Conference Abstract – MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients With Acquired Resistance to Combined RAF/MEK Inhibition

“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.


New Treatments for Advanced Melanoma Presented at AAD

“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.”


Immunotherapy, BRAF Inhibitor Sequence Affected Outcomes in Metastatic 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.”


Trial Supports Recent US FDA Approval of New Melanoma Combo Treatment

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.


US FDA OKs Combo Treatment for Melanomas with BRAF Mutations

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.


Melanoma: A 2013 ‘Progress Report’


The past year saw some remarkable advances in melanoma clinical research and treatment. This feature explores the most notable melanoma news of 2013: Continue reading…


New Targetable Genetic Abnormalities Found in Melanomas

More than one-third of melanomas are ‘pan-negative,’ meaning they lack known mutations that can be targeted for treatment. But now researchers have identified two new genetic abnormalities in pan-negative melanomas. These abnormalities consist of the BRAF gene joined with another gene (PAPSS1 or TRIM24), and so are called BRAF fusions. The new study showed that about 8% of pan-negative melanomas have BRAF fusions. Next, the researchers grew melanoma cells with these BRAF fusions in the lab and tested known targeted treatments on them. While these cultured cells were not sensitive to the BRAF inhibitor vemurafenib, they were sensitive to the MEK inhibitor trametinib, suggesting that MEK inhibitors could be used to target melanomas with these BRAF fusions.


Competitors Collaborate on Melanoma Combo Treatment

Two pharmaceutical giants are teaming up on a phase I/II clinical trial to see if their anti-melanoma drugs work better together than on their own. The drugs are GlaxoSmithKline’s Mekinist (trametinib), a U.S. Food and Drug Administration (FDA)-approved MEK inhibitor (a drug that targets MEK proteins), and Pfizer’s palbociclib, an experimental inhibitor of proteins called cyclin dependent kinases. These proteins make cells divide and are abnormally active in many cancers; the FDA has fast-tracked the review of using palbociclib to treat breast cancer. In addition, GlaxoSmithKline is already testing the combination of Mekinist with dabrafenib, the company’s experimental BRAF inhibitor.


Combination Treatment Extends Life in People with Melanoma

Two targeted treatments that are U.S. Food and Drug Administration (FDA)-approved for melanoma may be even more effective together. The drugs are dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. In a phase II clinical trial with 160 people, the median survival was nearly 2 years with the combination treatment compared to 20 months with dabrafenib alone. These findings were presented at the 10th International Congress of the Society for Melanoma Research in Philadelphia, Pennsylvania. Now, the dabrafenib/trametinib combo has advanced to phase III trials.