Speedy Review for Melanoma Combo Treatment

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.


How to Control Other Cancers Caused by Targeted Treatments for Melanoma

While effective against melanomas with BRAF mutations, BRAF inhibitors can also cause other cancers such as squamous cell carcinoma and RAS-mutant leukemia. In an overview of the field, researchers say that people treated with BRAF inhibitors may need long-term follow-ups. The researchers also suggest combining BRAF inhibitors with treatments that target the other cancers. These include MEK inhibitors, which control some but not all of the other cancers. In addition, people treated with BRAF inhibitors may need more aggressive screening if they have a family history of colorectal cancer.


Mechanism of MEK Inhibition Determines Efficacy in Mutant KRAS- Versus BRAF-Driven Cancers

“KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease1. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours23, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF.”


Mechanism of MEK Inhibition Determines Efficacy in Mutant KRAS- Versus BRAF-Driven Cancers

“KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease1. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours23, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF.”


Mechanism of MEK Inhibition Determines Efficacy in Mutant KRAS- Versus BRAF-Driven Cancers

“KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease1. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours23, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF.”


FDA Asked to Approve New Combination Treatment for Melanoma

Two new drugs that target melanomas were approved by the US Food and Drug Administration in May, and the drug developer has already filed for approval to use them in combination. The drugs are dabrafenib (Tafinlar), a BRAF inhibitor, and trametinib (Mekinist), a MEK inhibitor, and both are made by GlaxoSmithKline. The combination treatment request is based on promising results of a Phase I/II trial, which showed that the two drugs work better together than dabrafenib does alone. Results of a Phase III trial of the combination therapy are expected later this year.


Phase II Study of Selumetinib (sel) Versus Temozolomide (TMZ) in Gnaq/Gna11 (Gq/11) Mutant (mut) Uveal Melanoma (UM)

“Gq/11 mutations are early oncogenic events in UM resulting in MAPK pathway activation. We demonstrated decreased viability in UM cell lines harboring Gq/11 mut with sel, a small molecule inhibitor of MEK1/2 (Ambrosini, CCR 2012).”


First Drug that Treats Melanomas in the Eyes

About half of melanomas that start in the eye spread to other parts of the body, usually killing people within a year. But while there are a variety of therapies for melanomas in the skin, those in the eyes are biologically distinct and there has been no good way to treat them—until now. A clinical trial of 157 people showed that a drug called selumetinib can shrink melanomas of the eye, which form in a layer called uvea that includes the iris. Selumetinib is a MEK inhibitor that targets the most common uveal mutations (GNAQ and GNA11). The researchers found that tumors shrank in in half of those treated with selumetinib and did not grow again for twice as long compared to those treated with standard chemotherapy (an average of 16 vs 7 weeks). This work was presented at the American Society of Clinical Oncology’s 2013 meeting.


Paradoxical Oncogenesis—The Long-Term Effects of BRAF Inhibition in Melanoma

The clinical benefits of BRAF inhibition in patients with advanced-stage BRAF-mutant melanoma are now well established. Although the emergence of cutaneous squamous-cell carcinomas (SCCs) and secondary melanomas in patients on BRAF-inhibitor therapy have been well described, reports are emerging of additional secondary premalignant and malignant events, including RAS-mutant leukaemia, the metastatic recurrence of RAS-mutant colorectal cancer and the development of gastric and colonic polyps.”