I’m here to discuss firstly the translational results of the VALENTINO study. Just a brief recall to the study objective and design: VALENTINO investigated whether maintenance treatment with single agent panitumumab may be non-inferior than 5FU plus panitumumab following a four month induction with FOLFOX plus panitumumab in RAS wildtype metastatic colorectal cancer patients. The study actually enrolled 229 untreated and unresectable RAS wildtype metastatic colorectal cancer patients that were randomly allocated on a one to one basis to either FOLFOX-4 plus panitumumab, up to eight cycles, followed by maintenance treatment with 5FU plus panitumumab until disease progression or unacceptable toxicity or the same induction regimen followed by single agent panitumumab.
The first results of the study were presented at ASCO this year and were confirmed at ESMO with a longer follow-up time of about 18 months. The upper boundary of the 90% confidence interval was 1.85 so greater than the pre-specified non-inferiority margin of 1.515 so panitumumab was not non-inferior than 5FU plus panitumumab in the maintenance setting. Actually the ten months progression free survival rate was 49% in the panitumumab arm versus 59.9% in the 5FU plus panitumumab arm
So the pre-specified translational endpoint of the study was evaluation of tissue biomarkers, in particular our previously published PRESSING panel which groups together several very uncommon primary resistance mechanisms to anti-EGFR treatment beyond RAS and BRAF. So as in the initial PRESSING study, we performed several analyses, including silver in situ hybridisation for HER2 and MET amplification detection, next generation sequencing for PI3 kinase, PTEN, AKT1 mutations and also RAS mutations with a low fractional abundance that were missed by standard assessment at local centres and those saw immunohistochemistry followed by RNA sequencing for detection of ALK, ROS1, and TRAK 1, 2, 3 and RET diffusions, and multiplex PCR for microsatellite instability.
Actually 189 patients with RAS and BRAF wildtype status were analysed and a quarter of them were found to be PRESSING positive in their tumours. So, regarding the correlation with outcomes, patients with a PRESSING positive tumour had a significantly shorter progression free survival as compared to those with PRESSING negative ones. Median progression free survival was 7.7 months versus 12.1 months with a hazard ratio of about 2 and a p of 0.0001. However, in the predictive analysis the progression free survival benefit of adding 5FU to panitumumab in the maintenance setting was retained in patients with both PRESSING positive and negative tumours.
Additionally, we must point out that the distribution of PRESSING panel alterations was similar in patients with left and right sided primary tumours and also that right sided ones are most often primarily resistant to anti-EGFR based treatment even in the absence of PRESSING panel alterations so we decided to perform a post hoc combined analysis of both PRESSING panel and primary tumour location. So we defined as resistant those patients with PRESSING positive tumours and/or right sided primary tumour location and as sensitive those patients with left sided primary tumour and PRESSING negative status. So resistant patients with this analysis were up to one-third of the total and in resistant patients median progression free survival was again shorter than those with sensitive tumours and median PFS, in fact, was 8.1 months versus 13.2 months with the same hazard ratio of about 2 but a greater population and the same statistically significant p-value. Again, in the predictive analysis the benefit of adding 5FU was maintained in both resistant and sensitive tumours.
So there is a lot of room and space to improve the selection of patients that may be eligible for anti-EGFR based treatment beyond RAS and BRAF. Of course this study cannot give an answer on the predictive utility of this panel since panitumumab was given in both maintenance arms. But actually the study goes in the same direction of improving molecular selection, a term that we have called hyper-selection of patients, for validation by future prospective trials.