REGN5668 Takes Aim at MUC16 in Platinum-Resistant Gynecologic Cancers

For patients with platinum-resistant ovarian cancer (PROC) or endometrial cancer who have progressed following anti–PD-1 therapy, the therapeutic reserve is lacking with limited treatment options associated with modest response rates. Against this backdrop, an investigational MUC16-targeting bispecific antibody–based regimen is generating cautious optimism among gynecologic oncologists, and a phase 1/2 study (NCT04590326) now enrolling patients could help reshape how these cancers are managed.^1,2

Presented as a trial-in-progress update at the 2026 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, the ongoing study of REGN5668 in combination with immune checkpoint inhibitors represents a mechanistically novel approach.¹ With module 1 having enrolled its first patients in dose expansion and module 2 dose escalation advancing through multiple dose levels, the trial is building the foundational evidence base for what could become a new treatment paradigm.

“It’s an exciting time to be involved in research for recurrent gynecologic cancers. We’ve moved away from traditional cytotoxic therapies and now focused on informed targeted therapies. In this case, we’re targeting MUC16, which is an attractive target because it’s expressed on the cell surface of many gynecologic cancers, particular high-grade serous ovarian cancer and a lot of endometrial cancers. What’s attractive is that it doesn’t have the same toxicity profile [as other agents], and for some patients, we see durable responses, but without the same chemotherapy-related toxicity [profile],” Roisin E. O’Cearbhaill, MD, said in an interview with OncLive®.

O’Cearbhaill is the lead author of the first-in-human trial and research director of the Gynecologic Medical Oncology Service, clinical director of the Solid Tumor, Cellular Therapy Service, and an associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

What is the unmet need?

Patients with ovarian cancer whose disease recurs after platinum-based chemotherapy face reduced survival and limited salvage options. The same is true in recurrent endometrial cancer following first-line immunotherapy-containing regimens, where the prognosis after progression is increasingly poor.

What unites these patient populations is the unmet medical need for therapies that can extend survival, maintain quality of life, and produce durable responses. Current second- and later-line options in both settings carry meaningful toxicity burdens and deliver response rates that, although sometimes clinically meaningful, rarely translate into long-term disease control.

Why MUC16? The biological rationale

Mucin 16, commonly known as MUC16, is a cell surface glycoprotein that is highly expressed on both ovarian cancer and endometrial cancer tumor cells, making it an attractive therapeutic target for agents designed to selectively engage tumor tissue while sparing healthy cells.

REGN5668 is an immunoglobulin G4 (IgG4) bispecific antibody engineered to bridge MUC16-positive tumor cells to T cells by simultaneously binding MUC16 on the tumor and CD28 on T cells. CD28 is a critical co-stimulatory receptor on T cells and engaging it amplifies T-cell activation and cytotoxic function.

This mechanism is distinct from traditional checkpoint blockade or antibody-drug conjugates (ADCs). Rather than removing a brake from the immune system or delivering cytotoxic payload directly to tumor cells, REGN5668 acts as a bridge, connecting immune effector cells to their targets and providing the co-stimulatory signal needed for a robust T-cell response.

“REGN5668 is an IgG4-based bispecific [antibody], so a dual targeting monoclonal antibody [which is different from an ADC]. The idea is that, like an ADC, it engages with the target that’s expressed on the cancer cell, but in this case, the other arm is engaging the immune system or the T cells and [it is] often given in combination with checkpoint blockade to enhance that signaling and activation of the immune system,” O’Cearbhaill explained.

Ubamatamab, the companion bispecific antibody being explored in module 2 of this trial, bridges MUC16 on tumor cells to CD3 on T cells. Together with REGN5668's CD28 co-stimulation, the combination of these agents creates an activation cascade in the tumor microenvironment, potentially producing stronger and more durable antitumor responses than either agent alone.

How was the trial designed? Modules and patient population

The phase 1/2 study is a first-in-human trial evaluating the safety, tolerability, pharmacokinetics, and antitumor activity of REGN5668 across 2 treatment modules in patients with platinum-resistant recurrent ovarian cancer or endometrial cancer.

“There are 2 portions. In module 1, we’re in dose expansion where we’re looking at combining REGN5668 with cemiplimab [Libtayo] in ovarian cancer and an anti-LAG3 agent called fianlimab. The idea is that [combining these two agents] will help boost that immune activation,” O’Cearbhaill said.

Module 1: REGN5668 Plus Cemiplimab With or Without Fianlimab

Module 1 examines REGN5668 in combination with cemiplimab with or without fianlimab, anti–PD-1 and anti–LAG-3 antibodies, respectively, that target additional inhibitory T-cell immune checkpoints. In the ovarian cancer cohort, the triplet combination of REGN5668 plus cemiplimab and fianlimab is being evaluated. In the endometrial cancer cohort, REGN5668 is being combined with cemiplimab alone, with an option for an expansion cohort evaluating the triplet in patients with endometrial cancer, pending safety data.

Module 1 has completed dose escalation and entered dose expansion, having enrolled its first three patients at the recommended phase 2 dose (RP2D). This is a significant milestone for a first-in-human trial, indicating that the dose-escalation phase produced an acceptable safety profile sufficient to advance toward larger patient cohorts.

What early signals have been seen?

Although the trial is ongoing, results from module 1 dose escalation demonstrated early clinical activity and an acceptable REGN5668 safety profile in patients with platinum-resistant recurrent ovarian cancer.³

Patients in this phase received intravenous (IV) REGN5668 weekly at a dose ranging from 0.3 mg to 300 mg, plus 350 mg of IV cemiplimab beginning on days 21 through 28 every 3 weeks. Of the 28 patients who had been enrolled, 22 (79%) received at least 1 dose of cemiplimab. The median number of prior therapies was 3.5 (range 1-10). The median duration of exposure to REGN5668 and cemiplimab was 7.5 (range, 1.9-39.0) and 6.1 (range, 2.4-36.0) weeks, respectively.

Safety assessments showed fatigue (32%), nausea (29%), and pain (18%) to be the most frequent treatment-related adverse effects (TRAEs). Infusion-related reactions and cytokine release syndrome (CRS), all of which presented as grade 1 or 2 events, occurred in 14% of patients. No AEs led to death or treatment discontinuation, and no dose-limiting toxicities (DLTs) occurred.

With respect to efficacy, 1 patient experienced a confirmed partial response, with a 59% reduction in target lesion size from baseline, paired with a CA-125 response at the 300-mg dose. Six patients (21%) had stable disease. Investigators also claimed dose-dependent increases in REGN5668 exposure between the 1-mg and 300-mg IV weekly dosing.

This early signal is encouraging, particularly given that the patient population enrolled had already exhausted multiple lines of therapy.

Module 2: REGN5668 Plus Ubamatamab

Module 2 tests the dual bispecific combination of REGN5668 plus ubamatamab in an ovarian cancer cohort. Sarilumab, an anti–IL-6 receptor monoclonal antibody used clinically for rheumatoid arthritis, is being administered as prophylaxis for potential CRS, a known on-target risk with T-cell–redirecting therapies.¹ Module 2 dose escalation has progressed through multiple dose levels, with enrollment ongoing.

Who is eligible? Key inclusion and exclusion criteria

Within the ovarian cancer cohort, eligible patients must have histologically or cytologically confirmed advanced epithelial ovarian cancer (excluding carcinosarcoma), primary peritoneal cancer, or fallopian tube cancer, with relapse or disease progression on or after their most recent line of therapy. Patients must have been treated with at least 1 prior line of platinum-based systemic therapy and have a serum CA-125 level of at least 2-times the upper limit of normal.

For the endometrial cancer cohort, patients must have histologically confirmed disease with disease progression or recurrence after anti–PD-1 therapy and platinum-based chemotherapy, with exposure to no more than 4 prior lines of systemic therapy. At least 25% of tumor cells must be MUC16 positive, ensuring that patients enrolled on this arm have tumors with meaningful target expression. All patients must have an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and in the expansion cohorts at least 1 lesion measurable by RECIST 1.1 criteria.

Key exclusion criteria are broadly consistent with other immunotherapy trials in this space, ruling out patients with untreated or active CNS malignancies or metastases, recent significant autoimmune disease requiring systemic immunosuppressive treatment, prior treatment with a MUC16-targeted therapy, receipt of more than 5 prior lines of systemic therapy in the ovarian cancer cohort, and conditions requiring ongoing corticosteroid therapy within one week prior to study drug administration.

End points: what is the trial measuring?

Module 1’s primary end point is objective response rate (ORR) per RECIST 1.1 criteria. Secondary end points include best overall response (BOR), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) per RECIST 1.1 criteria, comprehensive safety outcomes including the incidence of treatment-emergent adverse effects (TEAEs), serious AEs, and deaths, grade 3 or greater laboratory abnormalities, CA-125 change from baseline, serum REGN5668 concentration over time, and the presence or absence of anti-drug antibodies against REGN5668, cemiplimab, or fianlimab.

Module 2’s primary end points center on safety, specifically the incidence of DLTs, TEAEs, serious AEs, deaths, grade 3 or greater laboratory abnormalities, and serum REGN5668 concentrations. As a dose-escalation module, establishing the maximum tolerated dose and RP2D is the central objective, with ORR, BOR, DOR, DCR, and PFS per RECIST 1.1 criteria serving as key secondary measures.

References

1. O’Cearbhaill RE, Bouberhan S, Van Nieuwenhuysen E, et al. A phase 1/2 study of REGN5668, a MUC16×CD28 costimulatory bispecific antibody, in combination with other targeted therapies, in patients with recurrent ovarian or endometrial cancer: trial in progress update. Presented at: 2026 SGO Annual Meeting; April 10-13, 2026; San Juan, Puerto Rico.
2. A study to find out how safe REGN5668 is and how well it works in adult women when given with either cemiplimab, or cemiplimab + fianlimab, or ubamatamab. ClinicalTrials.gov. Updated November 21, 2025. Accessed April 22, 2026. https://clinicaltrials.gov/study/NCT04590326
3. Winer IS, O’Cearbhaill RE, Bouberhan S, et al. REGN5668 (MUC16xCD28 bispecific antibody) with cemiplimab (anti-PD-1 antibody) in recurrent ovarian cancer: phase I dose-escalation study. Immuno-Oncology and Technology. 2023;20(suppl 1):100599. doi:10.1016/j.iotech.2023.100599