Durable Response to Sotorasib Plus Panitumumab in NRAS G12C-Mutated, Microsatellite Instability-High (MSI-H) Rectal Cancer Refractory to Immunotherapy

Oncogenic Rat sarcoma (RAS) mutations are common drivers of solid tumors, yet for decades they were regarded as “undruggable.” The development of mutation-specific Kirsten Rat sarcoma viral oncogene homolog (KRAS) G12C inhibitors such as sotorasib has challenged this paradigm and demonstrated clinical activity in KRAS G12C-driven cancers. Neuroblastoma RAS viral oncogene homolog (NRAS) G12C mutations are exceptionally rare in colorectal cancer, and their therapeutic vulnerability remains undefined. Here, we report an objective tumor response to the combination of the KRAS G12C inhibitor sotorasib and epidermal growth factor receptor (EGFR) blockade in a patient with advanced, NRAS G12C-mutated, mismatch repair-deficient rectal adenocarcinoma who developed a local recurrence after neoadjuvant therapy and surgery and subsequently experienced disease progression despite multiple lines of systemic treatment, achieving a durable clinical response lasting more than twelve months. This case provides real-world evidence that NRAS G12C mutations may confer sensitivity to G12C inhibitors combined with EGFR blockade. Molecular testing should include NRAS and Harvey rat sarcoma viral oncogene homolog (HRAS) isoforms.