Selection with a molecUlar PanEl foR Panitumumab EfficAcy in K-RAS and N-RAS wild type metastatic colorectal cancer (SUPER-PEAK)

BACKGROUND: Clinical reports with the use of monoclonal antibodies directed against the ligand-binding site of the epidermal growth factor receptor (EGFR) have shown practice-changing results in the treatment of colorectal cancer. However if on the one hand we are now able to exclude from anti-EGFR treatment more patients with putative refractory colorectal tumours (i.e. those harboring a RAS mutant status), on the other hand we are still incapable to accurately select responding patients among those without RAS mutations. Most of the biological factors analysed in the attempt to improve patients selection in this setting focused either on the EGFR-downstream signaling pathway or on the receptor itself. The presence of mutated BRAF is one of the most powerful prognostic factors for advanced and recurrent colorectal cancer and BRAF mutational status determination is incorporated in clinical practice. Moreover published research data suggested that EGFR gene copy number, PIK3CA mutations, PTEN mutations or copy number variations, may all represent predictive determinants for anti-EGFR therapy, however these factors were not incorporated into clinical practice particularly becouse prospective validation is lacking. Biologically enriched, prospective clinical trials are clearly needed in order to further identify the proportion of patients more likely to benefit from the use of first-line anti-EGFR antibodies. METHODS: The SUPER PEAK trial (Selection with a molecular PanEl foR Panitumumab Efficacy in K-ras and n-ras wild type metastatic colorectal cancer) is a multicentre, biologically enriched, prospectively stratified study. The study objective is to prospectively define a molecular panel able to identify patients more likely to benefit from the use of first-line panitumumab in combination with mFOLFOX in terms of overall response rate. Patients with RAS wild type metastatic colorectal cancer are tested for BRAF mutational status according to clinical practice. Moreover a supplementary evaluation of EGFR gene copy number and a pre-specified gene panel of markers (using the Ion Torrent technology on DNA samples from formalin-fixed paraffin-embedded -FFPE- tissues) is planned. Patients are divided into 2 prognostic groups on the basis of their biological and clinical profile: favourable and unfavourable (respectively high and low probability for improved RR). RESULTS: This report represents an interim analysis since the SUPERPEAK trial is currently ongoing as well as its enrollment. Globally from October 2014 to February 2020 21 patients were enrolled. As for the primary endpoint (i.e. RR), the presence of mutations in the factors PTEN, SMARCB1, VHL, FGFR2, FGFR3, MLH1 and sidedness were associated with a reduced ORR in the univariate analysis in the intention to treat population. Conversely, the mutations of p53, PIK3CA, MET and HER3, were not statistically related to RR. None of the patients showed a HER2 alteration. As for secondary endpoints (OS, PFS), the mutations of SMAD 4, GNAQ and Rb1 have been linked to an improved OS. Given the results observed in the intention to treat population and the imbalanced proportion in terms of primary tumour sidedness, we conducted a not preplanned analysis in a selected subgroup totally homogeneous for LSCRC as previously exposed. The molecular stratification for prediction of response to treatment evaluated in the LSCRC subgroup (i.e. favourable profile vs infavourable profile), with the limits peculiar to a not preplanned analysis, showed interesting results which are worthy of further development in the final analysis. As for safety, the treatment was confirmed to be safely and well tolerated with a predictable toxicity profile. The molecular stratification proposed for LSCRC could have a relevant role in identifying different risk categories among LSCRC. Further analysis of the present study would hopefully clarify the role of these potential biomarkers in the near future.