HER3 mRNA Overexpression May Point To Panitumumab Efficacy In Advanced RAS Wild-Type CRC

HER3 expression in colorectal tumours could serve as a biomarker to guide panitumumab use in patients with advanced disease

medwireNews: The tumoural expression levels of HER3 messenger (m)RNA could help pinpoint patients with RAS wild-type, advanced colorectal cancer (CRC) who are most likely to gain a survival advantage from the incorporation of panitumumab into their treatment regimen, research suggests.

Using data from the PICCOLO trial investigating the addition of panitumumab to irinotecan in the second line, Matthew Seymour, from St James’s Hospital in Leeds, UK, and co-investigators previously showed that the mRNA expression of the epidermal growth factor receptor (EGFR, also known as HER1) ligands epiregulin (EREG) and amphiregulin (AREG) could serve as biomarkers to guide the use of the EGFR inhibitor panitumumab in this setting .

As the activity of anti-EGFR agents could be influenced by interactions with other HER receptors, they focussed on HER3 for this current analysis, again relying on the PICCOLO data, this time including 308 participants for whom HER3 mRNA expression could be measured successfully. Of these, 209 harboured no mutations in any NRAS or KRAS codons, and were considered wild-type for RAS.

Among RAS wild-type participants, a significant interaction was observed between HER3 expression and treatment, such that higher HER3 levels were associated with prolonged progression-free survival (PFS) and overall survival (OS) only among those who received the EGFR inhibitor plus irinotecan, with significant hazard ratios (HRs) per twofold increase in expression of 0.71 and 0.73, but not among those treated with irinotecan alone (nonsignificant HRs of 0.96 and 0.93).

An exploratory analysis in which patients were dichotomised at the 66th percentile of HER3 expression showed that those considered high expressers derived a benefit from the addition of panitumumab, with a median PFS of 8.2 months versus 4.4 months for patients given irinotecan alone (HR=0.33), whereas those with low HER3 expression did not, at a respective 3.3 and 4.3 months (HR=0.96).

The findings were similar for OS, with median survival times of 14.6 and 13.2 months (HR=0.66) in the panitumumab and irinotecan alone groups, respectively, among the high expressers, and of 8.3 and 10.3 months (HR=1.56) among the low expressers.

And there was a significant interaction between the biomarker and treatment response for both PFS and OS, report Matthew Seymour et al in JAMA Oncology.

In another exploratory analysis, they stratified the patients by the tumoural expression levels of both HER3 and AREG/EREG, finding that those with high levels of both markers (n=42) derived a substantial benefit from the addition of panitumumab (HRs for PFS and OS of 0.24 and 0.36, respectively). By contrast, there was “no evidence of benefit” for participants with low HER3 and low AREG/EREG expression (n=87; HRs for PFS and OS of 1.14 and 1.44, respectively), the researchers write.

They believe that HER3 expression could be “a clinically useful selection biomarker” in this patient population, but add that “[p]rior to clinical application, revalidation of the findings and refining of the cut point is required, in well-designed hypothesis-based studies using other randomized data sets.”

Reference

Seligmann JF, Hatch AJ, Richman SD, et al. Association of tumor HER3 messenger RNA expression with panitumumab efficacy in advanced colorectal cancer. JAMA Oncol; Advance online publication 26 October 2017. doi:10.1001/jamaoncol.2017.3168

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