Advanced endometrial cancer (aEC) presents a formidable therapeutic challenge, particularly in patients with recurrent or metastatic disease. Historically, platinum-based chemotherapy is the mainstay treatment for aEC. However, the treatment paradigm has shifted with the emergence of immune checkpoint inhibitors (ICIs) and targeted therapies. Lenvatinib combined with pembrolizumab (LVB + PMB) has emerged as a promising regimen, particularly for patients with proficient mismatch repair (pMMR) tumors who typically respond poorly to ICI monotherapy. This review synthesizes recent data comparing LVB + PMB to chemotherapy, focusing on efficacy, safety, and molecular subtype-guided treatment selection. Findings from the KEYNOTE-775 and LEAP-001 trials are highlighted. We also delve into the molecular and immunologic landscape of aEC, providing a mechanistic rationale for treatment response and resistance. While LVB + PMB shows superior progression-free survival in second-line settings, its first-line application in unselected populations remains inconclusive. Therefore, strategic patient stratification and biomarker development remain key to maximizing clinical outcomes. Furthermore, we discuss the clinical implications of these findings, explore future research directions, including novel combinations and biomarkers, and provide recommendations for the evolving therapeutic landscape.
Alabi et al. (2025) studied this question.