Sunday, June 2, 2013

GSK Receives FDA Approval for Melanoma Drugs Dabrafenib and Trametinib

The approval of two new melanoma drugs TAFINLAR® (dabrafenib) and MEKINIST™ (trametinib) by the FDA this week is timely for melanoma patients whose tumors often develop resistance to other targeted therapies, such as Zelboraf. 

Dabrafenib is indicated for patients with BRAF V600E mutation. Another drug, vemurafenib (aka ZELBORAF) by Genentech which was approved in January 2011 also targets the same protein. BRAF V600E is an always-on signaling protein found in majority of melanomas. (Read more about vemurafenib or BRAF V600E here.)

The second drug, trametinib is the first MEK inhibitor to be approved for melanoma.  Unlike dabrafenib or vemurafenib, this drug's target is downstream of BRAF kinase and, thus trametinib can complement the other two drugs in clinical practice. Both drugs will be available by prescription in Fall 2013.

At present, dabrafenib is approved as single-agent oral treatment for unresectable melanoma (melanoma that cannot be removed by surgery) or metastatic melanoma (melanoma which has spread to other parts of the body) in adult patients with BRAF V600E mutation. And trametinib is approved as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutation.

Melanoma and BRAF mutations

About 5% of all skin cancers are melanomas but it is one of the most deadly of all skin cancers. Only one in two melanoma patients survive 1 year after diagnosis. The five-year survival rate is 16% and after 10-years, only 10% are cancer-free.

BRAF mutations are found in nearly half of all melanomas with 85% of these being V600E mutation and 10% being V600K. These mutations can be tested using companion diagnostic test approved by the FDA, THxID™-BRAF, available from bioMérieux S.A.

In the spirit of one-two-punch, combination trials including dabrafenib and trametinib, as well as vemurafenib and trametinib are ongoing.

Pivotal clinical trails

BREAK-3 Trial (dabrafenib Phase 3 trial)

The BREAK-3 trial included 250 patients with unresectable or metastatic melanoma with BRAF V600E mutation. This was a multicenter, international, open-label, randomized phase 3 clinical trial. The patients were randomized to receive dabrafenib or chemotherapy (dacarbazine) in 3:1 ratio. The median progression-free survival (PFS) in the dabrafenib group was 5.1 months vs 2.7 months in the chemo control group, and the objective response rate (ORR) was 52% vs 17% in the control group. 

The improvement in the median PFS with dabrafenib was significant in this study compared to the chemotherapy control (HR=0.33; [95% CI: 0.20, 0.54], p<0.0001). Further, 44% of the patients on chemotherapy (n=28) crossed over to the debrafenib arm at the time of disease progression.

METRIC Trial (trametinib Phase 3 trial)

The METRIC trial included 322 patients with unresectable or metastatic melanoma who were randomized 2:1 to receive trametinib or dacarbazine. The median PFS in the trametinib arm was 4.8 months vs 1.5 in the chemotherapy control arm.

The improvement in the median PFS in the trametinib arm was statistically significant compared to the chemotherapy control (HR= 0.47; [95% CI: 0.34, 0.65], p<0.0001). Further, 47% of the patients on chemotherapy (n=51) crossed over to the debrafenib arm at the time of disease progression.

Side Effects

Both drugs are not without serious side effects. The GSK press release lists several adverse events which were seen in clinical trails:
"Dabrafenib can cause serious side effects, some of which can be life threatening, including increasing the risk of developing new primary cutaneous malignancies (new skin cancers), tumour promotion in BRAF wild-type melanoma, serious febrile drug reactions (severe fevers), hyperglycaemia (blood sugar problems), uveitis and iritis (severe eye problems), haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and embryofoetal toxicity (potential harm to the unborn baby in pregnant women). Trametinib can cause serious side effects, some of which can be life threatening, including cardiomyopathy (heart problems, including heart failure), retinal pigment epithelial detachment (RPED) and retinal vein occlusion (RVO) (eye problems including blindness), interstitial lung disease or pneumonitis (lung or breathing problems), serious skin toxicity (rash) and embryofoetal toxicity."

GSK Press Release. 29 May 2013. [Link]
Drugs@FDA - dabrafinib approval. [Link]
Drugs@FDA - trametinib approval. [Link]

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1 comment:

  1. GlaxoSmithKline has taken a new drug applications for dabrafenib / trametinib combination in metastatic melanoma to the FDA. This approval would give more scope for further research on melanoma and its other uses. I also read a similar article on this. Hope you to like it.