The Future of Melanoma Treatment

According to the National Cancer Institute’s Surveillance Epidemiology and End Results data, melanoma of the skin was estimated to be the cause of death in almost 10,000 people in 2012.¹ Unfortunately, melanoma incidence has been on the rise in the United States since 1981, with annual increases of almost 3%; however, in white women under the age of 44 years, the increase has been double that, at 6.1%. The upward trend in this population may be due to the increased popularity of tanning bed use.²

Microtubule Inhibitor

Currently, there are five types of treatments available to patients diagnosed with melanoma. The treatment types are surgery, chemotherapy, radiation, immune therapy, and targeted therapy.³ Melanoma is classified as a chemotherapy-resistant tumor; however, a response rate of 10% to 15% has been noted with certain single agents. Dating back to 1972, the gold standard for treatment of metastatic melanoma has been dacarbazine.⁴ Drugs currently approved by the FDA for treatment of melanoma include aldesleukin, dabrafenib, dacarbazine, ipilimumab, trametinib, and vemurafenib.⁵ This article will explore pharmacologic agents currently being investigated for the treatment of melanoma.Nab-paclitaxel

Plasmid/Lipid Complex Containing MHC I

Solvent-based taxanes have limited utility due to limited efficacy and high rate of toxicity. In addition to adverse effects from the taxane, patients often experience reactions to the solvent. Albumin-bound paclitaxel is a 130-nanometer albumin-bound (nab) particle formulation of paclitaxel which does not require the use of a solvent. Utilization of nab-paclitaxel over traditional paclitaxel has the advantage of being able to deliver a higher dose while decreasing the incidence of serious grade 3 or 4 side effects.6 Further, the nab-paclitaxel formulation does not have the same “allergic” potential as the solvent-based formulation.^6,7 Of particular note, the albumin-binding secreted protein, acidic and rich in cysteine (SPARC) may play an important role in the effectiveness of nab-paclitaxel in melanoma. It is often overexpressed in a large number of malignancies, including melanoma, and is considered a poor prognostic indicator.⁷ While the exact role in melanoma treatment has yet to be fully defined, the efficacy of nab-paclitaxel has been comparable to standard dacarbazine treatment and single-agent paclitaxel, as well as other combination therapies._⁷ In a recent phase II trial in combination with carboplatin in patients with unresectable stage IV melanoma, the nab-paclitaxel/carboplatin combination had a slight advantage in survival rate over ipilimumab.⁶ However, the survival benefit was limited to the chemotherapy-naïve subgroup.⁶ Several more phase II trials evaluating nab-paclitaxel in combination with either bevacizumab or other agents have been completed, and results are pending.^6,8 Results of a phase III open-label, multicenter trial investigating nab-paclitaxel versus dacarbazine in treatment-naïve metastatic malignant melanoma demonstrated better median progression-free survival (PFS) and interim overall survival (OS) with nab-paclitaxel (PFS: 4.8 vs 2.5 months [hazard ratio (HR)= 0.792; 95.1% CI, 0.631-0.992; P = .044], OS: 12.8 vs 10.7 months [HR= 0.831; 99.9% CI, 0.578-1.196; P = .094]).⁹Velimogene aliplasmid

Vaccines

Velimogene aliplasmid is a new form of immunotherapy for the treatment of metastatic melanoma. MHC class I and II expression is important for detection and lysis of foreign antigens by the immune system. Oftentimes, tumor cells go undetected by class I-restricted T cells by downregulating these processes.^10-12 Velimogene aliplasmid consists of a DNA plasmid, which hosts the genetic code for MHC class I proteins, HLA-B7, and B2-microglobulin, which improve expression of the HLA-B7 gene.12 By encoding these three genes together, it provides several immune-stimulating features that increase the potential for tumor cell lysis. Several phase I studies have been conducted in small groups and demonstrated improved T-cell infiltration into tumor lesion, improved HLA-B7 surface expression, and promoted regression.^12,13 An unpublished phase III trial in 2001 compared velimogene aliplasmid combined with dacarbazine versus dacarbazine alone in chemotherapy-naïve patients.¹⁴ Response rates for dacarbazine were 11.6% and 13.2% for dacarbazine/velimogene aliplasmid. When comparing dacarbazine with dacarbazine/velimogene aliplasmid, survival durations were 9.24 months versus 10.75 months, respectively. Time to progression was 1.6 versus 1.9 months for dacarbazine and the combination. The authors concluded that velimogene aliplasmid did not increase clinical improvements beyond the standard of care. However, velimogene aliplasmid is currently being compared with dacarbazine alone in an ongoing phase III clinical trial investigating the safety/tolerability and OS rates of the two therapies.¹⁵MAGE-A3 ASCI (astuprotimut-r)

Since therapeutic vaccination with dendritic cells (DCs) for melanoma was first proposed in the 1990s, knowledge has grown with regard to their development and efficacy.¹⁶ With the boost from the recent FDA approval of sipuleucel-T in castration-resistant prostate cancer, DC-based vaccinations remain a focused area of interest in solid tumors including melanoma.¹⁶ While progress has been made in the understanding of DC-based vaccines, further study is needed in the hopes of realizing the dramatic results seen in animal models.^16,17 Several studies are currently recruiting participants to evaluate vaccine therapy, including an open-label, nonrandomized phase I/II study investigating the effect of MAGE-3 in patients with stage IV cutaneous melanoma.¹⁸ Another randomized phase II study is looking at the effectiveness of the vaccine in combination with IL-12 followed by daclizumab in patients with metastatic melanoma.¹⁹

Oncolytic Herpes Simplex VirusType 1(HSV-1) Granulocyte- Macrophage Colony-Stimulating Factor (GM-CSF)

Tyrosine Kinase Inhibitors

An oncolytic HSV-1 vaccine using GM-CSF to modulate antitumor immunity is being explored.^20,21 In addition to this cytokine-modified, cell-based vaccine activating the cytotoxic effects of macrophages to human melanoma cells, GM-CSF is a mediator for the maturation and mobility of DCs, and increases production of matrix metalloelastase, ultimately leading to the suppression of pulmonary metastases.²⁰ Treatment involves directly injecting the vaccine into the tumor, which avoids host immunity from destroying the virus.²¹ A small phase II clinical trial examined the use of GM-CSF as adjuvant therapy in stage III and IV malignant melanoma.²² The authors concluded that survival was significantly better for the overall patient population in the GM-CSF group (P = .001; P = .04 for stage III; P = .001 for stage IV). Median survival increased approximately 25 months in treatment groups, with minimal side effects noted. A current phase III study is examining the efficacy and safety of the oncolytic HSV1/GM-CSF vaccine compared with GM-CSF. The purpose is to investigate the overall survival (OS) rate.²³ Another phase III clinical trial is currently enrolling patients to investigate the safety of the vaccine over 12 months.²⁴Nilotinib

Nilotinib is an orally bioavailable, small-molecule tyrosine kinase inhibitor (TKI) that targets abl-kinases, c-KIT, and PDGFR. Currently, it is FDA-approved for patients with chronic myeloid leukemia.^25,26 While KIT has been well established as a therapeutic target in cancer, there is limited research in the area of melanoma.²⁶ In preclinical trials, evidence has shown that melanoma cell lines containing KIT mutations had a favorable response to treatment with imatinib, which also targets c-KIT.²⁶ Additionally, phase II trials have demonstrated overall response rates of 16% to as high as 30.2% with imatinib. Common reactions to treatment have included alopecia, skin rash, and headache. Multiple studies are ongoing in melanoma to determine the value of treatment in melanoma, specifically with KIT mutations.²⁶ A phase II study evaluating nilotinib in patients with melanoma from sun-damaged skin who did not respond to or could not tolerate treatment with another TKI is ongoing. Four other phase II studies investigating nilotinib in patients with melanoma are currently open to accrual.²⁷

Masitinib

MEK Inhibitors

Masitinib, an orally bioavailable TKI, is being investigated for use in both human and veterinary medicine simultaneously.²⁸ This small-molecule inhibitor of KIT, PDGFR (α + β), and Lyn has been conditionally approved by the FDA for use in dogs with cutaneous mast cell tumors.^29,30 Although no clinical data are available regarding human use of masitinib for melanoma treatment, preclinical data suggest patients carrying a c-KIT juxtamembrane (JM) mutation will respond.²⁸ One phase III study comparing masitinib with dacarbazine in patients with melanoma with a mutation in the JM domain of C-Kit is currently recruiting patients.³¹GDC-0973

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

IgG2 Monoclonal Antibody

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.⁴⁷Tremelimumab

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

BRAF Inhibitor

Another anti-CTLA-4 mAb under development is tremelimumab, which also blocks CTLA-4 signaling, and thus extends T-cell activation and stimulates T-cell proliferation.¹⁶ By restoring T-cell mediated immunity, it increases the patient’s ability to fight the tumor.¹⁶ While early clinical trials with tremelimumab suggested favorable results, a subsequent randomized phase III trial was ended early after failing to show superiority to a standard-of-care chemotherapy regimen.⁵⁰ Additionally, there were serious autoimmune reactions including colitis, rash, and endocrinopathy.¹⁶ Future analysis looks to study these agents in the adjuvant setting, as well as in combination with other agents targeting BRAF and c-KIT mutations.¹⁶Dabrafenib

Dabrafenib is a reversible, selective inhibitor of BRAF Val600GLu. Very similar to vemurafenib in its mechanism of action and pharmacodynamics, it differs in the length of its half-life (5.2 hours vs 50 hours).⁵¹ A phase II study used dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutation melanoma that had metastasized.⁵² Patients were placed into one of two groups, those who had not received any local treatments (cohort A) and those who had progressive brain metastases after previous local treatments (cohort B). Patients with the Val600Glu mutation in cohort A had a 39.2% response rate (n = 74; 95% CI, 28.0-51.2) and patients in cohort B had a 30.8% response rate (n = 65; 95% CI, 19.9-43.4). For those with the Val600Lys mutation, response rates were 6.7% (n = 15; 95% CI, 0.2-31.9) and 22.2% (n = 18; 95% CI, 6.4-47.6) in cohorts A and B. Grade 3 adverse events occurred in 22% of the total patient population. The authors concluded that dabrafenib is active in treating metastatic brain melanoma and has an acceptable safety profile.

Dabrafenib was further investigated in a phase III study that randomized patients with previously untreated stage IV or unresectable stage III BRAF-mutated melanoma to receive dabrafenib or dacarbazine.⁵³ Median PFS was 5.1 versus 2.7 months for dabrafenib compared with dacarbazine (HR= 0.30; 95% CI, 0.18-0.51; P <.001). Patients in the dabrafenib group had increased overall survival (HR= 0.16; 95% CI, 0.25-1.48). The most common adverse events listed for dabrafenib included fever, fatigue, arthralgia, and headache. Due to side effects, dose reductions occurred in 28% of patients.

Anti—Programmed Death 1 Agents

Currently, dabrafenib is being studied in a phase II clinical trial to further assess its safety and efficacy.⁵⁴ Simultaneously, a phase II clinical trial conducted in patients with BRAF-mutated metastatic melanoma of the brain is examining the overall intracranial response rate over approximately 15 years.⁵⁵ Other studies are also under way evaluating dabrafenib in melanoma.⁵⁶Programmed death 1 (PD-1) protein and its ligand, PD-L1, play a critical role in melanoma’s ability to escape the natural immune response.^48,57 In preclinical models, blockade of the interactions between PD-1 and PD-L1 improved immunologic response and enhanced in vitro antitumor activity.⁵⁷ According to Zitvogel and Kroemer48, the interaction between PD-1 and PD-L1 inhibits T lymphocyte proliferation, cytotoxicity, and cytokine release, induces apoptosis of tumor-specific T cells, and promotes the differentiation of CD4+ T cells into Foxp3-regulatory T cells, as well as the resistance of tumor cells to CTL attack.⁵⁷ Unlike CTLA-4 ligands, many tumors, including melanoma, have been shown to selectively express PD-L1, making it an excellent therapeutic target.⁵⁷ Overexpression of PD-L1 can suppress cytokine production and cytolytic activity of tumor-infiltrating CD4+ and CD8+ T cells.⁵⁷

BMS-936559

BMS-936559, formerly MDX-1105, is a human monoclonal antibody specific to PD-L1 (anti-PD-L1 mAb) that inhibits the binding of PD-L1 to both PD-1 and CD80.57 Results from a phase I clinical trial in patients with advanced cancer, including metastatic melanoma, indicated that treatment with BMS-936559 yielded a 6% to 17% objective response rate, and that the effect on disease stabilization was prolonged at 24 or more weeks.⁵⁷ Early evidence suggests that the adverse-effect profile is more favorable than that seen with anti-CTLA-4 treatments.^48,57 Grade 3 or 4 events occurred in 9% of the study population and were consistent with a mild autoimmune profile.^48,57 Curiously, there are currently no follow-up studies recruiting nor ongoing on the clinical trials website. There was a phase I anti-PD-L1 biomarker study for advanced melanoma listed, but it has a status of withdrawn with no reason given.⁵⁸

Nivolumab

Bcl-2 Inhibitor

On the other hand, nivolumab (BMS-936558), which is an anti-PD-1 mAb, has a wide array of studies either planned or ongoing.⁵⁹ While it is unclear why the focus has been shifted away from BMS-936559, it was observed in initial trials that the objective response rate was higher with nivolumab.⁴⁸Oblimersen Sodium

Conclusion

Oblimersen sodium is a new medication that downregulates the Bcl-2 protein and increases apoptosis of chemotherapy-treated human cancer xenografts.^60-62 Bcl-2 is an antiapoptotic protein that stops the release of cytochrome C, which is vital for triggering apoptosis of cancer cells.⁶⁰ Oblimersen consists of an 18-based phosphorothioate antisense oligonucleotide, which binds to Bcl-2 mRNA and mediates its cleavage.60 A phase I study comparing oblimersen/dacarbazine with dacarbazine alone demonstrated that patients in the oblimersen treatment arm had improved survival (P = .007) and increases in PFS (P <.001) over a minimum of 24 months. There were no increases in infections or bleeding events despite increases in neutropenia and thrombocytopenia with oblimersen. The purpose of another phase I trial in 2011 was to determine the safety and dosage of oblimersen in combination with temozolomide and albumin-bound paclitaxel in patients with stage III or IV melanoma.⁶³ A total of 14 grade 3 and 4 adverse events (fatigue, allergic reaction, neutropenia, thrombocytopenia, neuropathy, and hyponatremia) were recorded, but eventually resolved. The authors also reported complete response in two patients, and partial responses in 11 patients. A phase III, randomized, open-label, multicenter study comparing disease progression of patients treated with dexamethasone with or without oblimersen demonstrated no significant difference in response to time to progression or objective response rate.⁶⁴ Oblimersen is currently being tested in a phase I trial combining it with nab-paclitaxel and temozolomide in patients with advanced melanoma.⁶⁵The management and treatment of patients with metastatic melanoma is quickly evolving. Despite the limited and poor therapeutic options to date, a wide array of therapies are under development. Research has advanced the understanding of the disease processes, and we are gaining a better understanding of resistance mechanisms. Previously viewed as one disease, melanoma is now recognized as a heterogeneous mixture of cancer subtypes. Likewise, the traditional “one size fits all” model of treatment is no longer accepted as the most effective approach. Hydroxyurea, high-dose IL-2, and dacarbazine were the only drugs FDA-approved for treating metastatic melanoma in 2011. As of today, dabrafenib, ipilimumab, trametinib, and vemurafenib are FDA approved, and there are numerous other agents in the pipeline. Further investigation is needed because these newer agents have had only a limited benefit, with overall survival still very low. Combining newer agents with established older therapies may have value in treating this complex disease state, but combinations of the newer medications may yield the synergy that is desperately needed to overcome the flat rate of survival.

Along with some of the new breast cancer therapies, ipilumumab has put the cost-to-benefit argument directly in the national spotlight. Marginal gains in outcomes with increased toxicities does not make a good argument to payers. This is further aggravated in melanoma due to the relatively low number of cases annually and the cost of research and development: basic supply and demand. With these soaring costs of treatment and the burden on the healthcare system, ethical questions frequently enter the conversation.

While sharing the decision making and costs with the patient as well as educating the health providers certainly helps, properly characterizing the patient’s tumor is equally important. There is a big difference between blindly using a drug with little or no evidence that it will work and knowing that the tumor has the right markers for success. All things considered equal, the standard of care should likely be the first approach.

About the Authors

Affiliations:

Michael M. Mohundro, PharmD, is the director of Pharmacy at Our Lady of the Lake Regional Medical Center in Baton Rouge, LA. Alexis E. Horace, PharmD, is an assistant professor at the University of Louisiana at Monroe College of Pharmacy in Baton Rouge, LA.

Disclosures:

The authors report no financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Address correspondence to:

Michael M. Mohundro, PharmD, Department of Pharmacy, Our Lady of the Lake Regional Medical Center, 5000 Hennessy Blvd, Baton Rouge, LA 70808. E-mail: michael.mohundro@ololrmc.com.

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