The Future of Melanoma Treatment | Page 3

By Michael M. Mohundro, PharmD, and Alexis E. Horace, PharmD
Published Online: Thursday, June 6, 2013
Mutations in proto-oncogene B-Raf (BRAF) are common in 40% to 60% of melanomas, and the MAP/ERK kinase (MEK) pathway is a part of the mutation cascade.32 GDC-0973 is a new and highly selective, small-molecule MEK inhibitor being studied for its antineoplastic activity. Mutations in the MEK cascade contribute to increased cell proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis.33 Malignant melanomas commonly have single amino acid mutations (BRAFV600E) in a single loop of the kinase.33 GDC-0973 binds to MEK1 and inhibits ERK2 phosphorylation, ultimately decreasing tumor growth.34 Preclinical trials have shown that this novel agent in combination with vemurafenib and GDC-0941, a PI3K inhibitor, is effective in decreasing growth in those tumors harboring a BRAF mutation.33,34 An open-label, dose escalation, phase I clinical trial is currently recruiting patients with BRAFV600E malignant melanoma to evaluate the safety, tolerability, and pharmacokinetics of GDC-0973.35 Concurrently, a phase III clinical trial is also recruiting patients with untreated BRAFV600 mutations and unresectable, locally advanced metastatic melanoma to evaluate the safety and efficacy of vemurafenib compared with vemurafenib combined with GDC-0973.36

MEK162

MEK162 is another powerful inhibitor of MEK1 and MEK2. This novel agent is also being studied for inhibition of NRAS mutations. Research has shown that NRAS mutations are associated with a poor OS as well as the development of CNS metastases.37 Preclinical trials using in vitro and in vivo studies have shown MEK162 inhibited growth of NRAS, Val600GLU BRAF-mutated melanoma.32,38 Recently, MEK162 was investigated in an open label, phase II clinical trial. No patients had a complete response to therapy with MEK162. However, 20% of the NRAS-mutated melanoma group and 20% of the BRAF-mutated melanoma group had a partial response. The most common side effects included acneform dermatitis, rash, diarrhea, and increased creatine phosphokinase. Another phase II trial is in progress, which is assessing the safety and efficacy of MEK162 in malignant, cutaneous melanoma that has NRAS and BRAFV600 mutations.39 Future studies include a phase Ib/II study assessing the use of LEE011 in combination with MEK162 and phase III study investigating efficacy of MEK162 versus dacarbazine for metastatic melanoma. Both studies have yet to recruit participants.40,41

Trametinib

Trametinib is another small-molecule, selective inhibitor of MEK1 and MEK2 that can be taken orally.42 Trametinib has been shown to decrease cell proliferation and induce apoptosis.43 In vitro evidence suggests trametinib in combination with a BRAF inhibitor increased rate of tumor-infiltrating lymphocytes in selected biopsy material. However, responses to the treatment varied, and the authors were unable to definitively distinguish the role of MEK in the results.44 A phase III clinical trial assessing survival benefit in patients with BRAF-mutated melanoma received either trametinib or chemotherapy (dacarbazine or paclitaxel). Median duration of PFS was 4.8 months in the trametinib group compared with 1.5 months in the chemotherapy groups (n = 322; P <.001).45 An open-label, 2-stage, phase II study examined trametinib in patients with BRAF-mutated cutaneous melanoma.46 Patients were assigned to two cohorts: those previously treated with vemurafenib or dabrafenib (cohort A) or those previously treated with chemotherapy/or immunotherapy, but no BRAF treatment (cohort B). No cohort A patients had a confirmed clinical response; however, 20% experienced tumor reduction at the time of study cutoff. In cohort B, there was 1 complete response (2%) and 13 partial responses (23%), which resulted in a relative risk of 25% (95% CI, 14.1%-37.8%). Currently, there are several phase II and III clinical trials actively recruiting patients to further research trametinib in treating melanoma.47

IgG2 Monoclonal Antibody

Tremelimumab

While it has been demonstrated in the early stages of melanoma that the immune system mounts a strong response, tumors ultimately develop mechanisms to evade detection and destruction.16 Immunosuppressive adaptations include induction of immune tolerance, as well as resistance to cell death by activated effector arms of the immune system.16,48 Under normal physiologic conditions, the immune system has checkpoints and feedback mechanisms that establish tolerance to self-antigens and prevent autoimmunity.16 Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is one of the molecules that assists in maintaining immune homeostasis by downregulating T-cell activation. In 2011, the FDA approved ipilimumab, the first monoclonal antibody (mAb) directed against CTLA-4. While only demonstrating modest results, it was the first drug treatment for melanoma to show a significant increase in OS.16,49

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