Promising new drug dabrafenib has accelerated FDA approval for treatment of metastatic melanoma

In my last blog post I talked about how the project of genome sequencing led to the discovery that a mutation in the BRAF gene causes most metastatic melanomas.  This discovery was predicted to have a promising future in drug discovery that targeted this gene, which proved to be true.

            The most common mutation found in 80-90% of B-Raf mutant cancers is the B-RafV600E mutation.  This mutations substitutes valine with glutamic acid at amino acid 600, which mimics phosphorylation used to regulate growth activity.  The mutation leads to a 500-fold increase in activity of the protein compared to wild-type B-Raf, ultimately showing an oncogenic addiction in the MAPK signaling pathway.  This leads to tumor growth.

            Some of the first drugs that target the BRAF gene that were approved by the FDA include vemurafenib and descarbazine.  These drugs do not compare with the results of a new drug called dabrafenib, which is a selective and potent inhibitor of B-RafV600E.  Dabrafenib has recently been approved by the FDA in 2013 as a single-agent treatment of BRAFV600E or V600K mutation melanoma and in 2014 for combination therapy with trametinib.  More information on the FDA approval of the drug can be found here.  In this blog post I am going to focus on the discovery and trials of dabrafenib.

            In the past, people with BRAF-mutated melanoma have had a worse median overall survival rate of 11.1 months versus those without the BRAF mutation with 46.1 months of overall survival rate.  Vemurafenib is another chemical drug used in treating metastic melanoma by inhibiting the BRAF protein.  Vemurafenib and dabrafenib both decrease phosphorylation and cause cell cycle arrest to inhibit cell growth.  Dabrafenib is 20 times more selective at inhibiting V600E BRAF-mutants than wild-type BRAF versus vemurafenib’s rate of being 10 times more selective, though.

In preclinical trials of dabrafenib, mice were dosed with GSK2118436 (dabrafenib) at 0.1, 1, 10, and 100 mg/kg once a day for 14 days and dose-proportional reductions in tumor growth were observed.  The compound was originally different and was altered in order to keep the potency and selectively while reducing the weight and the clearance level in mice before being used in a Phase I trial.  

Figure 1: A graph showing the tumor size in mice in relation to dosage amount, the triangle with solid line shows untreated control, the circle with dotted line shows dose of 0.1 mg/kg, the square with solid lines shows 1 mg/kg, the circle with solid line shows 10 mg/kg, and the diamond with dotted line shows 100 mg/kg dosage of dabrafenib. n=8 mutation: V600E.

In the first human Phase I trial, the drug showed very promising results.  The treatment was tolerated well and did not have a toxicity maximum.  The recommended dosage to go onto Phase II trials was concluded to be 150 mg by mouth twice a day.  In Phase II trials, patients with V600E BRAF-mutation responded at a rate of 57% and patients with V600K mutations, which is the second most prevalent gene substitution in the BRAF-mutation, responded at a rate of 37%.  Patients both with V600E and V600K substitutions had a median progression-free survival of 5.5 months and 5.6 months.

Overall dabrafenib had higher response rates and progression-free survival compared to dacarbazine and higher selectivity for mutant BRAF genes than wild-type BRAF genes than vemurafenib.  These attributes make dabrafenib a promising new drug in the treatment of metastatic melanoma.  The clinical trials of dabrafenib and approval of the drug is an example of accelerated FDA approval of a promising drug.

Table 1: This table describes of dabrafenib in Phases I-III, versus dacarbazine, for brain metastasis, and in combination therapy with trametinib.

Some criticisms of this article that I have are that the article mentions that the drug dabrafenib has shown to have resistance when used as monotherapy within six months of treatment, but does not go into very much detail of how this is going to be addressed.  With some further research I found that in order to account for this resistance rate, dabrafenib and trametinib are used in combination to attack different parts of the MAPK signaling pathway.  With this combination therapy, though, there are serious side effects seen in patients.  These side effects are also not mentioned in the article.  In my next blog post I will go into more detail about the combination therapy and the side effects associated with it.


Sources Cited:
Kainthla, Radhika, et al. Dabrafenib for treatment of BRAF-mutant melanoma. Pharmacogenics and Personalized Medicine. Dovepress. 2014.
Rheault, Tara R., et al.  Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors. ACS Medicinal Chemistry Letters. American Cancer Society. 2013.