Superiority of combined BRAF and MEK inhibition versus BRAF inhibition alone: Lay Summary

Overview of three recent Phase III randomised studies

See also Technical Summary of this paper

About 50% of melanomas have a gene abnormality, or mutation, which makes the cancer grow and spread. This gene is called BRAF and the abnormality can be blocked with new type of medication called a BRAF inhibitor. Dabrafenib and trametinib are two such drugs. They are used extensively worldwide and are the standard of care in the UK. These drugs are initially a very effective treatment in most patients who have the BRAF mutation. However the tumour cells become resistant to the drugs after about six months of treatment and the cancer can start to grow once again.

Another group of drugs that are able to block this pathway is called MEK inhibitors. Although they are not as effective as BRAF blocking drugs on their own, they can also be used in tandem with BRAF inhibitors.

The combination of these two classes of drugs has now been tested in three large clinical trials conducted around the world. The objective of the studies was to evaluate whether the combination of BRAF and MEK inhibitors is more beneficial than using a BRAF inhibitor alone.

In one clinical trial, involving 423 patients, the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib was compared to a treatment consisting of dabrafenib alone. The combination showed improved results, with patients staying on treatment longer before cancer resistance developed. Patients receiving the combined treatment also had greater tumour shrinkage (‘tumour response’) compared with patients on the single drug (67% vs. 51% of those being treated). Running a high temperature was a common side effect, occurring in half the patients receiving the combined treatment. Secondary skin cancers are another possible side effect of BRAF inhibitors; it was found that this problem occurred less often when patients were treated with the two drugs together.

In a larger trial, involving 704 patients, the combination of dabrafenib plus trametinib was tested against vemurafenib. The trial aimed to see if there was a potential benefit, in terms of longer life expectancy, for patients receiving the drug combination. Results showed that patients given the combined treatment did indeed live longer and because of this the study was stopped early so that all patients could receive the combination.

In a third study, of 495 patients, the BRAF inhibitor vemurafenib was compared with vemurafenib in combination with the a new MEK inhibitor, cobimetinib. Patients given this combined treatment stayed on treatment around three months longer compared with those receiving vemurafenib only. 68% of patients in the combination group had tumour response, compared with 45% taking vemurafenib alone. This treatment was well tolerated in each groups of patients, skin rash being the most common side effect in both groups.

The results of these three studies show that combining a BRAF inhibitor with a MEK inhibitor can help to delay the melanoma becoming resistant to treatment and extend life expectancy. Although side effects were more common in patients receiving combination treatment, they could be managed by a short break in treatment or a reduction in the dose of the tablets.

The combination of dabrafenib and trametinib is licensed in the US and Australia but not yet in the UK. Until recently British patients were able to access this combination through a company-sponsored ‘Compassionate Use Programme’. NHS England has decided that the dabrafenib-trametinib combination will no longer be available to patients.

See also Technical Summary of this paper

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