Neoadjuvant daromun effective and safe for resectable, locally advanced melanoma

Prof Axel Hauschild - University Hospital, Schleswig-Holstein, Germany

So I presented a trial which was named the PIVOTAL trial. The trial design is very simple, it was a 1:1 randomisation towards the neoadjuvant intralesional use of daromun, I will explain the drug in a moment, compared to immediate surgery alone for patients with skin metastasis and lymph node metastasis. So it was a neoadjuvant trial and patients were allowed to have prior treatment as well as an adjuvant treatment after the surgery was performed.

Daromun is a new agent which has been published only the phase II data and in vitro data. This agent has two components – one component is directed against fibronectin which is found in tumour vascularisation and is directing interleukin-2 tumour infiltrating lymphocytes into the tumour, an influx. The second component is tumour necrosis factor-alpha which is inducing tumour necrosis. In mice the mouse tumours have only been killed if both components have been used together, that’s the reason why this is a fusion product which is given intralesionally. It was done four times in four weeks, so one time per week, and the patients’ endpoint was relapse free survival and this was positive fortunately. The hazard ratio was 0.59, a 41% reduction in the risk of recurrence as well as the risk to die. The secondary endpoint, distant metastasis free survival, was also positive – 0.6 is the hazard ratio, a 40% reduction in the risk of development of distant metastases.

So very good results. Also pointing out that there is a systemic benefit for the patients, it’s not only a local benefit. The good thing about it is that there was almost no systemic toxicity, it’s all local toxicity. If we inject we cause inflammation, patients may have pain, they have redness of the injected lesions and sometimes they have also inflamed tumours which can induce systemic reactions like fever. This was well manageable and there were only very few patients not receiving the full package of four scheduled injections.

We have no overall survival data, it’s completely immature at this point in time after two years of observation period but we are very happy. Now the company is submitting the data to the European Medical Agencies and hoping for a positive response.

As an alternative for patients who might have a fear of serious toxicities with the combined immune checkpoint inhibition or patients who have received already ipilimumab/nivolumab because the mode of action is completely different. So the advantage is that we can inject intralesionally causing no toxicity. The data with relapse free survival and distant metastasis free survival are good, very clinically meaningful, and therefore it’s something different.