Ubamatamab Monotherapy Elicits Responses in Heavily Pretreated Ovarian Cancer

Ubamatamab (REGN4018) monotherapy produced early clinical activity and an acceptable risk/benefit profile in heavily pretreated patients with ovarian cancer, according to data from a phase 1 trial (NCT03564340) presented at the 2022 ESMO Congress.

Findings showed that patients who received at least 1 dose of ubamatamab at 20 mg or higher (n = 42) achieved an overall response rate (ORR) of 14.3% and a disease control rate (DCR) of 57.1%. Additionally, 23.8% of patients experienced a CA-125 response.

Ubamatamab is a human bispecific antibody designed to bridge MUC16 on cancer cells with CD3-expressing T cells to facilitate T-cell activation and cytotoxicity. Preclinical models examining immune-deficient mice showed that ubamatamab combined with human immune cells led to dose-dependent antitumor activity against intraperitoneal MUC16-expressing ovarian tumor cells and malignant ascites.

The first-in-human, dose-escalation study examined ubamatamab monotherapy in women who were at least 18 years old with relapsed advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. Patients were also required to have received at least 1 line of platinum-based chemotherapy and have CA-125 at least 2 times above the upper limit of normal.

The trial used a modified 3+3 design, and patients received intravenous ubamatamab once per week at doses ranging from 0.1 mg to 800 mg. Step-up dosing was used for the initial 2 doses to mitigate risk of cytokine release syndrome (CRS).

The primary end points of the trial were safety and pharmacokinetics. Secondary end points included a preliminary efficacy estimate by ORR per RECIST v1.1 criteria.

The median age of all enrolled patients (n = 78) was 61 years (range, 31-80), and the median number of lines of prior therapy was 4.5 (range, 1-17). Histology included high-grade serous (91%), clear cell (2.6%), high-grade endometrioid (1.3%), low-grade serous (1.3%), and other (3.8%). The median CA-125 serum at baseline was 709 U/mL (range, 107-10,000). Additionally, 33% of patients had visceral metastases and 58% had PS2+ immunohistochemistry (IHC) staining greater than 75%.

Additional data showed that patients with visceral metastases who received at least 20 mg of ubamatamab (n = 29) had an ORR of 20.7%, a disease control rate of 72.4%, and a CA-125 response rate of 31.0%. Those rates among patients with PS2+ IHC staining above 75% (n = 13) were 30.8%, 61.5%, and 46.2%, respectively.

The estimated median duration of response among those with a confirmed response in the overall population treated at 20 mg or higher was 12.2 months.

Among patients to receive treatment at any dose, all 78 experienced at least 1 treatment-emergent adverse effect (TEAE) of any grade. Investigators recorded at least 1 grade 3 or higher TEAE in 65.4% of patients. TEAEs led to deaths in 3 patients.

No instances of grade 3 or higher CRS were reported, though 74.4% of patients did experience grade 1/2 CRS. One patient experienced immune effector cell–associated neurotoxicity syndrome.

Additionally, 87.2% of patients experienced an any-grade TEAE with pain, including abdominal pain (74.4%), back pain (37.2%), and noncardiac chest pain (17.9%). Grade 3 or higher TEAEs with pain occurred in 23.1% of patients, comprising abdominal pain (20.5%), back pain (7.7%), and noncardiac chest pain (1.3%).

Other notable any-grade TEAEs included anemia (51.3%) and neutropenia (12.8%). Grade 3 or high rates of anemia and neutropenia were 24.4% and 7.7%, respectively.

Presenting study author David O’Malley, MD, a professor in the Department of Obstetrics and Gynecology at The Ohio State University Comprehensive Cancer Center, noted that data from the phase 1 trial support additional investigation of ubamatamab. The phase 2 dose-ranging portion of the study is open, where ubamatamab is being investigated alone and in combination with cemiplimab (Libtayo). Furthermore, subcutaneous step-up dosing of ubamatamab is being investigated to mitigate CRS.

Reference

van Nieuwenhuysen E, O’Malley DM, O’Cearbhaill RE, et al. Ubamatamab (REGN4018, MUC16xCD3 bispecific antibody) monotherapy in patients with recurrent ovarian cancer: Phase 1 dose-escalation analysis. Ann Oncol. 2022;33(suppl 7):S784. doi:10.1016/j.annonc.2022.07.651