Melanoma|October 3, 2012 4:32 pm

Review of BRAF/MEK Combo NEJM data

The great results from multiple clinical trials treating advanced melanoma keep coming, as the NEJM publication from this GSK (Glaxo SmithKline)-sponsored trial recently affirmed.

This trial was a Phase I-II trial of combination therapy for advanced melanoma harboring a v600 (“e” or “k”) genetic mutation with two currently experimental GSK drugs, dabrafenib (an oral BRAF inhibitor, similar to the approved Genentech Roche drug vemurafenib or Zelboraf) and trametinib, an oral MEK inhibitor for which there is no current comparable drug commercially available. The study was presented at ESMO (European Society of Medical Oncology) 2012 and published by NEJM on September 29, 2012.

The rationale for the study was the known ability of melanoma to overcome BRAF inhibition fairly quickly, generally within 6-7 months, through multiple pathways, principally via alternative activation of the MAPK biochemical pathway through the MEK enzyme, promoting cellular growth. Pre-clinical studies suggested that combination BRAF and MEK inhibition could potentially overcome or at least delay disease progression from this escape route, The other potential benefit of combination therapy was thought to be reduction of the incidence of new squamous cell carcinomas (SCC), seen in 20-25 % of patients treated with Zelboraf, suggested by the finding of MEK mutations in SCCs.
Multiple dose levels were tested in the Phase I aspect of this study and there was no dose limiting toxicity encountered. In other words the full doses of each individual drug can be given together with acceptable safety, although there are significant side effects with this treatment.

In the Phase II portion, combination therapy was compared to single drug, BRAF inhibitor, monotherapy. Most notably, SCC development in patients who received both drugs was reduced relative to those receiving only the BRAF inhibitor, although this was not statistically significant. There was an apparent increase in fevers and chills in combo therapy patients

Another primary endpoint was PFS or progression-free-survival. This was improved by combo therapy from a median value of 5.8 months to 9.4 months. Almost no patients failed to respond to treatment, regardless of drug(s) received. Overall survival, due to relatively short term follow up, cannot be compared at this point

This study also looked at overall response rate which was increased in the combination therapy arm by about 50%, from 46% to 74%. The duration of response was also longer, from 5.6 (monotherapy) to 10.5 (combo) months

As the financial analysts would say, the “top-line” results of this study, which will need to be confirmed in ongoing Phase III larger studies

(for patients with metastatic melanoma that harbors the BRAF v600 mutation and taking into account the small size of the study which carries some risk that its results will not be reproduced in larger scale Phase III trials, and unless otherwise noted when compared to BRAF inhibitor monotherapy…

–BRAF/MEK combo therapy appears to delay (but does not seem to prevent) onset of resistance to therapy

–BRAF/MEK combo therapy appears to reduce the incidence of SCC formation, but with an increased chance of fevers and chills which did not limit dosing, and with the addition of unique MEK inhibitor toxicities like dermatitis.

–BRAF/MEK combo therapy appears to almost double PFS although may not extend survival, particularly since this trial allowed crossover to combo therapy when monotherapy failed. This may be a difficult endpoint in any event because treatment failures may subsequently receive Ipilimumab which could also confer a survival benefit.

–The increase in PFS was appropriately associated with an approximate doubling of response duration and about a 50% increase in response rate

If these results hold up, the BRAF/MEK combo will likely replace mono therapy with a BRAF inhibitor alone (except… see below).

But what are the next level of conclusions or more accurately, the questions and hypotheses raised by these exciting experimental results?

–I am intrigued by the possibility of treating BRAF treatment “failures” with the BRAF/MEK combo therapy. Can the combo therapy be used as a salvage regimen? There are patients in the Phase I part of the trial that had previously failed BRAF inhibitor monotherapy, but the results are not in the paper. In addition, most of the Phase II monotherapy failures crossed over to combo therapy after progression, yet most were still alive at one year, the last milestone reported.

–For patients who fail monotherapy after initially responding, what percentage go on to respond to combo therapy? How long does their “second remission” last? Or taken another way, is there a potential benefit to initial monotherapy until progression if you get another 9-10 months of response (PFS) on combo therapy? Is there a survival benefit to initial monotherapy followed by combo therapy at time of progression?

–Should these drugs be used to treat until progression? Or is it better to treat to some pre-defined optimal response, before the cancer “learns” how to bypass the mutated BRAF, then follow on with a second type of treatment such as Ipilimumab? And if so, what would be an optimal response, and how would you best anticipate it and switch therapies?

–On a more basic level, what is the pattern of resistance to combo therapy? Are there brand new escape pathways being forced by combo therapy or are they the same non-MAPK routes previously described after monotherapy?

Conclusion: This is only the next step in the ongoing discovery process of the BRAF pathway, its mutations and bypasses, which continues to improve the treatment of melanoma. I look forward to the next reports.


Eric D. Whitman, MD

Senior Editor,

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