Neoadjuvant Treatment of Fulzerasib Plus Cetuximab N01 in KRAS G12C Mutated Locally Advanced Colorectal Cancer With or Without Resectable Metastases (FALCO)

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; KRAS G12C Mutant Advanced Solid Tumors; Fulzerasib; Cetuximab N01
• Intervention / Treatment: Drug: fulzerasib; cetuximab N01

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kefeng Ding, PhD; Phone Number: 86-571-87784720; Email: dingkefeng@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310000
      • Recruiting
      • Second Affiliated Hospital, Zhejiang University School of Medicine
      • Contact: Kefeng Ding, PhD; Phone Number: 86-571-87784827; Email: dingkefeng@zju.edu.cn
      • Principal Investigator: Kefeng Ding, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.

• The main organ functions well and meets the following criteria:

  1. Blood routine examination criteria (corrected for no blood transfusion or use of hematopoietic stimulating factor drugs within 7 days before screening): hemoglobin (HGB) ≥ 90g/L (if chronic anemia is caused by chronic blood loss from the tumor and the researcher evaluates the stability of vital signs, it can be included in the group); absolute neutrophil count (NEUT) ≥ 1.5 × 109/L; platelet count (PLT) ≥ 75 × 109/L;
  2. Biochemical tests must meet the following standards: total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN) (Gilbert syndrome subjects, ≤ 3 × ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 ULN; serum creatinine (CR) ≤ 1.5ULN or creatinine clearance rate (CCR) ≥ 50ml/min.
  3. Coagulation or thyroid function tests must meet the following criteria: prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5 × ULN (without anticoagulant therapy); thyroid stimulating hormone (TSH) ≤ ULN; If there are abnormalities, T3 and T4 levels should be examined (if there is no T3 in the center, T4 can be replaced by FT3 and FT4), and if the level is normal, it can be selected.
• Cardiac ultrasound evaluation: Left ventricular ejection fraction (LVEF) ≥ 50%.

Exclusion Criteria:

Those who meet any of the following criteria will not be included in this trial:

• Patients with MSI-H/dMMR present;
• Patients with multiple metastases that cannot be resected;

• Combined diseases and medical history:

  1. Has had or is currently suffering from other malignant tumors within the past 3 years. The following situations can be included in the group:

     Cured cervical carcinoma in situ, non melanoma skin cancer, and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor infiltrating basement membrane)];

  2. Patients with active inflammatory bowel disease within the first 4 weeks of enrollment;
  3. Uncontrollable pleural effusion, pericardial effusion, or ascites that require repeated drainage;
  4. Unrelieved toxic reactions above CTCAE grade 1 caused by any previous anti-tumor treatment (excluding hair loss and ≤ grade 2 neurotoxicity caused by oxaliplatin);
  5. Within 4 weeks prior to the start of the study, any bleeding events ≥ CTCAE grade 3 occurred in patients with unhealed wounds, ulcers, or fractures;
  6. History of arterial/venous thrombotic events within 6 months, such as cerebrovascular accidents (including transient ischemic attacks, intracerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;
  7. Individuals with a history of substance abuse involving psychotropic drugs who are unable to quit;
  8. Subjects with any severe and/or uncontrolled diseases, including: uncontrolled hypertension (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg despite standard antihypertensive treatment); myocardial ischemia or myocardial infarction ≥grade 2, arrhythmia (QTc ≥450 ms in males, QTc ≥470 ms in females, and ≥grade 2 congestive heart failure (New York Heart Association (NYHA) classification); active or uncontrolled severe infections (≥CTC AE grade 2 infection); cirrhosis, active hepatitis*; (*Active hepatitis [Hepatitis B reference: HBsAg positive and HBV DNA positive (>2500 copies/mL or >500 IU/mL); Hepatitis C reference: HCV antibody positive and HCV viral load exceeding the upper limit of normal] Note: For subjects meeting enrollment criteria, those with hepatitis B surface antigen positive or hepatitis B core antibody positive, or hepatitis C patients, must receive continuous antiviral treatment to prevent viral activation); renal failure requiring hemodialysis or peritoneal dialysis; history of immunodeficiency, including HIV positive or other acquired or congenital immunodeficiency diseases, or organ transplantation history; poorly controlled diabetes (fasting blood glucose (FBG) >10 mmol/L); urinalysis indicating proteinuria ≥++, and confirmed 24-hour urine protein quantification >1.0g; a history of confirmed neurological or psychiatric disorders requiring treatment, including epilepsy or dementia.
• Tumor-related symptoms and treatment: Previously received targeted drug therapy (including G12C inhibitors, bevacizumab, etc.);
• According to the investigator's judgment, subjects with serious diseases that pose a significant risk to their safety or affect the completion of the study, or those deemed ineligible for enrollment due to other reasons.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; neoadjuvant therapy with fulzerasib and cetuximab N01	Drug: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall response rate	the proportion of patients achieving pCR or cCR after neoadjuvant therapy	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
objective response rate	the proportion of participants with a best overall response of either CR or PR	1 year
1-year disease -free survival rate	the proportion of participants who are alive and free of disease recurrence or metastasis at 1 year after randomization	1 year
3-year disease -free survival rate	the proportion of participants who are alive and free of disease recurrence or metastasis at 3 years after randomization	3 years

Collaborators and Investigators

• Sponsor: Zhejiang University
• Investigators: Principal Investigator: Kefeng Ding, PhD, Second Affiliated Hospital, Zhejiang University School of Medicine

Publications and helpful links

General Publications

• Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016 Mar-Apr;66(2):115-32. doi: 10.3322/caac.21338. Epub 2016 Jan 25.
• Fakih MG, Kopetz S, Kuboki Y, Kim TW, Munster PN, Krauss JC, Falchook GS, Han SW, Heinemann V, Muro K, Strickler JH, Hong DS, Denlinger CS, Girotto G, Lee MA, Henary H, Tran Q, Park JK, Ngarmchamnanrith G, Prenen H, Price TJ. Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol. 2022 Jan;23(1):115-124. doi: 10.1016/S1470-2045(21)00605-7. Epub 2021 Dec 15.
• Dy GK, Govindan R, Velcheti V, Falchook GS, Italiano A, Wolf J, Sacher AG, Takahashi T, Ramalingam SS, Dooms C, Kim DW, Addeo A, Desai J, Schuler M, Tomasini P, Hong DS, Lito P, Tran Q, Jones S, Anderson A, Hindoyan A, Snyder W, Skoulidis F, Li BT. Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated KRAS G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100. J Clin Oncol. 2023 Jun 20;41(18):3311-3317. doi: 10.1200/JCO.22.02524. Epub 2023 Apr 25.
• Kuboki Y, Fakih M, Strickler J, Yaeger R, Masuishi T, Kim EJ, Bestvina CM, Kopetz S, Falchook GS, Langer C, Krauss J, Puri S, Cardona P, Chan E, Varrieur T, Mukundan L, Anderson A, Tran Q, Hong DS. Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial. Nat Med. 2024 Jan;30(1):265-270. doi: 10.1038/s41591-023-02717-6. Epub 2024 Jan 4.
• Rona Yaeger et al. A phase 1b study of sotorasib combined with panitumumab as second-line treatment of KRAS G12C-mutated colorectal cancer. JCO 42, 128-128(2024).
• Ying Yuan et al. Efficacy and safety of IBI351 (GFH925) monotherapy in metastatic colorectal cancer harboring KRASG12C mutation: Preliminary results from a pooled analysis of two phase I studies. JCO 41, 3586-3586(2023).
• Yuan Y, Deng Y, Jin Y, Guo Z, Pan Y, Wang C, Wang Z, Hu Y, Hua D, Meng X, Zhang Z, Zhao M, Dong X, Huang D, Li X, Liu L, Sun M, Wang H, Wang X, Yang N, Zhang M, Hu S, Wu D, Huang J, Zhang S, Huang M, Ding K. Efficacy and safety of IBI351 (fulzerasib) monotherapy in KRASG12C inhibitor-naive Chinese patients with KRASG12C-mutated metastatic colorectal cancer: a pooled analysis from phase I part of two studies. Signal Transduct Target Ther. 2025 Jul 25;10(1):241. doi: 10.1038/s41392-025-02315-7.
• Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M, Ou SI, Leal TA, Bekaii-Saab TS, Paweletz CP, Heavey GA, Christensen JG, Velastegui K, Kheoh T, Der-Torossian H, Klempner SJ. Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. N Engl J Med. 2023 Jan 5;388(1):44-54. doi: 10.1056/NEJMoa2212419. Epub 2022 Dec 21.
• Formica V, Sera F, Cremolini C, Riondino S, Morelli C, Arkenau HT, Roselli M. KRAS and BRAF Mutations in Stage II and III Colon Cancer: A Systematic Review and Meta-Analysis. J Natl Cancer Inst. 2022 Apr 11;114(4):517-527. doi: 10.1093/jnci/djab190.
• Prior IA, Hood FE, Hartley JL. The Frequency of Ras Mutations in Cancer. Cancer Res. 2020 Jul 15;80(14):2969-2974. doi: 10.1158/0008-5472.CAN-19-3682. Epub 2020 Mar 24.
• Global Burden of Disease Cancer Collaboration; Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, Dicker DJ, Chimed-Orchir O, Dandona R, Dandona L, Fleming T, Forouzanfar MH, Hancock J, Hay RJ, Hunter-Merrill R, Huynh C, Hosgood HD, Johnson CO, Jonas JB, Khubchandani J, Kumar GA, Kutz M, Lan Q, Larson HJ, Liang X, Lim SS, Lopez AD, MacIntyre MF, Marczak L, Marquez N, Mokdad AH, Pinho C, Pourmalek F, Salomon JA, Sanabria JR, Sandar L, Sartorius B, Schwartz SM, Shackelford KA, Shibuya K, Stanaway J, Steiner C, Sun J, Takahashi K, Vollset SE, Vos T, Wagner JA, Wang H, Westerman R, Zeeb H, Zoeckler L, Abd-Allah F, Ahmed MB, Alabed S, Alam NK, Aldhahri SF, Alem G, Alemayohu MA, Ali R, Al-Raddadi R, Amare A, Amoako Y, Artaman A, Asayesh H, Atnafu N, Awasthi A, Saleem HB, Barac A, Bedi N, Bensenor I, Berhane A, Bernabe E, Betsu B, Binagwaho A, Boneya D, Campos-Nonato I, Castaneda-Orjuela C, Catala-Lopez F, Chiang P, Chibueze C, Chitheer A, Choi JY, Cowie B, Damtew S, das Neves J, Dey S, Dharmaratne S, Dhillon P, Ding E, Driscoll T, Ekwueme D, Endries AY, Farvid M, Farzadfar F, Fernandes J, Fischer F, G/Hiwot TT, Gebru A, Gopalani S, Hailu A, Horino M, Horita N, Husseini A, Huybrechts I, Inoue M, Islami F, Jakovljevic M, James S, Javanbakht M, Jee SH, Kasaeian A, Kedir MS, Khader YS, Khang YH, Kim D, Leigh J, Linn S, Lunevicius R, El Razek HMA, Malekzadeh R, Malta DC, Marcenes W, Markos D, Melaku YA, Meles KG, Mendoza W, Mengiste DT, Meretoja TJ, Miller TR, Mohammad KA, Mohammadi A, Mohammed S, Moradi-Lakeh M, Nagel G, Nand D, Le Nguyen Q, Nolte S, Ogbo FA, Oladimeji KE, Oren E, Pa M, Park EK, Pereira DM, Plass D, Qorbani M, Radfar A, Rafay A, Rahman M, Rana SM, Soreide K, Satpathy M, Sawhney M, Sepanlou SG, Shaikh MA, She J, Shiue I, Shore HR, Shrime MG, So S, Soneji S, Stathopoulou V, Stroumpoulis K, Sufiyan MB, Sykes BL, Tabares-Seisdedos R, Tadese F, Tedla BA, Tessema GA, Thakur JS, Tran BX, Ukwaja KN, Uzochukwu BSC, Vlassov VV, Weiderpass E, Wubshet Terefe M, Yebyo HG, Yimam HH, Yonemoto N, Younis MZ, Yu C, Zaidi Z, Zaki MES, Zenebe ZM, Murray CJL, Naghavi M. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2017 Apr 1;3(4):524-548. doi: 10.1001/jamaoncol.2016.5688.

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2031

Study Registration Dates

• First Submitted: May 6, 2026
• First Submitted That Met QC Criteria: May 11, 2026
• First Posted (Actual): May 12, 2026

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 11, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: chemotherapy-free; fulzerasib; cetuximab N01; KRAS G12C mutant; locally advanced colorectal cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms
• Other Study ID Numbers: FALCO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No