Exceptional Response to Lenvatinib plus Pembrolizumab after Pembrolizumab Failure in MLH1-Methylated dMMR/MSI-High Endometrial Cancer: A Case Report

Endometrial cancer with deficient mismatch repair (dMMR) is a promising target for immune checkpoint inhibitor (ICI) therapy. However, dMMR tumors are heterogeneous, and those with MLH1 promoter methylation respond less favorably to pembrolizumab monotherapy than Lynch syndrome-associated cases. Evidence for optimal treatment strategies in pembrolizumab-refractory dMMR tumors remains limited. Case Presentation: We report a woman in her 50s with recurrent endometrial carcinoma who was initially treated with surgery for stage IA, grade 1 endometrioid carcinoma. After recurrence with peritoneal dissemination and liver metastases, she received paclitaxel plus carboplatin with temporary response, followed by pembrolizumab monotherapy after detection of MSI-high status. However, disease progression occurred after two cycles. Immunohistochemistry revealed loss of MLH1 and PMS2 expression, and EPM2AIP1 immunohistochemistry suggested MLH1 promoter methylation. Given her preserved performance status, Lenvatinib plus pembrolizumab (LP) therapy was initiated. Tumor markers, including CA125, decreased rapidly. Radiological assessments demonstrated marked shrinkage of peritoneal and liver metastases, with a durable response lasting at least six months. Adverse events, including stomatitis, hand–foot syndrome, arthritis, hypothyroidism, anorexia, fatigue, and fever, were manageable with supportive care and dose modification. Conclusion: This case illustrates that LP therapy can achieve a favorable response in dMMR endometrial cancer with MLH1 promoter methylation after pembrolizumab failure. Further studies are warranted to clarify the biology of methylated dMMR tumors, establish individualized treatment strategies, and develop practical diagnostic systems to identify MLH1 promoter methylation.