EGFR Ligand Expression Predicts Panitumumab Response in Advanced CRC

High expression levels of EGFR ligands epiregulin (EREG) and amphiregulin (AREG) are associated with increased benefit from panitumumab in patients with RAS wildtype advanced colorectal cancer, according to a new analysis. This could help guide treatment decisions in RAS wildtype patients with advanced colorectal cancer.

“For EGFR blockade to be effective, upregulation of EGFR signaling may be required in addition to an intact signal transduction pathway,” wrote study authors led by Matthew T. Seymour, MD, of St. James’s University Hospital in Leeds, United Kingdom. EREG and AREG are commonly overexpressed in colorectal cancer, and “ligand overexpression may be an indicator of tumor EGFR dependence.”

The current study was a preplanned retrospective biomarker analysis from the PICCOLO trial, which compared irinotecan alone to irinotecan along with panitumumab. Of the 696 PICCOLO patients, the new analysis included 323 patients with successful measurement of ligand expression. The results were published online ahead of print in JAMA Oncology.

The two EGFR ligands were highly co-expressed, with a correlation coefficient of 0.78 (P < .001). A total of 140 patients (43.3%) were found to be “high expressors,” meaning that expression of either ligand was in the top tertile; 56.7% were “low expressors,” with neither ligand in the top tertile.

The primary population for this analysis was 220 of the 323 patients who had RAS wildtype advanced colorectal cancer. Among those patients, those with high ligand expression had a median progression-free survival of 8.3 months with panitumumab vs 4.4 months with irinotecan alone, for a hazard ratio of 0.38 (95% CI, 0.24–0.61; P < .001).

Among those with low ligand expression, this effect was not found. The median progression-free survival with panitumumab in these patients was 3.2 months, compared with 4 months with irinotecan alone, for a hazard ratio of 0.93 (95% CI, 0.64–1.37; P = .73). Significant differences were not found for response rate or overall survival.

“This study confirms for the first time the utility of EREG and AREG mRNA expression as a predictive biomarker for anti-EGFR therapy in RAS wildtype patients, and proposes a simple model-either high vs neither high-to combine information from both ligands,” the authors wrote. “With alternative new options emerging for patients with advanced colorectal cancer, it becomes ever more important to ensure that the use of anti-EGFR therapy is confined to those who will benefit from it.”

In an accompanying editorial, authors led by David Cunningham, FMedSci, of Royal Marsden Hospital in London, noted the lack of overall survival benefit in the study. “The results of this study alone, although intriguing, are insufficient to change current practice,” they wrote, noting that this does not mean the results don’t have clinical utility. “Although the current model requires further validation, it represents an important refinement of our understanding of the use of anti-EGFR therapies for patients with advanced colorectal cancer.”