Abstract
Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.
Highlights
Colorectal cancer (CRC) represents the third most common cancer worldwide and the second cause of cancer-related death [1,2]
Patients with metastatic CRC (mCRC), Eastern Cooperative Oncology Group (ECOG) Performance status (PS) 0–2, who had progressed within 4 weeks to a bevacizumab plus standard first-line chemotherapy and who were not candidates for primary metastasectomy were included in this trial
VELOUR was an international, double-blinded, phase III trial in which 1226 patients with mCRC, who had progressed to oxaliplatin-based first-line treatment, were randomized to receive either combination of FOLFIRI plus aflibercept or FOLFIRI plus placebo
Summary
Colorectal cancer (CRC) represents the third most common cancer worldwide and the second cause of cancer-related death [1,2]. MSI-H and immune activation (14%); CMS2, with canonical CRC alterations (37%); CMS3, with metabolic dysregulation (13%); and CMS4, with mesenchymal features (23%) [22,34] Those subtypes reflect distinct biological states and have been shown to be both prognostic for OS and predictive for benefit from cetuximab and bevacizumab in the CALGB 80405 and AIO-FIRE3 trials. Patients classified as CMS1 appear to derive more benefit from bevacizumab, while those classified CMS2 appear to derive more benefit from cetuximab [35,36] In this intricate scenario, a therapeutic sequential strategy using the most effective combinations of chemotherapy and target agents both in first- and second-line settings is desirable to maximize patient outcomes. We discuss the potential rationale supporting the use of sequential strategies, using the available agents after first-line therapy
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