It’s a great pleasure that this abstract has been chosen for the Presidential Symposium with the press conference and I’d like to present to you exciting new data on an adjuvant treatment with targeted therapies, namely a BRAF and a MEK inhibitor. This trial was named COMBI-AD standing for adjuvant treatment in a combinational setting and dabrafenib and trametinib as BRAF and MEK inhibitor were used for resected stage 3 malignant melanomas who were carrying a BRAF V600 mutation.
The background of the clinical trial needs not to be illustrated in this room so I will make it very short. Patients with fully resected lymph node metastases and in-transit metastases have still a very high risk for a relapse. Despite recent advances, additional treatment options are needed in the adjuvant setting. I need to say that there is a lack of consistent improvement of interferons which led to the conclusion that there is a very high medical need and potential toxicities going along, as illustrated by Dr Weber, with high dose ipilimumab which has been approved in the United States but which has not been approved in Europe.
This is the study design; there is the key eligibility criteria on the left hand side. It was completely resected stage 3a, b and c malignant melanomas. This is in contrast to the previous clinical trials which have been shown. This included stage 3 e proportion which is typically patients with lymph node metastases identified by a sentinel node biopsy. All patients had a V600E or K mutation; they were surgically free and randomised within twelve weeks and they had a very good performance status. No prior radiotherapy or other systemic therapies were allowed. They were randomised in a 1:1 fashion to either the combo with conventional dose, which has been approved for stage 4 melanoma already and is used in the routine, compared to a placebo treatment. The primary endpoint of the trial was relapse free survival.
One of the secondary endpoints was overall survival and distant metastasis free survival and I can present you already today, because the follow-up is long enough, data on not only relapse free survival but also on the other endpoints.
This is the result on the primary endpoint, the relapse free survival. What you see here is a remarkable relapse free survival curve. I’d like to remind you again that this is a placebo controlled trial and this is the best Kaplan-Meier survival curve for relapse free survival we have ever seen for malignant melanoma. You see the differences after one year, two years and three years and you see that the benefit is maintained over the years. This corresponds to a hazard ratio of 0.47, so a 53% improvement of relapse free survival. The median has not been reached for the combo treatment but has been reached for the placebo arm. This corresponds to a p-value, and in the interest of time you don’t need to count it now, of point thirteen zeros and therefore it’s very impressive.
This is the overall survival and you see a hazard ratio of 0.57, so a 43% improvement in the risk to die from metastatic melanoma. Again, a very impressive result which maintains over time.
This is a summary of safety but before I come to the safety I need to make one comment because Dr Weber was talking about the impact of salvage therapies for overall survival. I will present in the Presidential Session two slides on salvage therapies and what you can see is that both groups, the placebo group and the verum group with dabrafenib and trametinib, received the same amount of salvage therapies. 74% of the patients received systemic treatment for progressive disease and therefore it’s extremely unlikely that overall survival is impacted by any salvage therapies because it was so balanced between the two groups.
I need to go back to the safety summary. What you see here is a number of grade 3 and 4 toxicities corresponding to 41% for BRAF plus MEK inhibition. There were fortunately no fatal events for dabrafenib and trametinib and there were AEs leading to treatment discontinuation in 26% of the patients. That’s a bit more than we expected in advance but this is in the adjuvant setting so the pressure of the patients on the drug may be not the same as for the stage 4 melanoma setting. There were no new toxicities which were not described for stage 4 melanoma.
This is a brief conclusion, I hope that I could convince you that this is a very remarkable hazard ratio of 0.47 with a very narrow confidence interval for this new treatment modality for the adjuvant treatment. The relapse free survival benefits were observed across all twelve subgroups which have been evaluated so there is not a single subgroup which is an outlier. I will show this slide in the afternoon today. In particular, all stage 3 categories benefitted in the same way. There is, in addition to this, a benefit in distant metastasis free survival, the time to distant metastases, and in overall survival which has been demonstrated with remarkable hazard ratios. It has a manageable safety profile with this combination of treatment and I believe it is a good novel adjuvant treatment option for mutated patients who represent 40% of the melanoma population.
This day, September 11, will make a change in our textbooks and in our current guidelines because we have at least two new treatment options and this is a very good new treatment opportunity for our patients and a good day for melanoma patients. Thank you very much.