Investigation of Ubamatamab With or Without Cemiplimab Continues in Recurrent Ovarian Cancer

The preliminary efficacy, safety, and optimal dose of the MUC16xCD3 bispecific antibody ubamatamab (REGN4018) alone or in combination with cemiplimab-rwlc (Libtayo) continues to be explored in patients with advanced platinum-resistant ovarian cancer in the phase 2 portion of an ongoing, first-in-human, phase 1/2 study (NCT03564340).¹

The primary end point of the dose-expansion phase, which includes the phase 2 cohort, is objective response rate (ORR) per RECIST v1.1 criteria. Efficacy findings from the phase 2 portion will be used to select the optimal dose of ubamatamab for future research.

“There’s a lot of interest in [evaluating] next-generation immuno-oncology [IO] interventions, such as bispecific antibodies or adaptive cell therapies, to see whether we can capitalize on the immune milieu to target ovarian cancer,” first author Kathleen N. Moore, MD, MS, said in an interview with OncLive®. “This is one of more exciting programs [evaluating the benefit of IO approaches] in a randomized phase 2 setting [with a] fairly open population of patients.”

Moore is an associate director of Clinical Research at the Oklahoma University (OU) Health Stephenson Cancer Center, director of the Oklahoma TSET Phase I Program, and a professor in the Section of Gynecologic Oncology at The University of Oklahoma College of Medicine in Oklahoma City.

Patients with ovarian cancer who develop resistance to platinum-based chemotherapy have limited options for subsequent treatment. Accordingly, there is a substantial need to bolster the efficacy of current therapeutics and expand the treatment armamentarium. However, efforts to leverage IO approaches in platinum-resistant ovarian cancer have been met with minimal success thus far.

“Particularly in patients with high-grade serous ovarian cancer, we’ve seen modest to no efficacy for traditional checkpoint inhibitors, as we have in other solid tumors,” Moore said in the interview. “[The efficacy of] that [approach] hasn’t translated to patients with ovarian cancer for a variety of reasons related to the tumor microenvironment.”

Single-agent ubamatamab previously demonstrated safety and early activity in the form of durable responses in patients with pretreated recurrent ovarian cancer in the phase 1 portion of the study. Findings from the monotherapy dose-escalation phase were presented at the 2022 ESMO Congress, and showed that the overall response rate (ORR) was 14.3% and the disease control rate (DCR) was 57.1% in those given at least 1 dose of intravenous ubamatamab between 20 mg and 800 mg (n = 42). Moreover, a CA-125 response was seen in 23.8% of patients. Those who experienced a confirmed response at a 20 mg or higher dose of ubamatamab experienced an estimated median duration of response of 12.2 months.²

“These bispecific antibodies…are trying to [harness] inherent mechanisms to get [dormant] T cells in the tumor to recognize MUC16 and generate this ‘army of T cells’ programmed against MUC16,” Moore explained. “[Essentially, they] use your own [body’s mechanisms] to create this immune response in the tumor which, for whatever multifactorial reason, isn’t happening either de novo or with the help of traditional checkpoint inhibition.”

Based on these clinical and pharmacokinetic data, investigators continued the evaluation of ubamatamab either alone or in combination with cemiplimab in the phase 2 dose-expansion portion of the study.

The randomized phase 2 cohort is enrolling patients aged 18 years or older with histologically- or cytologically-confirmed advanced epithelial ovarian cancer, with the exception of carcinosarcoma and primary peritoneal or fallopian tube cancer.

To be eligible, patients must be resistant to platinum chemotherapy. Platinum resistance is defined as having relapsed within 6 months of receiving at least 4 four cycles of platinum-based therapy in the first-line setting with a partial response or better or progression on or within 6 months of completing later lines of therapy.

Regarding prior therapy, patients must have previously received bevacizumab (Avastin) or be ineligible to receive bevacizumab. Those with BRCA mutations or a known homologous recombination deficiency may have received a PARP inhibitor; others must be ineligible to receive a PARP inhibitor. Patients are also required to have a minimum serum CA-125 level of 2-times the upper normal limit.

“The MUC16 protein has an extracellular tail [referred to as] CA125, which is cleaved...we use it as a biomarker of response to chemotherapy,” Moore explained. “By selecting patients who have an elevated marker, we can make sure that the patients who are coming on study do express MUC16 on their cancer [cells].”

Other key eligibility criteria include radiographic documentation of progression on prior therapy with 1 or more measurable lesions according to RECIST v1.1 criteria, an ECOG performance status of 0 or 1, adequate organ and bone marrow function, and a life expectancy of at least 3 months.

Patients are ineligible for the study if they previously received anticancer immunotherapies, including PD-(L)1 inhibitors within 5 half lives of the first dose, or CAR T-cell therapy within 30 days of first study dose. Patients could not have previously discontinued anti–PD(L)1 therapy due to toxicity, nor could they have received more than 4 lines of chemotherapy or been previously treated with an MUC16-directed therapy.

Other exclusion criteria included having any concurrent malignancy or untreated/active primary brain tumor, central nervous system metastases, spinal cord compression, or a history of clinically significant cardiac disease no less than 6 months before screening.

In the phase 2 portion of this trial, investigators aim to enroll up to 150 patients. Screening will be conducted up to 28 days before treatment initiation. Participants will be randomly assigned 1:1:1 to 3 treatment arms. Those in arms 1 and 2 will receive intravenous ubamatamab every 3 weeks at doses of either 250 mg or 800 mg. Those in arm 3 will be given 250 mg of ubamatamab plus 350 mg of cemiplimab once every 3 weeks. All treatment arms will receive weekly step-up dosing of ubamatamab to reduce the likelihood of cytokine release syndrome (CRS).

“The toxicities [associated with ubamatamab are schedule dependent, but not dose dependent,” Moore noted. “Because of that, the first 2 weeks [of treatment] must be administered in either an outpatient monitoring unit for at least 24 to 48 hours, or an inpatient setting depending on [the] clinical trial setting.”

Treatment arms with 3 or more ORRs will be expanded to 50 patients, and a standard Simon’s 2-stage design will be utilized in expansion cohorts. An interim analysis will be conducted after the first 20 patients are enrolled.

“The [randomized aspect of the] study design in and of itself isn’t that special…[However], it is a unique design when you look at the specifics of the questions that are being asked [regarding dose optimization] and the novelty of this new agent in ovarian cancer,” Moore said.

Secondary objectives in the dose-expansion portion include the safety, duration of response, progression-free survival, and pharmacokinetics of ubamatamab with and without cemiplimab. Key exploratory end points in this phase include an evaluation of the predictive ability of baseline MUC16 immunohistochemistry expression and other biomarkers, and analysis of ubamatamab’s effect on quality of life and physical functioning.

“We’re looking at all those avenues to make sure we move forward with the most efficacious and safest dose in the population [that is] most likely to benefit, so that we’re not exposing patients with no chance of benefitting from a novel therapy,” Moore emphasized.

The study is actively accruing patients onto both arms of the dose-expansion portion as well as the randomized phase 2 cohort.

Disclosures: Dr Moore reported the following disclosures: consulting or advisory roles with AADi, Alkermes, AstraZeneca, Blueprint Medicines, Caris Life Sciences, Clovis Oncology, Eisai, Genentech/Roche, GlaxoSmithKline/Tesaro, Hengrui Pharmaceutical, I-Mab, Immunogen, InxMed, Iovance Biotherapeutics, Merck, Mereo BioPharma, Mersana, Myriad Genetics, Novartis, Novartis/Pfizer, Onconova Therapeutics, OncXerna Therapeutics, VBL Therapeutics, and Verastem/Pharmacyclics.

Research funding was received from Agenus, Amgen, Artios, AstraZeneca, Bolt Biotherapeutics, Bristol-Myers Squibb, Clovis Oncology, Cyteir, Daiichi Sankyo/Lilly, Genentech, Immunocore, Immunogen, Lilly, Lilly Foundation, Merck, Novartis Pharmaceuticals UK Ltd., Novogen, PTC Therapeutics, Regeneron, Takeda, Tesaro, Verastem, honoraria from Great Debates and Updates, Physicans' Education Resource, Prime Oncology and Research to Practice. Dr Moore has leadership positions with GOG Partners and NRG Oncology; patents and royalties from UpToDate; travel expenses from AstraZeneca and GlaxoSmithKline.

References

1. Moore KN, Bouberhan S, Hamilton EP, et al. First-in-human phase 1/2 study of ubamatamab, a MUC16xCD3 bispecific antibody, administered alone or in combination with cemiplimab in patients with recurrent ovarian cancer. J Clin Oncol. 2023;41(suppl 16):TPS5624. doi:10.1200/JCO.2023.41.
2. 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