Comparison of First-Line Therapy for Advanced Colorectal Cancer: Trifluridine/Tipiracil Combined with Panitumumab Versus Trifluridine/Tipiracil Combined with Bevacizumab

Colorectal cancer is a malignant disease caused by the uncontrolled proliferation of cells in the intestinal mucosa. If the colon or rectum is affected, it is referred to as colorectal carcinoma. If the disease has already spread to other organs, these secondary lesions are called metastases. In most cases, these metastases can no longer be surgically removed. A cure (curative treatment) is then no longer possible; therapy is limited to improving the patient’s condition and prolonging life (palliative care). Genetic testing of the tumor tissue is necessary to determine the appropriate treatment, as certain genetic alterations can lead to varying responses to available medications. For example, a mutation in the RAS gene can render so-called EGFR inhibitors, such as panitumumab, ineffective. The standard treatment for metastatic colorectal cancer consists of intensive chemotherapy in combination with targeted drugs. Depending on the genetic characteristics of the cancer cells, patients receive either bevacizumab—a drug that blocks the tumor’s blood supply and is used primarily in patients with RAS mutations or unknown RAS status— or chemotherapy with panitumumab or cetuximab—so-called EGFR inhibitors—which are effective only if the cancer cells do not have a mutation in the RAS gene (RAS wild-type). Bevacizumab and panitumumab are so-called antibodies and are also referred to as immunotherapies. Some patients are not suitable for intensive chemotherapy due to advanced age, comorbidities, or poor general health, or they refuse the treatment because of severe side effects. These patients then receive a reduced-intensity chemotherapy regimen with capecitabine (the tablet form of the chemotherapeutic agent 5-FU) in combination with bevacizumab. If cancer treatment is not an option, the alternative is purely supportive care to alleviate symptoms. If the disease continues to progress after treatment, there are additional treatment options that are tailored individually to each patient. If disease activity increases again after the initial treatment (first-line therapy), the patient is switched to a different drug or a different combination of drugs. In such a situation, for example, trifluridine/tipiracil is used or has already been approved for this purpose. Trifluridine acts as a cytotoxic agent, and tipiracil ensures that trifluridine is not broken down in the body.

The goal of the FIRE-8 study is to determine whether trifluridine/tipiracil, as a first-line therapy, could be a better-tolerated alternative to intensive chemotherapy, and it also tests whether the combination with bevacizumab or panitumumab is more effective. To this end, patients are randomly assigned to two groups. In Group 1 (Arm A), patients receive trifluridine/tipiracil in combination with panitumumab. These patients are compared with patients in Group 2 (Arm B), who receive trifluridine/tipiracil in combination with bevacizumab. Trifluridine/tipiracil is taken as a tablet; panitumumab and bevacizumab are administered as intravenous infusions. Treatment in both study arms is administered in 28-day cycles and is experimental—meaning it has not yet been approved for this indication. Patients and medical staff know which medications they are receiving; thus, the study is open-label. Treatment as part of the study continues until the disease progresses or until it is discontinued due to side effects. Follow-up as part of the study lasts for up to three years.

Women and men aged 18 and older who have metastatic colorectal cancer that can no longer be surgically removed are eligible to participate in the study. Only patients who do not have a RAS mutation (RAS wild-type) may participate. In addition, patients may only participate in the study if they are either unsuitable for intensive chemotherapy for medical reasons (e.g., due to age, comorbidities, or poor general health) or if they consciously decide against such treatment. Patients with brain metastases are excluded from participation. Prior treatment of the tumor is permitted only if it was administered at a stage of the disease when the cancer had not yet metastasized.