Unlocking New Treatment Possibilities for Metastatic Endometrial Cancer With KRAS G12C Mutation

Endometrial carcinoma (EC) is a heterogeneous malignancy with diverse molecular subtypes that influence prognosis and treatment response. While conventional therapies such as surgery, chemotherapy, and radiation remain the mainstay of treatment, recurrent and metastatic EC poses significant therapeutic challenges, particularly in aggressive histologic subtypes like clear cell carcinoma. Advances in genomic profiling have revealed that KRAS mutations occur in approximately 10%-30% of EC cases, with the KRAS G12C variant representing a rare but potentially targetable alteration. KRAS G12C inhibitors, including sotorasib and adagrasib, have revolutionized the treatment landscape for certain malignancies, particularly non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), where they have received FDA approval. The efficacy of these agents in other KRAS G12C-mutated solid tumors remains under investigation, with limited clinical data available in endometrial cancer. To date, only three documented cases have reported responses to KRAS G12C inhibitors in EC, highlighting the need for further exploration of targeted strategies in this setting. Here, we present a unique case of a 77-year-old woman with metastatic endometrial clear cell carcinoma who exhibited a durable response to adagrasib after progressing on multiple lines of standard treatment. This case highlights the potential clinical utility of KRAS G12C inhibitors in EC and highlights the importance of molecular profiling in identifying actionable mutations that may guide treatment decisions. This report, contributing to the limited body of evidence that includes three prior cases evaluating the role of sotorasib and adagrasib across several solid malignancies, highlights the clinical and translational relevance of adagrasib in advancing precision-targeted therapy for KRAS G12C-mutated tumors.