Second-line regorafenib for advanced RAS-mutant colorectal cancer

Regorafenib as Second-line Treatment of Patients With RAS-mutant Advanced Colorectal Cancer: a Multicentre, Phase 2 Study

This trial will test whether regorafenib given as a less-intensive, personalized second-line option can preserve quality of life and extend survival for people with RAS‑mutant metastatic colorectal cancer who had a long first-line benefit or have only one metastatic site.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: National Cancer Institute, Naples (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy
• Locations: 1 site (Naples, Italy)
• Trial ID: NCT07213570 on ClinicalTrials.gov

What this trial studies

STREAM-2 is an open-label, randomized, multicenter phase 2 trial enrolling 60 patients with RAS‑mutant metastatic colorectal cancer who progress after first-line therapy but have favorable prognostic features (PFS > 6 months in first line and/or a single metastatic site). Patients are randomized 1:1 to receive either regorafenib with a dose‑escalation strategy given in 4-week cycles or a standard second-line treatment chosen by the investigator given in 2-week cycles. Tumor measurements are documented at baseline and reassessed regularly (every 8 weeks), and patients continue treatment until progression, unacceptable toxicity, or other discontinuation criteria. All patients enter follow-up after treatment and are followed until death with subsequent therapies recorded.

Who should consider this trial

Good fit: Ideal candidates are adults with histologically confirmed metastatic RAS‑mutant colorectal adenocarcinoma who progressed after first-line therapy but had PFS > 6 months or have only one metastatic site, with ECOG ≤ 1, measurable disease, and adequate organ function.

Not a fit: Patients with rapidly progressive disease, multiple metastatic sites, poor performance status, non‑RAS tumors, or inadequate organ function are unlikely to benefit from this less-intensive regorafenib strategy.

Why it matters

Potential benefit: If successful, this approach could offer a less intensive, oral second-line option that helps maintain quality of life while potentially extending survival for a selected group of patients.

How similar studies have performed: Regorafenib has shown modest survival benefit in refractory mCRC, but using it earlier as a personalized, less-intensive second-line approach for this favorable-prognosis subgroup is relatively novel and not yet well proven.

Eligibility criteria

Inclusion Criteria:

1. Written informed consent to study procedures and to correlative studies.
2. Either sex aged ≥ 18.
3. Histologically proven of colorectal adenocarcinoma.
4. Diagnosis of metastatic disease.
5. RAS mutant at initial diagnosis assessed at local centers according with a validated method defined by EMA and known MMR/MSI status.
6. Achieved a PFS in first line \> 6 months with chemotherapy in combination to antiangiogenic treatment OR with one metastatic site at study entry
7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry.
8. Imaging-documented measurable disease, according to RECIST 1.1 criteria.
9. Estimated life expectancy of more than 12 weeks
10. Adequate bone marrow hematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L and hemoglobin ≥ 9 g/dL.
11. Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 2 (in case of biliary stent) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5 X ULN.
12. Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥50 mL/min in females (calculated according to Cockroft-Gault formula).
13. Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range.
14. Known dihydropyrimidine dehydrogenase (DPYD) activity is mandatory. Additional analysis of polymorphisms uridine diphosphate-glycosyltransferase 1 (UGT1A1) enzyme is recommended but not mandatory.

Exclusion Criteria:

1. Prior malignancy within five years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
2. Any contraindication to regorafenib.
3. Not received immunotherapy if dMMR or MSI-H.
4. Major surgical intervention within 4 weeks prior to enrollment.
5. Pregnancy and breast-feeding.
6. Any brain metastasis.
7. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study.
8. History of poor co-operation, non-compliance with medical treatment, unreliability or any condition that may impair the patient's understanding of the Informed consent form.
9. Participation in any interventional drug or medical device study within 30 days prior to treatment start.
10. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment.
11. Complete deficiency of activity of dihydropyrimidine dehydrogenase (DPYD)

Where this trial is running

Naples, Italy

• Istituto Nazionale Tumori | "Fondazione Pascale" — Naples, Italy, Italy (Recruiting)

Study contacts

• Study coordinator: Antonio Avallone, MD

Conditions Colorectal Cancer Metastatic; metastatic colorectal cancer; liquid biopsy; Regorafenib; RAS-mutation