Dual PD-1 and CTLA-4 targeting in endometrial carcinoma: integrating efficacy, toxicity, and biomarkers into clinical practice

The management of advanced endometrial cancer (EC) has been transformed by immunotherapy, raising a pivotal clinical challenge: selecting patients with mismatch repair-deficient (dMMR) disease for intensive dual PD-1/CTLA-4 blockade versus standard PD-1 monotherapy. We conducted a narrative review of phase II/III clinical trials and key translational studies published up to 2023 to critically appraise current evidence. In dMMR EC, the conventional ipilimumab-nivolumab combination yields higher objective response rates (ORR ≈ 63%) than PD-1 monotherapy (ORR ≈ 48%) but is associated with a substantially increased incidence of grade ≥ 3 immune-related adverse events (≈ 23% vs. ≈ 12%). The development of bispecific antibodies like cadonilimab, which demonstrates robust efficacy with a lower incidence of high-grade toxicity (grade ≥ 3 treatment-related adverse events: 8.3%), presents a promising strategy to improve the therapeutic index. For clinicians, the current decision-making process must be highly individualized, weighing factors such as tumor burden, pace of disease, and patient tolerance for toxicity in the absence of validated biomarkers to guide treatment intensity beyond dMMR status. We also addressed the critical importance of accurate MMR/MSI testing and the clinical implications of a well-documented methodological discordance rate. In contrast, for patients with mismatch repair-proficient (pMMR) tumors, the evidence firmly supports alternative regimens, such as lenvatinib plus pembrolizumab, over dual PD-1/CTLA-4 blockade. Navigating the evolving landscape of immunotherapy in EC requires a nuanced, patient-centric approach. The integration of novel bispecific antibodies may soon simplify the balance between efficacy and toxicity, but until then, treatment selection remains a deliberate process, underscoring the gynecologic oncologist's pivotal role in personalizing care.