Cholangiocarcinoma (CCA), a rare malignancy originating from bile duct epithelial cells, often presents a challenging prognosis due to its rarity, delayed diagnosis, and early recurrence post-curative-intent treatments. Additional complexities include difficulties in achieving R0 resection during surgical intervention and the lack of effective second-line treatments following the failure of first-line regimens, particularly in unresectable advanced cases.In this case study, we demonstrate a durable response to a combination regimen of pembrolizumab and lenvatinib in a patient with distal CCA. Despite the regimen’s interim median Progression-Free Survival (PFS) of 6.1 months (95% CI, 2.1-6.4), our patient achieved a clinical and radiological PFS of approximately two years. The underlying mechanisms, potentially involving the upregulation of immune response pathways through undisclosed means or influenced by lenvatinib’s activation of T cells, might augment the sensitivity to PD-1 antibodies like pembrolizumab, contributing to the patient’s sustained response over two years.This case also highlights the significance of the patient’s initial good health condition, multidisciplinary care, and the potential impact of molecular subtyping on treatment selection in a patient with distal CCA who underwent numerous diagnostic procedures, intricate surgical interventions, and subsequent treatment regimens over seven years. Additionally, we underscore significant landmark trials and emerging combination therapies, including chemotherapies, immunotherapy, and targeted treatments in this report.
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