Background：KRAS mutations are the most common genetic alterations in colorectal cancer (CRC), associated with aggressive tumor biology and poor prognosis. For metastatic CRC harboring KRAS mutations, first-line standard treatment is chemotherapy plus bevacizumab. However, its anti-angiogenic effects contraindicate perioperative use. KRAS G12C, the first druggable KRAS target, accounts for \~3% of CRC KRAS mutations. KRAS G12C inhibitor monotherapy shows efficacy in post-standard-therapy metastatic CRC, while combination with RAS-MAPK pathway blockade demonstrates superior efficacy. Based on promising frontline data combining KRAS G12C inhibitors with anti-EGFR antibodies in metastatic CRC, we evaluate neoadjuvant fulzerasib plus cetuximab N01 in locally advanced KRAS G12C-mutated CRC, with or without resectable metastases.
Methods：Single-arm, multicenter, phase II trial (N=40). Eligibility: age 18-80 years, ECOG 0-1, histologically confirmed colorectal adenocarcinoma (stages T4N0-2M0, T3N2M0, T0-4N0-2M1a \[resectable metastases confirmed by multidisciplinary discussion\]), KRAS G12C mutation, NRAS/BRAF wild-type, pMMR/MSS. Neoadjuvant therapy: fulzerasib (qd, po, d1-28) plus cetuximab N01 (500 mg/m², IV, q2w) for 2 months. Safety assessments (CBC, liver/renal function, QoL) every 2 weeks; CEA monthly. Tumor response assessed by CT chest/abdomen and rectal MRI at 2 months. Radical surgery for responders (cCR patients may choose watchful waiting). Adjuvant therapy per pathological response. Follow-up: CEA every 3 months, CT every 6 months. Primary endpoint: overall response rate (pCR or cCR). Secondary endpoints: ORR, 1-year DFS, 3-year DFS, QoL. RECIST v1.1 for disease assessment; NCI-CTCAE v5.0 for adverse events.
Hypothesis：This chemotherapy-free neoadjuvant regimen combining a KRAS G12C inhibitor with cetuximab N01 may enhance perioperative safety and improve prognosis and quality of life in patients with KRAS G12C-mutated CRC.
The subjects voluntarily joined this study, signed an informed consent form, and showed good compliance;
Age: 18-80 years old, PS score 0-1;
Colorectal adenocarcinoma diagnosed by histopathology, preoperative staging: T4N0-2M0, T3N2M0, T0-4N0-2M1a (with metastatic lesions present, requiring MDT evaluation as resectable); PMMR/MSS, KRAS G12C mutation, and both NRAS and BRAF wild-type
Locally advanced colorectal cancer requires initial diagnosis of patients who have not received systematic treatment in the past. Patients with resectable metastatic lesions are required to have not received targeted therapy in the past, and new metastases after adjuvant therapy can be included in this study.
Patients with MSI-H/dMMR present;
Patients with multiple metastases that cannot be resected;
Patients with active inflammatory bowel disease within the first 4 weeks of enrollment;
Uncontrollable pleural effusion, pericardial effusion, or ascites that require repeated drainage;
Zhejiang University
Lead sponsor
Second Affiliated Hospital, School of Medicine, Zhejiang University
Sponsor institution