Better news for MEK and BRAF/MEK combos!

MEK (still available only in trials for melanoma) is a downstream inhibitor in the same pathway as the BRAF inhibitors.  Meaning - it turns off the signal the melanoma cells are getting to grow.  MEK162 seems to work in patients with NRAS mutations as well as those having V600 BRAF.  Patients with NRAS showed a 68% rate of clinical benefit per Sosman, quoted in Uptodate.com.  This is important since, while most MEK products have only been tested in V600 BRAF positive patients, at least one MEK product (MEK 162) has activity in, and is therefore an option for, patients who are not positive for the BRAF mutation, though it does require the NRAS mutation.  (Clear as mud, yes????)

In September of 2012 the New England Journal of Medicine published the article, "Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations."  By: Flaherty, Infante, Sosman, Falchook, Weber, et al. 

Basically, they noted that "resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted [trials] of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor."

So...in 247 patients with metastatic melanoma and  BRAF V600 mutations, they gave various doses of dabrafenib or trametinib to 85 patients and randomly assigned 162 patients to a combo of dabrafenib plus trametinib or dabrafenib only. (Seriously!!!  Who names this shit?????)

Anyhow...Squamous cell carcinoma was seen in 7% of patients getting the combo, but in 19% of patients getting monotherapy.  Fever was more common in the combo group. "Median progression-free survival in the [combo] group was 9.4 months, as compared with 5.8 months in the monotherapy group.  The rate of complete or partial response with combo therapy was 76% vs 54% with monotherapy."

Bottom line....despite increased fevers....the combination group did better in regard to fewer skin lesions and better in progression-free survival.

Meanwhile...the MEK inhibitor trametinib (GSK 1120212), according to a report in Nature Biotechnology, published online on Jan 9, "might be close to reaching the market". The writer reports that, on December 4, an FDA advisory committee "discussed the drug's effectiveness for treating unresectable or metastatic BRAF V600 mutation positive melanoma, including safety monitoring in light of ophthalmologic and cardiac toxicities observed in adults taking the drug." Several MEK products (MEK 162 from Novartis, AZD 6244 [called selumetinib] from AstraZenceca, GADC-0973 from Genentech, as well as trametinib from GlaxoSmithKline, noted above) are to be in Phase 3 trials in 2013. "Roche is also starting a phase 3 trial in melanoma combining its BRAF inhibitor (Zelboraf/vemurafenib) with Genentech's MEK inhibitor." "For now, trametinib is the only MEK inhibitor with major clinical data behind it..."   As demonstrated in the article I reported on above.  An assistant professor at Moffitt is quoted saying...."results may start to iron out as more companies go into bigger trials."

Bottom, bottom line(s)....
I am glad more MEK products are coming to trial.
I hope all of them work as they should....as melanoma patients will be desperately trying to get into these trials...and ratties will pay the price if they don't.
MEK products may turn out to be effective in a broader group of patients than originally thought.
It seems that combinations of MEK and BRAF inhibitors may be yet another way to make the amazing results of BRAF inhibitors more durable and their side effects more tolerable.

Keep making things better, ratties.  - c