The METRIC trial of trametinib, five years on

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Published: 10 Sep 2017
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Prof Dirk Schadendorf - Essen University Hospital, Essen, Germany

Prof Schadendorf speaks with ecancer at ESMO 2017 about the METRIC trial in melanoma, which initially showed a survival benefit for trametinib.

He reports that, with 5 years of safety and survival data now available, the initial benefits have not translated to a long term survival benefit.

Prof Schadendorf discusses how a changing landscape of targeted and combination therapies has now opened treatment options and dramatically extended patients life expectancy, so while trametinib monotherapy may not retain its initial benefits, it has been an essential stepping stone to the latest generation of melanoma treatments.

ecancer's filming has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

METRIC is a really ancient study dating back to the discovery that we have BRAF mutations in melanoma. This was the time between 2010 and 2011 where the first BRAF inhibitors were tested in this subset of patients and vemurafenib and dabrafenib as monotherapy and BRAF inhibitors showed some clinical efficacy and the first breakthrough of targeted therapies in melanoma. At that time it was clear that also MEK inhibition has some effect in vitro on cell lines turning down the cell proliferation. Based on these initial results GSK at that time, now Novartis, has made the decision to test trametinib, a MEK inhibitor, as a monotherapy in BRAF mutant melanoma patients. So this trial was done as a phase III study with registrational intent comparing trametinib against best investigator’s choice of chemotherapy.

This study was published initially in 2012 in The New England Journal of Medicine reporting on improvement in response rate in comparison to investigator’s choice chemotherapy, improvement in PFS and also in overall survival which was subsequently confirmed with a short follow-up time. This presentation here at ESMO 2017 is reporting on the five year landmark of this study and disappointingly you don’t see any survival difference any more. This has disappeared because either patients have died or subsequent treatments, and we have now luckily a lot of other options – checkpoint blockade, a combination of BRAF/MEK, which is also having influence on overall survival. The small survival difference which was seen after one and two years is gone after five years.

That’s got to be disappointing for everyone involved.

Yes. It was already clear in 2012, 2013, that monotherapy with a MEK inhibitor would not be the best choice to treat patients because there are side effects, mainly cutaneous side effects. The clinical efficacy in terms of response rate, PFS and overall survival of BRAF inhibitors was much better, tolerability was much better. Actually the MEK inhibitor has found its way in the clinic in the combination with BRAF inhibition so nowadays the combination of BRAF inhibition plus MEK inhibition, this dual MAP kinase blockade, is the standard of care for patients carrying a BRAF V600 mutation.

We can say that the inception of the trial was only five, six years ago but a completely different landscape in terms of treating the disease. So that leaves us in a better place now, trametinib or not.

Indeed. We have seen over the last six years dramatic change in the landscape of treatment options for melanoma patients. So ten years ago the five year survival rate for melanoma patients in its metastatic stage was around 5%; nowadays with eight, nine new agents available or combinations available the five year survival rate has increased to close to 50%.

It’s a shame to have found that there is no overall survival at this distance for trametinib but still its role in the world is taking place.

Yes. We have now, in contrast to six years ago, we have effective drugs which have shown to modulate overall survival, to improve overall survival. We have BRAF MEK combination as a new standard and we have two combinations approved at the moment. In addition we have also breakthrough results using checkpoint blockade – ipilimumab and PD-1 antibodies, nivolumab and pembrolizumab have been approved and also the first combination of nivolumab and ipilimumab has improved overall survival. With the newest three year overall survival data for checkpoint blockade we are already in the range between 50-60% so this is good news for our patients and families affected by melanoma.