and PARP inhibitors (45.5%).

Additional data showed that patients who were previously treated with bevacizumab (n = 30) had an ORR of 33.3% (95% CI, 17.3%-52.8%), with a median DOR of 6.3 months (95% CI, 1.2-NE). The DCR with the combination in this subset was 66.7% (95% CI, 47.2%-82.7%). Patients who received prior bevacizumab had a median PFS of 5.4 months (95% CI, 3.3-9.1).

In the subset of patients who were bevacizumab naïve (n = 14), the ORR was 64.3% (95% CI, 35.1%-87.2%) in patients naïve to bevacizumab, with a median DOR of 5.6 months (95% CI, 1.0-NE). The DCR in this subset was 100% (95% CI, 76.8%-100.0%). Bevacizumab-naïve patients experienced a median PFS of 7.6 months (95% CI, 5.3-NE).

A CA-125 response was observed in 75% (95% CI, 56.6%-88.5%) of evaluable patients in the ITT population; 60.0% (95% CI, 36.1%-80.9%) of patients pretreated with bevacizumab experienced a CA-125 response, along with 100% (95% CI, 73.5%-100%) of bevacizumab-naïve patients.

The biomarker analysis demonstrated that of the samples collected from 33 patients, 39.4% had an angiogenic or immune-suppressed tumor microenvironment subtype and were considered biomarker positive. Additionally, 60.6% of samples were classified as immune-active or immune-desert tumor microenvironments, making those patients biomarker negative.

Biomarker-positive patients (n = 13) experienced an ORR of 62% (95% CI, 31.6%-86.1%), with a DCR of 100% (95% CI, 75.3%-100%). In biomarker-negative patients (n = 20), the ORR achieved with the combination was 25% (95% CI, 8.7%-49.1%), with a DCR of 65% (95% CI, 40.8%-84.6%).

Regarding safety, all patients in the ITT population experienced at least 1 adverse effect (AE) of any grade; 79.5% experienced at least 1 grade 3 or higher AE. Notably, 1 patient had a grade 5 AE of sudden cardiac death 119 days after starting treatment. That patient experienced increased abdominal pain related to their disease during the study and reported nausea on day 113. After being hospitalized with worsening dehydration and diarrhea related to paclitaxel and ovarian cancer, sudden cardiac death occurred 6 days later; it was determined by the investigator to not be related to study treatment, but to platinum-resistant disease.

Treatment-related AEs (TRAEs) occurred in 90.9% of all patients. The TRAEs that were most frequently experienced included hypertension (68.2%), fatigue (47.7%), headache (27.3%), dyspnea (20.5%), neutropenia (18.2%), diarrhea (18.2%), pulmonary hypertension (18.2%), edema peripheral (15.9%), nausea (13.6%), increase brain natriuretic peptide (11.4%), thrombocytopenia (4.5%), duodenal ulcer (2.3%), and large intestine perforation (2.3%).

The most common grade 3 or 4 TRAEs included hypertension (40.9%), neutropenia (6.8%), and thrombocytopenia (4.5%). No grade 5 TRAEs occurred, and 15.9% of patients had a treatment-related serious AE. Notably, 6.8% of patients discontinued study treatment due to TRAEs.

A phase 3 trial (NCT05043402) will further evaluate navicixizumab in patients with platinum-resistant ovarian cancer; the trial is not yet recruiting.

References

1. Fu S, Corr Br, Culm-Merdek K, et al. Phase Ib study of navicixizumab plus paclitaxel in patients with platinum-resistant ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. Published online April 19, 2022. doi:10.1200/JCO.21.01801
2. Armstrong DK, Alvarez RD, Bakkum-Gamez JN, et al. Ovarian cancer, version 2.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(2):191-226. doi:10.6004/jnccn.2021.0007
3. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302-1308. doi:10.1200/JCO.2013.51.4489
4. Jimeno A, Moore KN, Gordon M, et al. A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors. Invest New Drugs. 2019;37(3):461-472. doi:10.1007/s10637-018-0665-y