New Targeted Therapies in Melanoma
New Targeted Therapies in Melanoma
Researchers who work to combine therapies to block multiple activated pathways in melanoma may overcome the intrinsic and acquired resistance to BRAF inhibitors. Given that the reactivation of the MAPK pathway is responsible for the majority of resistance, it is logical to combine BRAF inhibitors with MEK inhibitors. A study to assess dabrafenib/trametinib demonstrated an improvement in PFS. The median PFS was 9.4 months for patients treated with dabrafenib/trametinib compared with a PFS of 5.8 months in patients treated with dabrafenib alone. An improved survival rate was seen with trametinib compared with chemotherapy in patients with BRAF-mutant metastatic melanoma: median PFS was 4.8 months with trametinib and 1.5 months with chemotherapy.
Vemurafenib has also been combined with the MEK inhibitor GDC-0973 for patients with metastatic melanoma. Early-phase studies have shown preliminary efficacy and tolerability of this combination. A phase III study is planned of this combination.
Clinical trials are ongoing to study other combinations, including alternative MEK inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and heat shock protein 90 inhibitors combined with BRAF inhibitors (NCT01616199, NCT1657591, NCT01271803, NCT01777776).
NRAS mutations are present in approximately 15% to 20% of cutaneous melanomas. Because tumors with NRAS mutations rarely, if ever, harbor BRAF mutations, they may represent a distinct subpopulation for potential targeted therapy, with approximately 40% of BRAF wild-type melanomas harboring a mutation in NRAS. Drug development in this subset of melanoma has been difficult as multiple pathways are unregulated by this mutation. Studies are currently evaluating the role of MEK inhibitors in this population of patients (NCT00866177, NCT01320085). MEK162 achieved responses in more than 20% of the 28 treated patients with mutant NRAS. However, results with trametinib are not as promising, with no objective clinical response seen in 9 patients with NRAS mutation.
Also seen in this population of patients with melanoma is the activation of PI3K signaling. Available data regarding the efficacy of combining PI3K inhibition with MEK inhibition are limited, but studies are ongoing.
Targeting the cell cycle via cyclin-dependent kinase (CDK) inhibitors in NRAS-mutant melanoma is another area of research. CDK4 has been implicated in mouse models in resistance to MEK inhibitors. A CDK4/6 inhibitor (PD-0332991) demonstrated antitumor activity in melanoma. CDK4/6 inhibitors for melanoma are currently being studied in clinical trials.
Overcoming Resistance
Researchers who work to combine therapies to block multiple activated pathways in melanoma may overcome the intrinsic and acquired resistance to BRAF inhibitors. Given that the reactivation of the MAPK pathway is responsible for the majority of resistance, it is logical to combine BRAF inhibitors with MEK inhibitors. A study to assess dabrafenib/trametinib demonstrated an improvement in PFS. The median PFS was 9.4 months for patients treated with dabrafenib/trametinib compared with a PFS of 5.8 months in patients treated with dabrafenib alone. An improved survival rate was seen with trametinib compared with chemotherapy in patients with BRAF-mutant metastatic melanoma: median PFS was 4.8 months with trametinib and 1.5 months with chemotherapy.
Vemurafenib has also been combined with the MEK inhibitor GDC-0973 for patients with metastatic melanoma. Early-phase studies have shown preliminary efficacy and tolerability of this combination. A phase III study is planned of this combination.
Clinical trials are ongoing to study other combinations, including alternative MEK inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and heat shock protein 90 inhibitors combined with BRAF inhibitors (NCT01616199, NCT1657591, NCT01271803, NCT01777776).
NRAS
NRAS mutations are present in approximately 15% to 20% of cutaneous melanomas. Because tumors with NRAS mutations rarely, if ever, harbor BRAF mutations, they may represent a distinct subpopulation for potential targeted therapy, with approximately 40% of BRAF wild-type melanomas harboring a mutation in NRAS. Drug development in this subset of melanoma has been difficult as multiple pathways are unregulated by this mutation. Studies are currently evaluating the role of MEK inhibitors in this population of patients (NCT00866177, NCT01320085). MEK162 achieved responses in more than 20% of the 28 treated patients with mutant NRAS. However, results with trametinib are not as promising, with no objective clinical response seen in 9 patients with NRAS mutation.
Also seen in this population of patients with melanoma is the activation of PI3K signaling. Available data regarding the efficacy of combining PI3K inhibition with MEK inhibition are limited, but studies are ongoing.
Targeting the cell cycle via cyclin-dependent kinase (CDK) inhibitors in NRAS-mutant melanoma is another area of research. CDK4 has been implicated in mouse models in resistance to MEK inhibitors. A CDK4/6 inhibitor (PD-0332991) demonstrated antitumor activity in melanoma. CDK4/6 inhibitors for melanoma are currently being studied in clinical trials.
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