FOLFIRI with cetuximab versus bevacizumab for left-sided metastatic colorectal cancer when tumor is RAS/BRAF wild-type but blood shows RAS mutations

Phase III Study in mCRC Patients With RAS/BRAF Wild Type Tissue and RAS Mutated in LIquid BIopsy to Compare in First-line Therapy FOLFIRI Plus CetuxiMAb or BevacizumaB (LIBImAb Study)

This trial tests whether giving bevacizumab plus FOLFIRI instead of cetuximab plus FOLFIRI, or switching early to bevacizumab when RAS mutations appear in blood, helps people with left-sided metastatic colorectal cancer whose tumor tissue is RAS/BRAF wild-type but whose liquid biopsy shows RAS mutations.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 280 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Azienda USL Reggio Emilia - IRCCS (Government)
• Drugs / interventions: Cetuximab, Bevacizumab, chemotherapy
• Locations: 4 sites (Coppito, L'Aquila and 3 other locations)
• Trial ID: NCT04776655 on ClinicalTrials.gov

What this trial studies

This is a prospective, randomized Phase 3 trial using serial liquid biopsies to guide first-line antibody choice with FOLFIRI in left-sided metastatic colorectal cancer. Patients who have RAS mutations on their initial liquid biopsy are randomized 1:1 to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab. Patients who are RAS wild-type on the first liquid biopsy start FOLFIRI plus cetuximab and undergo a second liquid biopsy after 8 cycles; if RAS mutations emerge without clinical or radiologic progression they are randomized 1:1 to continue cetuximab or switch to bevacizumab. Plasma KRAS/NRAS and BRAF V600 mutations are tested using the Idylla system, and treatment continues until progression, unacceptable toxicity, withdrawal, or other safety concerns. The primary outcome is progression-free survival.

Who should consider this trial

Good fit: Adults with unresectable, left-sided metastatic colorectal adenocarcinoma that is RAS/BRAF wild-type on tumor tissue, who are chemotherapy‑naïve for metastatic disease, eligible for first-line FOLFIRI, have measurable disease, and ECOG performance status up to 2 are ideal candidates.

Not a fit: Patients whose tumor tissue already harbors RAS or BRAF mutations, those previously treated for metastatic colorectal cancer, or those with right-sided primary tumors are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could prolong progression-free survival by using blood-based RAS testing to choose or change the antibody given with FOLFIRI.

How similar studies have performed: Prior work has shown that RAS mutations detected in blood predict resistance to anti‑EGFR therapy and that anti‑VEGF therapy is an effective alternative, but using serial liquid biopsy to guide an early switch is a relatively novel strategy with limited phase‑III proof to date.

Eligibility criteria

Inclusion Criteria:

1. Provision of written informed consent;
2. Male or female \> 18 years of age;
3. Histologically confirmed diagnosis of colorectal adenocarcinoma RAS/BRAF wild type (analysed either on primary and/or related metastasis);
4. Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease;
5. Patient with left colorectal cancer;
6. Patients suitable for first line chemotherapy;
7. Life expectancy \> 3 months;
8. At least one site of measurable disease per RECIST criteria ver. 1.1;
9. ECOG Performance status = 2;
10. Adequate bone marrow, liver and renal function assessed before starting study treatment;
11. If DPD status is known it must be wild type. No restrictions are applied if DPD status in unknown;
12. Women of childbearing potential must have a negative blood pregnancy test within 24 hr prior to the start of study treatment. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive.
13. Subjects and their partners must be willing to avoid pregnancy during the trial and until 5 months for WOCBP (Women of Childbearing Potential) and 7 months for male subjects with female partners of WOCBP after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator (barriers contraceptive measure or oral contraception).

Exclusion Criteria:

1. Previous chemotherapy treatment, with the exception of patient treated in adjuvant setting completed at least 6 months before the randomization;
2. Any contraindication to the use of Cetuximab, Bevacizumab, Irinotecan, 5FU or folinic acid;
3. Radiotherapy to any site within 4 weeks before the randomization;
4. Serious, non-healing wound, ulcer, or bone fracture;
5. Evidence of bleeding diathesis or coagulopathy;
6. Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy;
7. Additional malignancy in the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy;
8. Active and untreated brain (CNS) metastases and/or carcinomatous meningitis;
9. Active infection requiring systemic therapy or active disseminated intravascular coagulation;
10. History of Human Immunodeficiency Virus (HIV) (HIV 1/2 antobodies);
11. Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection;
12. Chronic, daily treatment with high-dose aspirin (\>325 mg/day);
13. Any previous venous thromboembolism \> NCI CTCAE Grade 3;
14. History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment. History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea;
15. Current, recent (within 10 days prior to study treatment start) or ongoing treatment with anticoagulants for therapeutic purposes;
16. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study;
17. History of any severe hypersensitivity reactions to any monoclonal antibody;
18. A significant concomitant disease which, in the investigating physician's opinion, rules out the patient's participation in the study

Where this trial is running

Coppito, L'Aquila and 3 other locations

• Ospedale San Salvatore — Coppito, L'Aquila, Italy (Recruiting)
• Ospedale Civile di Guastalla — Guastalla, Reggio Emilia, Italy (Recruiting)
• AUSL/IRCCS di Reggio Emilia — Reggio Emilia, Reggio Emilia, Italy (Recruiting)
• Azienda ULSS 3 Serenissima — Mirano, Ve, Italy (Recruiting)

Study contacts

• Study coordinator: Carmine Pinto, MD

Conditions Colorectal Cancer; Metastatic Colorectal Cancer; RAS Mutation; mCRC; liquid biopsy; RAS