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

Обзор

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.

Вмешательства

• Препарат 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

Первичные конечные точки

• overall response rate [Срок оценки: 1 year]

Вторичные конечные точки (3)

• objective response rate [Срок оценки: 1 year]
• 1-year disease -free survival rate [Срок оценки: 1 year]
• 3-year disease -free survival rate [Срок оценки: 3 years]

Критерии участия

Критерии включения

• 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:

• 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;
• 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.
• 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%.

Критерии исключения

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:

• 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 \[Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor infiltrating basement membrane)\];

• Patients with active inflammatory bowel disease within the first 4 weeks of enrollment;
• Uncontrollable pleural effusion, pericardial effusion, or ascites that require repeated drainage;
• Unrelieved toxic reactions above CTCAE grade 1 caused by any previous anti-tumor treatment (excluding hair loss and ≤ grade 2 neurotoxicity caused by oxaliplatin);
• 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;
• 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;
• Individuals with a history of substance abuse involving psychotropic drugs who are unable to quit;
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Second Affiliated Hospital, Zhejiang University School of Medicine — Ханчжоу

Публикации

• 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).
• 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. PMID 38177853
• 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 t PMID 40715048
• 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. PMID 36546659
• 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 PMID 34919824
• 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 Anal PMID 37098232
• 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. PMID 34542636

Идентификаторы

NCT: NCT07581912 · FALCO

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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