Overall survival update from the BREAK-3 study

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

I was a global principle investigator for the BREAK-3 trial and this was conducted after we have received the results from the phase I and phase II trials which were very promising. So they indicated high response rates in patients with V600E mutations and this was the basis to create a randomised phase III trial.

How many patients were involved in the study?

We treated a total of 250 patients randomised 3 to 1 to dabrafenib compared to DTIC, the so-called reference drug and standard chemotherapeutic agent. The trial was conducted in 2011 which means that the patients have been randomised within a short time-frame.

What were your findings?

What we aim for is to treat patients with stage 3b and c and stage 4, which means these were patients with unresectable soft tissue disease, as well as patients with advanced metastatic melanoma. What we were aiming for is to demonstrate an improvement in progression free survival, PFS. The reason for this is because we allowed in this clinical trial crossover of patients who received chemotherapy which means they crossed over to dabrafenib once they demonstrated a progressive disease. Therefore the primary endpoint was progression free survival and overall survival was a secondary endpoint.

What did your previous study show?

We have presented a BREAK-3 update at ASCO 2013 in Chicago and here the hazard ratio was 0.37, in contrast to 0.30 in the very first report which has been published in Lancet. We for the first time presented overall survival data and this was 18.2 months median survival for dabrafenib compared to 15.6 months for DTIC. This was not statistically significant and also I need to say that the DTIC overall survival data in medians were highly impacted by the crossover of patients from DTIC after progressive disease. In other words, 70% of the patients who were initially treated with chemo received some sort of BRAF inhibitor once they failed to respond from the chemo.

What new data did you present at ESMO 2014?

The overall survival update showed a median overall survival time for dabrafenib treated patients of 20.0 months. The previous analysis, 2013, just a gentle reminder, showed 18.2 months. For DTIC it remained the same, it was 15.6 months in 2013 and 2014 as median overall survival. So this is very good data but statistically it’s not significant. I need to remind you it was a three to one randomisation towards dabrafenib compared to DTIC and there was a crossover, as I explained already. But for me the most interesting result from this year’s analysis is certainly that we, for the first time, can present the two-year, which means 24 months, update as a landmark analysis and this is survival of 45% of patients on one hand treated initially with dabrafenib  and only 32% for DTIC treated patients who crossed over.

Were there any other interesting findings?

I need to say that there is 10% of patients who are still under treatment and had no progressive disease, so they are still under treatment with dabrafenib with no progressive disease. Another 9% of patients are still under treatment with dabrafenib for more than seven months but the difference here is they have had a progressive disease but they were treated despite the progressive disease because the investigators thought this might be an insignificant progressive disease and they might have some sort of benefit. So there is 19% of patients who are still under treatment.

What adverse effects did you see?

In general, the updated analyses, both updated analyses, 2013 and ’14, show the same pattern. So there were no additional toxicities which were not known at the first report published in Lancet in 2012. We had some grade 3/4 toxicities but no changes over the last year’s analysis and there might be a little bit more arthralgia with CTC grades 1 and 2 which is those with mild to moderate adverse events. There is some sort of adverse events regarding fever and chills.

What follow up treatment did these patients receive?

We evaluated carefully the follow-on therapies of these patients and there is a clear pattern. Those patients who received DTIC in the BREAK-3 trial were mainly treated, 70% of the patients, with a BRAF inhibitor: 60% of them it was dabrafenib, 10% with vemurafenib, the other BRAF inhibitor. There is a group of patients in both cohorts, the previously DTIC and the previously dabrafenib treated patients, who received the CTLA4 antibody ipilimumab. And certainly some patients received also some sort of chemotherapy. So the vast majority of patients were treated after progressive disease and this might also contribute to some sort of overall survival improvement but this is uncertain and needs to be evaluated.

What are the implications of these data?

It’s very promising if 20 months as a median is presented here, simply because this doesn’t mean that everybody died at two years. You see the two year landmark analysis of 45% also indicates that there might be patients who had long-term survival.

GSK provided financial support and reviewed this video for accuracy.