Case Report: triple therapy with pembrolizumab, ipilimumab, and lenvatinib in mitotane- and radiation-refractory, cortisol-secreting stage IV adrenocortical carcinoma: a genomically guided approach.

Adrenocortical carcinoma (ACC) is a rare malignancy with limited therapeutic options following the failure of standard adjuvant therapies. We present a 54-year-old female with stage IV cortisol-secreting ACC that progressed despite radical adrenalectomy, adjuvant radiation, and mitotane therapy. Comprehensive genomic profiling revealed a complex molecular landscape: a "double hit" driving hypercortisolism (GNAS activation and HSD11B2 alteration) and a high tumor mutational burden (11.6 mutations/megabase) driven by converging instability mechanisms (MSH6, TP53, DAXX, DNMT3A, and KMT2A somatic mutations, and TOP2A overexpression), despite stable microsatellite status. Guided by this profile, a salvage regimen of pembrolizumab, ipilimumab and lenvatinib was initiated. The patient achieved a profound clinical response with resolution of Cushing's syndrome and induction of adrenal insufficiency. Follow-up 18F-FDG PET/CT confirmed a sustained partial response per response evaluation criteria in solid tumors (RECIST) 1.1, accompanied by significant metabolic improvement with regression of metastatic burden with evident central photopenia in peritoneal lesions. This case illustrates how multi-faceted genomic analysis can rationalize aggressive combination immunotherapy in refractory ACC.