Drug Combo Cuts Death by One-Third in Metastatic Melanoma with BRAF V600E or V600K Mutations

The gist: Certain metastatic melanoma patients who have not yet been treated may do better if they take the drugs dabrafenib and trametinib than if they take vemurafenib. This was true for patients who had BRAF V600E or V600K mutations in their tumors. The patients participated in a clinical trial to compare the two treatment approaches.

“Patients with previously untreated BRAF V600E or V600K metastatic melanoma had a significant improvement in overall survival when treated with a combination of a BRAF inhibitor and a MEK inhibitor compared with treatment with a BRAF inhibitor alone, according to the results of a study published in the January 1 issue of the New England Journal of Medicine.

“In fact, patients treated with dabrafenib and trametinib had a 31% relative risk reduction for death compared with patients assigned monotherapy with the BRAF inhibitor vemurafenib, with no significant increase in toxicity.

“ ‘Together with the previously reported phase II and phase III trials of dabrafenib plus trametinib, as compared with dabrafenib monotherapy, these data provide clear evidence for the benefit of this combination therapy over BRAF monotherapy in prolonging survival,’ wrote study author Caroline Robert, MD, PhD, Gustave Roussy and INSERM Unité 981, Villejuif-Paris Sud, and colleagues.”


Dabrafenib–Trametinib Combination Extended Survival in Metastatic Melanoma

The gist: A recent clinical trial with volunteer patients compared two treatments for metastatic melanoma. It showed that one of the treatments might give longer survival times for people whose tumors have mutations called BRAF V600E or BRAF V600K. This treatment combines the drugs dabrafenib and trametinib. In the trial, some patients were treated with the combination, and some were treated with only the drug vemurafenib (aka Zelboraf). People who took dabrafenib and trametinib lived several months longer than people who took vemurafenib. None of the patients had taken any previous treatments for their melanoma.

“The combination of dabrafenib and trametinib significantly extended OS compared with vemurafenib monotherapy in patients with treatment-naive metastatic melanoma who harbored BRAF V600E or V600K mutations, according to results of a randomized, open-label phase 3 study.

“The regimens demonstrated comparable toxicity profiles, researchers wrote.

“ ‘Together with the previously reported phase 2 and 3 trials of dabrafenib plus trametinib as compared with dabrafenib monotherapy, these data provide clear evidence for the benefit of this combination therapy over BRAF monotherapy in prolonging survival,’ Caroline Robert, MD, PhD, head of the dermatology unit at Institut Gustave-Roussy in Paris, and colleagues wrote.”


Targeted Combination Therapy Halts Disease, Extends Life in Advanced Melanoma Patients

The gist: Researchers tested a new melanoma treatment in a clinical trial—a research study with volunteer patients. The treatment combines the targeted drugs dabrafenib and trametinib. All of the patients who participated in the trial had inoperable stage IIIC or stage IV melanoma. Also, each patient’s tumors had one of two particular mutations in the BRAF gene, known as V600E and V600K. In the trial, patients who were treated with the combination therapy had significantly lower chances of their cancer worsening and lower chances of death.

“A world-first study in today’s New England Journal of Medicine heralds the efficacy of a targeted combination drug therapy after reporting major declines in the risk of disease progression and death in people with metastatic melanoma.

“The multi-centre, double-blind, randomised, phase 3 trial compared oral dabrafenib (150 mg twice daily) and oral trametinib (2 mg once daily) combination therapy with oral dabrafenib (150 mg twice daily) and placebo.

“All trial patients had inoperable stage 3C or 4 metastatic melanoma that had a BRAF gene mutation V600E or V600K. Among cancer patients with metastatic melanoma, about 40 per cent have a BRAF gene mutation – an abnormality that assists some melanoma tumours to grow and spread.

“Led by Associate Professor Georgina Long of Melanoma Institute Australia at the University of Sydney, the finding affirms accumulating evidence of the efficacy of targeted combination therapies in extending life and halting disease progression in patients with cancers that carry genetic mutations that resist monotherapies.”


GSK's Melanoma Study Stopped Early on Survival Boost

The gist: In the U.S. and Australia, oncologists are allowed to prescribe a treatment that combines the drugs Mekinist (trametinib) and Tafinlar (dabrafenib) for people with unresectable or metastatic melanoma whose tumors have a V600E or V600K mutation in the BRAF gene. European regulators would like to see more data on the benefits and risks of the treatment before approving it for European patients. The company that produces the treatment was conducting a clinical trial with volunteer patients to capture that data, but has now decided to halt the trial, which was comparing the combo treatment to the drug Zelboraf (vemurafenib). The trial found that the combo treatment has such a significant improvement on patient survival that the patients who had been taking vemurafenib for comparison should be allowed to switch to the combo treatment, and the trial ended early.

“GlaxoSmithKline has stopped a Phase III study of its combination therapy for advanced cutaneous melanoma ahead of schedule after it showed a significant survival benefit.

“The UK drug giant said an Independent Data Monitoring Committee (IDMC) has made the recommendation as it emerged patients with metastatic melanoma – carrying a BRAFV600 mutation – who took a combo of Mekinist (trametinib) and Tafinlar (dabrafenib) demonstrated an overall survival benefit compared to those taking vemarufenib.

“Safety signals were also good, remaining consistent with that for the MEK inhibitor and BRAF inhibitor observed to date, the firm said.”


Clinical Characteristics and Outcomes with Specific BRAF and NRAS Mutations in Patients with Metastatic Melanoma

“Hotspot mutations in BRAF and NRAS are the most common somatic events in patients with melanoma. These mutations occur at highly conserved residues, but include several different substitutions. To determine whether specific mutations are clinically important to differentiate, tumor characteristics and clinical outcomes were compared among patients with advanced melanoma with 1) BRAF V600E versus V600K mutations and 2) NRAS exon 1 versus exon 2 mutations.”