Seligmann JF, et al. - Researchers aimed to assess HER3 messenger RNA expression as a prognostic and predictive biomarker for anti-epidermal growth factor receptor (EGFR) therapy in a randomized clinical trial of panitumumab. In this study, high HER3 expression identified patients with RAS wild-type (wt) who gained considerably from panitumumab, and those who did not, with statistically meaningful biomarker-treatment interactions for progression-free survival (PFS) and overall survival (OS). Finding seemed to provide information regarding the mechanism of anti-EGFR agents and of potential clinical utility.

Methods

• Pretreatment samples from the PICCOLO trial that tested the addition of panitumumab to irinotecan therapy in patients with KRAS wt advanced colorectal cancer who experienced failure with prior fluoropyrimidine treatment underwent a prospectively planned retrospective biomarker study.
• In patients with RAS wt, researchers assessed HER3 as a prognostic marker, then as a predictive biomarker, first as a continuous variable and then as a binary (high vs low) variable.
• In addition, they assessed relationship with MEK-AKT pathway mutations and EGFR ligands epiregulin and amphiregulin (EREG/AREG).

Results

• Higher HER3 was weakly prognostic for OS (hazard ratio [HR] per 2-fold change, 0.91; 95% CI, 0.83-0.99; p=.04) but not for PFS (HR, 0.93; 95% CI, 0.83-1.05; p=.25) in 308 patients (mean age at randomization, 61.6 years; 193 men).
• In patients with RAS wt, higher HER3 was predictive, being associated with prolonged PFS on irinotecan plus panitumumab (IrPan) (HR, 0.71; 95% CI, 0.61-0.82; p < .001), but not irinotecan (HR, 0.96; 95% CI, 0.82-1.13; p=.65), with significant interaction between biomarker and treatment (p=.001).
• For OS, similar interaction was seen (p=.004).
• In an exploratory binary model, HER3 was predictive of panitumumab benefit dividing the population at the 66th percentile: in patients with high HER3 expression, median PFS was 8.2 months (IrPan) vs 4.4 months (irinotecan) (HR, 0.33; 95% CI, 0.19-0.58; p < .001).
• No benefit in PFS was observed among patients with low HER3 expression: 3.3 months (IrPan) vs 4.3 months (irinotecan) (HR, 0.96; 95% CI, 0.67-1.38; p=.84), with significant interaction (p=.002).
• With significant interaction (p=.01), the binary model was also predictive for OS.
• HER3 and ligand data in combination suggested that patients with HER3-high, AREG/EREG-high tumors gained considerably from panitumumab (PFS HR, 0.24; 95% CI, 0.11-0.51; p < .005 and OS HR, 0.36; 95% CI, 0.18-0.73; p=.004).
• Conversely, no benefit was observed among patients with HER3-low, AREG/EREG-low tumors(PFS HR, 1.14; 95% CI, 0.73-1.79; p=.57 and OS HR, 1.44; 95% CI, 0.92-2.26; p=.11).