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Neoadjuvant Treatment of Fulzerasib Plus Cetuximab N01 in KRAS G12C Mutated Locally Advanced Colorectal Cancer With or Without Resectable Metastases
Sponsor: Zhejiang University
Summary
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.
Key Details
Gender
All
Age Range
18 Years - 85 Years
Study Type
INTERVENTIONAL
Enrollment
40
Start Date
2026-04-30
Completion Date
2031-12
Last Updated
2026-05-12
Healthy Volunteers
No
Interventions
fulzerasib; cetuximab N01
Eligible subjects will receive neoadjuvant therapy comprising fulzerasib ((qd, po, d1-28) and cetuximab N01 (500 mg/m², IV, q2w) for two months
Locations (1)
Second Affiliated Hospital, Zhejiang University School of Medicine
Hangzhou, Zhejiang, China