“Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP–ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. This study represents an initial clinical genomic study of acquired resistance to combined RAF/MEK inhibition in BRAF-mutant melanoma, using WES and RNA-seq. The presence of diverse resistance mechanisms suggests that serial biopsies and genomic/molecular profiling at the time of resistance may ultimately improve the care of patients with resistant BRAF-mutant melanoma by specifying tailored targeted combinations to overcome specific resistance mechanisms.”
Editor’s note: We previously covered the benefits of a dabrafenib/trametinib combo for advanced-stage melanoma. However, some patients’ tumors become resistant to this drug combination and new treatment routes need to be considered. This study is exploring how molecular testing of specific genetic mutations in patients’ tumors might be used to help guide treatment decisions after they become resistant to the dabrafenib/trametinib combo.
“In recent years, the FDA has approved new drugs for the treatment of advanced melanoma, which has presented new ways to treat the disease, according to a presentation at the American Academy of Dermatology annual meeting.
“ ‘In the last four years there have been four new drugs that have been FDA-approved for melanoma and what’s even more exciting is that they really speak to two new ways to treating melanoma,’ Allan C. Halpern, MD, MSc, chief of dermatology service at Memorial Sloan-Kettering Cancer Center, told Healio.com.
“The most recent FDA approval, in January, was the combination of a BRAF inhibitor and a MEK inhibitor for treating advanced melanoma.”
“Prior treatment with immunotherapy did not limit response to BRAF inhibitors among patients with metastatic melanoma, according to results of a retrospective study.
“However, patients who underwent initial treatment with BRAF inhibitors and subsequently received immunotherapy with ipilimumab (Yervoy, Bristol-Myers Squibb) demonstrated poorer outcomes, results showed.
“Patients with BRAF-positive metastatic melanoma have several treatment options, including BRAF inhibitors vemurafenib (Zelboraf, Hoffmann-La Roche) and dabrafenib (Taflinar, GlaxoSmithKline), the MEK inhibitor trametinib (Mekinist, GlaxoSmithKline), and the immunotherapy agents ipilimumab and interleukin-2. Yet, there are limited data with regard to optimal sequencing, according to researchers.”
The US Food and Drug Administration just granted accelerated approval for a treatment that combines two drugs that target melanomas with BRAF mutations — but this was contingent on the results of an ongoing phase III clinical trial. The drugs are the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist). Now the latest results of the trial are in and they look good. This combination treatment is not approved elsewhere in the world, and the trial included 423 people from Australia, Europe, and North and South America. Final results are expected later this year and will be presented at a scientific meeting. In addition, another trial is comparing this combination treatment to the BRAF inhibitor vemurafenib (Zelboraf), which is also FDA-approved.
The application for dabrafenib (Tafinlar) as a treatment for certain lung cancer cases has been given a boost with the U.S. Food and Drug Administration (FDA) designating it a breakthrough therapy. Tafinlar is being investigated as a therapy for patients with non-small cell lung cancer (NSCLC) who have a mutation called BRAF V600E in the BRAF gene and have received at least one previous round of chemotherapy. In a recent clinical trial, Tafinlar exhibited antitumor activity in such patients. The breakthrough therapy designation provides increased drug development guidance from the FDA and accelerated approval for drugs that treat serious or life-threatening conditions and that provide a substantial improvement over currently available treatments. Tafinlar is already approved for use in certain types of skin cancer.
Good news for people with melanomas that have BRAF mutations — the US Food and Drug administration just greenlighted using two targeted treatments at the same time. The two targeted treatments are the BRAF inhibitor Tafinlar (dabrafenib) and the MEK inhibitor Mekinist (trametinib), and both were previously FDA-approved for separate use. Melanomas often become resistant to BRAF inhibitors, and adding the MEK inhibitor could prevent or stave off this resistance.
The U.S. Food and Drug Administration (FDA) has granted a priority review of whether two melanoma drugs work better together. The drugs are a BRAF inhibitor called Tafinlar (dabrafenib) and a MEK inhibitor called Mekinist (trametinib); both are already FDA-approved for use separately. Tumors, however, often become resistant to BRAF inhibitors, growing back after an initial period of shrinking. The hope is that adding a MEK inhibitor will prevent this resistance. The FDA’s ruling on this combination targeted treatment is expected in January 2014.
“On May 29, 2013, dabrafenib (Tafinlar) was approved for treatment of patients with unresectable or metastatic melanoma withBRAF V600E mutation as detected by a U.S. Food and Drug Administration (FDA)-approved test.1,2 Concurrent with this approval, FDA approved the THxID BRAF assay (bioMérieux, Inc) for detection of BRAF V600E mutations. Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma, due to the potential risk of tumor promotion.”