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

Abstract

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.

Circulating Tumor DNA Is Capable of Monitoring the Therapeutic Response and Resistance in Advanced Colorectal Cancer Patients Undergoing Combined Target and Chemotherapy

“…Therefore, ctDNA detection appeared to be a useful method for the molecular genotyping and sensitive for monitoring mutational status, which potentially helps to develop treatment strategy targeting actionable variations. Our observations were supported by several previous reports focusing on the monitoring capability of NGS-based liquid biopsy in late-stage CRC therapy (4,(19)(20)(21)(22)(23)(24). However, the regimes used in these studies varied according to different situation.…”

“…However, the regimes used in these studies varied according to different situation. Some studies focused on the monitoring of cetuximab-based therapy for RAS wild type patients (19)(20)(21), while others emphasize the monitoring of multiple targets, including EGFR, HER2, SMAD4, and NF1 (4, 21-23). Interestingly, one study investigated the ability of both mutation and methylation markers in monitoring (24).…”

Population-based SEER analysis of survival in colorectal cancer patients with or without resection of lung and liver metastases

“…These therapeutic concepts are well approved in large randomized trials in the first line as well second line settings [11,28]. As refractory patients will be seen more frequently in sequential treatment of mCRC re-challenge concepts have been investigated with promising results [29,30].…”

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

“…It was found that 21% of patients responded to irinotecan plus cetuximab in the third-line setting, suggesting that the sensitivity to the anti-EGFR antibody was restored over the period of subsequent therapy. The mechanism underlying this loss of resistance is unknown, but the second-line chemotherapy in the absence of cetuximab might play a key role [66]. To date, most anti-HER2 agents, which failed to show clinical benefit, have been examined in the second-line setting, and little is known about their efficacy in the third-or later-line setting.…”