MEK Inhibitor Reduces Progression of BRAF-mutated Melanoma and Might also Benefit Others


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In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

The MEK inhibitor trametinib improved progression-free and overall survival compared to chemotherapy in a phase III trial including 322 patients who had metastatic melanoma with a BRAF V600E or V600K mutation. Findings from this study were published in The New England Journal of Medicine1 and presented at the 2012 ASCO Annual Meeting (see page 3). These data and findings from other studies showing improved survival in patients receiving BRAF inhibitors, or BRAF and MEK inhibitors combined, position these targeted therapies as first-line treatment for patients with BRAF-mutated melanoma.

Reduced Role of Chemotherapy

The lead author of the trametinib trial, Keith T. Flaherty, MD, explained in an interview with The ASCO Post that it “was the last trial to be done before BRAF inhibitors were widely available, certainly before their approval.” (Trial participants were screened between December 2010 and July 2011; vemurafenib [Zelboraf], so far the only BRAF inhibitor to receive FDA approval, was approved in August 2011.) “Now we are well into an era where both physicians and patients would look at chemotherapy as our least attractive option,” said Dr. Flaherty, who is Director of Developmental Therapeutics at Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School in Boston.

BRAF mutations, most commonly V600E and V600K, have been identified in approximately 50% of patients with advanced melanoma. “Even for those who lack the mutation, we would still opt for immunotherapy with ipilimumab (Yervoy) or, in some cases, even interleukin-2 (Proleukin), albeit for a smaller number of people. But we would still favor that over chemotherapy, generally speaking,” Dr. Flaherty said. “The role of chemotherapy is now in patients with fairly symptomatic, burdensome, metastatic disease when they first walk in the door for treatment, who don’t have a BRAF mutation and might not have time to respond to the immune therapies, which can take a while to kick in. In those cases, chemotherapy is still offered as a sort of temporizing measure.”

Data from the trametinib study was also presented at the ASCO Annual Meeting by Caroline Robert, MD, PhD, Head of Dermatology at the Institut Gustave Roussy in Paris. Dr. Robert and Dr. Flaherty contributed equally to the New England Journal article. Major publications including The New York Times, The Wall Street Journal, and The Boston Globe, also reported results of the study.

‘We Knew They Were Coming’

Patients were randomly assigned in a 2:1 ratio to receive either trametinib once daily or intravenous chemotherapy, consisting of either dacarbazine or paclitaxel every 3 weeks. Median progression-free survival was 4.8 months with trametinib vs 1.5 months with chemotherapy. At 6 months, overall survival was 81% in the trametinib group vs 67% in the chemotherapy group, despite crossover, which was permitted for patients in the chemotherapy group experiencing disease progression.

Although 51 of 108 patients on the chemotherapy arm crossed over to trametinib therapy, the investigators nevertheless observed a 46% reduction in the risk of death among patients receiving trametinib. “It is possible that the between-group difference in overall survival might have been even more significant in the absence of crossover,” they wrote.

This study began while ipilimumab and vemurafenib were still investigational, and progression-free survival was chosen as the primary endpoint out of concern that postprotocol therapy with either of those drugs could confound results for overall survival.

“We knew they were coming,” Dr. Flaherty said. “I was heavily involved in all phases of the vemurafenib trials, and we knew full well in designing this trial that it was just a matter of months before vemurafenib was going to be available—first through expanded access and then approval, meaning that in the lifespan of a trial like this, as you are following patients over 1 or 2 years, nearly all patients would eventually be able to get a BRAF inhibitor. That’s good for the patients; it’s just bad for the overall survival endpoint, because at some point that would influence the outcome of the trial.”

Progression-free survival, however, is a “within-the-trial issue,” Dr. Flaherty noted. “Patients usually don’t seek other therapy until their disease gets worse, in which case the progression-free survival couldn’t possibly be altered.” He added that the FDA and European regulatory authorities “agreed that was a reasonable justification for designing the trial the way we did.”

A final overall analysis is planned when 80% of randomly assigned patients have died or otherwise been lost to follow-up, “We haven’t even crossed the 40% mark,” Dr. Flaherty said. “When we do the final analysis, we will also be accounting for what other therapies they got, and we obviously expect that to influence the outcome.”

Combining BRAF and
MEK Inhibitors

The overall response rate for patients receiving trametinib was 22%, compared to 48% in a randomized phase III trial with vemurafenib. “Although the response rate associated with trametinib appears to be inferior to that with vemurafenib, the two agents appear to provide similar improvements in progression-free and overall survival, as compared with chemotherapy,” according to the trametinib trial report. A direct comparison of trametinib and vemurafenib would be needed to definitively determine whether one is superior to the other, but currently there is less interest in head-to-head comparisons than in combining BRAF and MEK inhibitors to treat melanoma, Dr. Flaherty noted.

A phase I/II trial combining BRAF and MEK inhibitors was presented at the ASCO Annual Meeting2 and reported in a previous issue of The ASCO Post.3 The study found that trametinib combined with the BRAF inhibitor dabrafenib produced median progression-free survival of 7.4 months among patients with advanced melanoma and the V600E BRAF mutation and that the progression-free survival increased to 10.8 months among patients receiving the highest study doses of both drugs—2 mg of trametinib once a day and 150 mg of dabrafenib twice a day. That full-dose combination will be tested against single-agent BRAF inhibitors in two different phase III trials.

“That is the only combination going forward at this time because it looks to be the most effective and it is also perfectly safe to give the two together,” Dr. Flaherty stated. One trial based mainly in the United States will compare the combination to dabrafenib, and another more global trial will compare the combination to vemurafenib. Both trials are for patients with advanced or metastatic melanoma, but Dr. Flaherty said that adjuvant trials are expected to launch in 2012.

Based on emerging evidence, Dr. Flaherty said “it would look like the combination is working better than either agent does alone.” If that is borne out by the phase III trials, “a future trial would likely test the question of which is the best approach—starting with a MEK inhibitor vs starting with a BRAF inhibitor vs starting with both—understanding that people who get only a BRAF or MEK inhibitor could then receive the other agent as a backup approach.”

Broader Application

Near the end of the trametinib study report, the authors state, “Selective BRAF inhibitors appear to be relevant only in the treatment of BRAF-mutated cancers, whereas extensive preclinical data and limited clinical data suggest that MEK inhibitors may be a component of effective therapy for a broad spectrum of cancers with other oncogenic drivers.” Those cancers include melanomas without an identified BRAF mutation as well as some other common cancers.

About 25% of all cancers have RAS mutations, and “some subset of that 25% is sensitive, meaning will respond with tumor shrinkage that is clear and objective, to a MEK inhibitor,” Dr. Flaherty explained. “The big ticket items are pancreatic cancer, where 90% to 95% have KRAS mutations; colon cancer, where about 40% have KRAS mutations; and lung cancer, about 30%. These are common cancers, and those percentages equate to huge numbers of patients.” In addition, “some patients with neither a BRAF or a RAS mutation have responded to MEK inhibitors in trials,” Dr. Flaherty noted. ■

Disclosure: Dr. Flaherty served as a consultant to GlaxoSmithKline.

References

1. Flaherty KT, Robert C, Hersey P, et al: Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. June 4, 2012 (early release online).

2. Weber JS, Flaherty KT, Infante JR, et al: Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. 2012 ASCO Annual Meeting. Abstract 8510. Presented June 4, 2012.

3. Helwick C: Dual BRAF and MEK inhibition is active in advanced melanoma. The ASCO Post. June 15, 2012.


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