BRAF/MEK Increases Overall Survival in Melanoma

Antoni Ribas, MD, PhD


October 09, 2014

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Ovations for Melanoma Data

Hello. I am Antoni Ribas, professor of medicine at the University of California-Los Angeles. Welcome to this edition of Medscape Oncology Insights in melanoma, which is coming to you from the 2014 Congress of the European Society for Clinical Oncology (ESMO) in beautiful Madrid, Spain.

It has been another great conference for melanoma advances. We have heard exciting new data. The conference had to open an extra plenary session just dedicated to melanoma. I will talk about the three presentations in that plenary session, which was very well attended and well regarded.

The first study is a phase 3 randomized trial[1] of nivolumab vs investigator's choice of chemotherapy in patients who had previously received and progressed on ipilimumab. The findings were presented by Dr Jeffery Weber from the Moffitt Cancer Center.

Until recently, we haven't had agents that worked; but nivolumab, a PD-1 antibody, has shown some activity in patients who had progressed on ipilimumab. In 405 patients, this study prospectively tested the single-agent nivolumab vs whatever the investigator thought was the best chemotherapy for the patient. The primary endpoint was objective response rate, which was 32% in patients on nivolumab and 11% in patients on chemotherapy. Nivolumab triples the response rate of chemotherapy in patients who previously progressed on ipilimumab. These data will be of high relevance for patients with melanoma and their physicians, but these findings also go way beyond melanoma.

Two Inhibitors Are Better Than One

We had two definitive phase 3 clinical trials,[2,3] both comparing the combination of BRAF and a MEK inhibitor compared with a BRAF inhibitor alone. The standard of care in Europe is to use a single-agent BRAF inhibitor. The standard of care in the United States, on the basis of accelerated approval of the combination of dabrafenib and trametinib, is a combination of a BRAF and a MEK inhibitor. We needed definitive data to support this combination. That has been provided beyond any doubt at this conference. One of the phase 3 trials, coBRIM,[2] combined vemurafenib and the MEK inhibitor cobimetinib. The other trial, COMBI-v, compared dabrafenib and trametinib with single-agent vemurafenib.

The coBRIM trial is a global multicenter study, conducted in more than 100 sites around the world and enrolling 495 patients. The primary endpoint was progression-free survival (PFS). The hazard ratio for PFS was 0.51, which tells us that there was a 49% improvement on the combination of vemurafenib and cobimetinib compared with vemurafenib alone. The median PFS of vemurafenib single agent was 6.2 months (which is what we expect from vemurafenib alone; we have always said that BRAF inhibitors have a median PFS of 6-7 months) and 9.9 months—close to 10 months—with the combination of dabrafenib and trametinib.

There was an early readout of overall survival (OS). It's premature and was triggered not by the OS events but by the PFS events. The hazard ratio is very encouraging at 0.65, but the median was not reached in either arm. Obviously we will have to follow up with this study to know the impact on OS.

Another BRAF-MEK Combo Boosts Overall Survival

The COMBI-v study[3] looks at a combination of dabrafenib and trametinib compared with single-agent vemurafenib. This study was run in multiple sites around the globe and enrolled 704 patients. The primary endpoint was OS, and that was met with a hazard ratio of 0.60, showing a 40% improvement in being on dabrafenib and trametinib compared with vemurafenib. This is the first study that had definitive improved OS data for the combination of a BRAF and a MEK inhibitor compared with a BRAF inhibitor alone. The median OS in patients on single-agent vemurafenib was 17.2 months and the median of the combination has not been reached. The PFS also is consistent with the OS data. The hazard ratio was 0.56, with 7.3 months of PFS with vemurafenib alone and 11.4 months with the combination of dabrafenib and trametinib.

With these studies, we are reaching a very clear conclusion: It's better to give the combination of BRAF and MEK inhibitors than to give BRAF inhibitors alone to patients who have a BRAF-mutant advanced melanoma. The conclusion from the nivolumab trial was that in patients who have progressed on ipilimumab, it's much better to give them nivolumab or a PD-1 inhibitor, even if it's single-agent compared with the physician's choice of chemotherapy.

Thank you for joining me for Medscape Oncology Insights. This is Antoni Ribas, reporting from ESMO 2014.


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