Systemic Treatment Strategies Beyond Chemotherapy in Recurrent or Advanced Endometrial Cancer: A Systematic Review and Meta-Analysis

Introduction: Optimal systemic treatment for recurrent or advanced endometrial cancer (EC) remains uncertain, particularly in the second-line setting. While first-line chemotherapy with paclitaxel and carboplatin is widely used, its efficacy is limited. Recent evidence suggests that adding immune checkpoint inhibitors (ICIs) to chemotherapy (ChT) can improve progression-free survival (PFS). In addition, hormonal therapies (such as progestins and aromatase inhibitors), targeted therapies and ICIs used alone or in combination are emerging as potential treatment options. Objectives: Our objective was to systematically evaluate the efficacy and safety of systemic therapies beyond standard ChT for patients with recurrent or advanced EC, focusing on progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), prospective studies, and retrospective studies up to June 2024 on PubMed, Embase, and CENTRAL. Studies evaluating systemic therapies—chemotherapy, hormonal therapy, targeted agents, and ICIs—in recurrent or advanced EC were included. Primary outcomes were PFS and OS; secondary outcomes included grade ≥ 3 treatment-related adverse events. Risk of bias was assessed using the Cochrane RoB 2 and MINORS tools, and GRADE was applied to evaluate the certainty of evidence. Results: Five RCTs evaluated the addition of ICI to conventional ChT. In mismatch repair-deficient (MMRd) patients, the addition of ICI significantly improved PFS and OS compared to the ChT-only group. In mismatch repair-deficient (MMRd) patients, the median PFS (mPFS) was 8.39 months in the ChT group and 22.73 months in the ICI group (HR: 0.34, p < 0.001). OS results were 26.48 and 41.36 months, respectively. In mismatch repair-proficient (MMRp) patients, mPFS was 9.4 months in the ChT group and 10.18 months at the ICI group (HR: 0.72, p = 0.002). OS was 27.37 and 27.79 months, respectively. We conducted several exploratory single-arm subgroup analyses and multiple individual patient data (IPD) meta-analyses across several clinically relevant subgroups, including patients treated with progestins, lenvatinib plus pembrolizumab, PI3K/AKT/mTOR inhibitor monotherapy, and PI3K/AKT/mTOR inhibitors in combination with aromatase inhibitors. Detailed descriptive analyses were performed for each subgroup. Conclusions: Combining chemotherapy with ICIs appears to show the most favorable survival outcomes, especially in MMRd tumors. Taking into account the methodological limitations inherent in the elaboration of lower-level evidence and IPD, hormonal and targeted therapies might be considered viable options, with efficacy and safety profiles dependent on tumor biology. Better stratification of the EC patient cohort is warranted.