Early Promise With REGN5668 Combinations in Gynecologic Cancers

In an interview during SGO, Roisin E. O'Cearbhaill, MD, of Memorial Sloan Kettering Cancer Center discussed the rationale and early progress of a phase 1/2 clinical trial evaluating REGN5668, a MUC16×CD28 costimulatory bispecific antibody, in patients with recurrent ovarian or endometrial cancer.

A key challenge in these disease settings has been the limited efficacy of single-agent immunotherapy. As O’Cearbhaill explained, immune checkpoint inhibitors alone have produced disappointing results, underscoring the need for strategies that more effectively engage the tumor microenvironment. REGN5668 is designed to address this gap by simultaneously targeting MUC16 on tumor cells and activating CD28 on T cells, thereby enhancing immune synapse formation and promoting a more robust antitumor response.

The trial is exploring REGN5668 in combination with other immunotherapies, including the PD-1 inhibitor cemiplimab and the anti–LAG3 agent fianlimab, with the goal of amplifying immune activation through complementary mechanisms. These combinations aim to reinvigorate exhausted T cells while also overcoming immune suppression within the tumor microenvironment, potentially improving clinical outcomes compared with existing approaches.

Early findings discussed in the interview are encouraging. O’Cearbhaill noted that some patients have experienced meaningful and durable responses, supporting the biologic rationale behind bispecific antibody strategies. The study includes multiple modules evaluating different combinations, with dose escalation completed in some cohorts and ongoing in others. These efforts are helping to establish the recommended dosing strategies for future expansion phases.

Importantly, the trial is also closely evaluating safety and tolerability. Strategies such as step-up dosing, staggered administration of combination agents, and the use of prophylactic interventions are being incorporated to mitigate potential adverse effects. These approaches are critical for safely delivering combination immunotherapy regimens in a patient population that often has limited treatment options.

Overall, the emerging data suggest that REGN5668-based combinations may represent a promising new direction in the treatment of recurrent gynecologic cancers. While the study is still ongoing, the early signals of activity and manageable safety profile provide a strong foundation for further clinical development and future combination strategies.