Optimising the use of cetuximab in the continuum of care for patients with metastatic colorectal cancer.

The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in combination with chemotherapy is a standard of care in the first-line treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC) and has demonstrated efficacy in later lines. Progressive disease (PD) occurs when tumours develop resistance to a therapy, although controversy remains about whether PD on a combination of chemotherapy and targeted agents implies resistance to both components. Here, we propose that some patients may gain additional clinical benefit from the reuse of cetuximab after having PD on regimens including cetuximab in an earlier treatment line. We conducted a non-systematic literature search in PubMed and reviewed published and ongoing clinical trials, focusing on later-line cetuximab reuse in patients with mCRC. Evidence from multiple studies suggests that cetuximab can be an efficacious and tolerable treatment when continued or when fit patients with mCRC are retreated with it after a break from anti-EGFR therapy. Furthermore, on the basis of available preclinical and clinical evidence, we propose that longitudinal monitoring of RAS status may identify patients suitable for such a strategy. Patients who experience progression on cetuximab plus chemotherapy but have maintained RAS wt tumour status may benefit from continuation of cetuximab with a chemotherapy backbone switch because they have probably developed resistance to the chemotherapeutic agents rather than the biologic component of the regimen. Conversely, patients whose disease progresses on cetuximab-based therapy due to drug-selected clonal expansion of RAS- mutant tumour cells may regain sensitivity to cetuximab following a defined break from anti-EGFR therapy. Looking to the future, we propose that RAS status determination at disease progression by liquid, needle or excisional biopsy may identify patients eligible for cetuximab continuation and rechallenge. With this approach, treatment benefit can be extended, adding to established continuum-of-care strategies in patients with mCRC.
Competing Interests: Competing interests: RMG has declared no conflicts of interest. DS discloses advisory board membership for and honoraria for talks from Amgen, Janssen, Merck KGaA, Sanofi, Roche and Servier. PR and FA are employees of Merck KGaA, Darmstadt, Germany. ZAW discloses consultation for and honoraria from Lilly, Genentech and Novartis. JT discloses honoraria from Merck, Amgen, Roche, Celgene, Baxalta, Lilly, Servier and Sanofi. CM discloses advisory board membership for and honoraria for talks from Amgen, Merck KGaA, Roche, Sanofi, Servier and Symphogen. SaSi discloses advisory board membership for Amgen, Roche, Novartis, Ignyta, Bayer, Sanofi and Eli Lilly. SeSt discloses advisory role and honoraria for talks from Amgen, Bayer, Eli Lilly, Merck KGaA, Roche, Sanofi and Takeda.