Abstract A072: KRAS G12C mutation and metastatic colorectal cancer: Are we ready for neo-adjuvant? A case report.

Abstract Background: KRAS G12C mutation (mut) represent a clinically actionable target in colorectal cancer (CRC), with emerging therapies offering new treatment avenues. The combination of adagrasib, a KRAS G12C inhibitor, and cetuximab, an anti-EGFR antibody, is currently approved for second-line treatment of metastatic CRC harboring this mutation. Despite this advancement, 5-fluorouracil (5-FU)-based chemotherapy remains the standard in upfront settings, as prior trials with anti-EGFR and anti-VEGF agents have failed to demonstrate significant benefit beyond metastatic disease. However, unlocking KRAS inhibition could change this paradigm, underscoring a critical unmet need in this patient population. Methods: We present the case of a 54-year-old woman with MSS, MMR-proficient rectal adenocarcinoma harboring a KRAS G12C mut, initially staged cT3cN2M0. She underwent to total neoadjuvant therapy with chemoradiation followed by FOLFOX and low anterior resection with diverting ileostomy, showing downstaging to ypT2N0. Surveillance identified early metastatic relapse to the liver and lung. She was started on FOLFOX with progression of disease and presented to our institution for a second opinion. In consideration of the KRAS G12C mut she was started on off-label adagrasib (600 mg BID) plus cetuximab (500 mg/m2 biweekly) as neoadjuvant therapy. Results: Following two months of targeted therapy, liver and lung metastases were resected. Pathology showed a complete and near complete pathologic response in the lung and liver metastases, respectively. Post-operative restaging showed no evidence of disease (NED), and ctDNA (Signatera) was negative. A growing nodule in the lung was later resected, confirming KRAS G12C on next-generation sequencing (NGS) without additional mutations. Post-operative CT showed a sub-centimeter lung nodule of unclear etiology, and she resumed adagrasib-cetuximab as “adjuvant” therapy. After four months and a radiographic complete response (CR), she discontinued therapy due to fatigue and rash. She remains in CR off treatments with full resolution of side effects. Conclusion: This case illustrates the effective use of adagrasib plus cetuximab as neoadjuvant and maintenance therapy in a patient with resectable metastatic KRAS G12C-mutated CRC. It raises the question of whether targeted therapy should be further explored in earlier treatment phases for select patients, especially those with limited response to standard chemotherapy. Citation Format: Sebastian N. Correa, Yun Shin Chun, Ara Vaporciyan, Scott Kopetz, M. Pia Morelli. KRAS G12C mutation and metastatic colorectal cancer: Are we ready for neo-adjuvant? A case report [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A072.