SUPERPEAK – Clinical Trial

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 and will hopefully further improve in the next future available therapeutic options for patients diagnosed with this highly deadly disease. After several years of intense translational research and clinical absence of predictive factors, the introduction of RAS mutational status seemed to possess the necessary potential for a full translation into clinical practice of the concept of targeted therapy in this setting. However, if on the one hand we are now able to exclude from anti-EGFR treatment more patients with putative refractory colorectal tumors (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. In first-line, randomized trials objective response rate approached in fact 50-60% with the use of chemotherapy in combination with anti-EGFR treatment (cetuximab or panitumumab), thus suggesting that a nonnegligible proportion of patients, ranging from 50% to 40%, did not fully benefit from the use of anti-EGFR targeted antibodies although in the absence of a mutation of the RAS genes. Most of the biological factors analyzed in the attempt to improve patients’ selection in this setting focused either on the EGFR-downstream signaling pathway or on the receptor itself. Published research data suggested that EGFR gene copy number, PI3KCA mutations, PTEN mutations or copy number variations, and BRAF mutations may all represent predictive determinants for anti-EGFR therapy. These factors were not incorporated into clinical practice particularly because 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.

The objectives of this study are 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 (RR), early tumour shrinkage (ETS), depth of response (DoR), median progression free-survival (PFS) and median overall survival (OS). The SUPER-PEAK will be a multicenter, biologically enriched, prospectively stratified study.

Patients will be 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). Prognostic group allocation will be blind to treating physicians. Patients will subsequently receive mFOLFOX +panitumumab as per indication. In more details, patients with RAS wild type metastatic colorectal cancer will be tested for a pre-specified panel of markers using the Ion Torrent technology on DNA samples from formalin-fixed paraffin-embedded (FFPE) tissues. The following gene-panel will be used (Hotspot regions in Ion Ampliseq Cancer Hotspot panel: ~2,800 mutations of 50 oncogenes and tumor suppressor genes).

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The study population includes 230 patients of either sex aged ≥ 18 years with metastatic melanoma and BRAF V600 mutation. Combinations and sequential treatment explored in the SECOMBIT study have been carefully selected on the grounds of the existing data in literature.

Partners:

Prof. Mario Scartozzi, Medical Oncology Unit, University of Cagliari, Cagliari (PI); Dr. Valeria Pusceddu, Medical Oncology Unit, AOU, Cagliari; Prof. Giuseppe Palmieri, Unità Genetica dei Tumori CNR, Sassari; Italy