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 past year saw some remarkable advances in melanoma clinical research and treatment. This feature explores the most notable melanoma news of 2013: Continue reading…
We already knew that melanomas can resist BRAF inhibitor drugs by activating a particular cancer pathway (a group of proteins in a cell that work together to control cell multiplication, which can lead to tumor growth)—but new research shows that this resistance can also be caused by activating a second cancer pathway. The first pathway is called MAPK and the second is called PI3K-PTEN-AKT. The researchers studied 100 melanomas that resisted the BRAF inhibitors vemurafenib or dabrafenib, and found that 70% had mutations in the first pathway, while 22% had mutations in the second pathway. Moreover, mutations in both pathways could occur in the same tumor, suggesting that thwarting resistance to BRAF inhibitors may require targeting both pathways with a combination treatment.
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.
“Inhibitors of BRAF protein kinase, such as Vemurafenib and Dabrafenib, have shown remarkable antitumor activity in patients with BRAF mutant melanoma. However, most of the patients developed drug resistance during the course of treatment, leading to resumed tumor growth. This drug resistance challenge underscores the need to improve on current BRAF-targeted therapy. In this study, we have shown that phenformin, a biguanide used for treating type 2 diabetes, enhances the antitumor activities of BRAF inhibitors in both cultured melanoma cells and a genetically engineered BRAFV600E-driven mouse model of melanoma. Our preclinical findings suggest that combining phenformin with a BRAF inhibitor may be a more effective treatment than a single-agent BRAF inhibitor for treating patients with melanoma whose tumor harbor BRAF mutations.”
“Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.”
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.