COMBI-AD is one of the first studies, or the first study, it was targeted therapy, a dual MAP kinase blockade using dabrafenib and trametinib in patients who are free of disease of melanoma. These are stage 3 melanoma patients, so patients who got operated on their sentinel node and got elective lymph node dissection. We know that this patient cohort has roughly a 70% relapse chance over the next five years. These patients got treated in a placebo-controlled study which was a registration study comparing placebo to dabrafenib-trametinib. These clinical trial results have been presented and published the end of last year, after ESMO last year, and have shown a strong a significant benefit in favour of dabrafenib-trametinib with a hazard ratio of 0.5, so it’s a clear benefit and actually with a survival time of close to 28 months it showed also an overall survival benefit at that time point already which was highly statistically significant in favour of the combination.

So the question also was the safety profile of this combination since roughly 25% of the patients dropped out of the treatment. The treatment duration is one year and roughly 25% of the patients dropped out because of side effects. The side effects we know from dabrafenib-trametinib also in the stage 4 are mostly pyrexia, fever and patients in stage 4, having metastatic disease, are willing to accept more toxicity. That is a life threatening disease if you have distant metastases in your body. In the adjuvant setting the patients are free of disease, they feel normal, healthy and if you have chills, if you have fever, particularly at the beginning of the treatment, there are some patients who have a higher likelihood also to walk away from the treatment.

So quality of life was measured in those patients staying on track and clearly demonstrated that the most important thing for a patient obviously which is affecting quality of life is tumour progression. So obviously quality of life is improved in those patients who are free of disease, which is possibly not surprising. But that’s quite obvious looking at these patients, that progression is also having a major impact on patients’ quality of life.

So I guess the summary is that the combination works and for those who do tolerate it the outcomes are…?

Yes, one of the lessons we have to take is patient education to manage expectations of what to achieve and also the expectations of what kind of side effects one can expect is of critical importance. If a patient knows that fatigue or fever might come how to deal with that is of critical importance. So a brief stop of the drug, a treatment pause, is not harmful, we know that already from stage 4, and then continue without affecting your quality of life too much, then to overcome this initial side effect peak.