Emma Hitt, PhD

Figure 1. Cancer Mortality Rates by State: Melanoma

*Age-adjusted 2000 US population; white and nonwhite and both sexes, 1990-2004, all ages. Source: ratecalc.cancer.gov

Until recently, the cornerstone of therapy for metastatic melanoma had been chemotherapy with dacarbazine (DTIC) and immunotherapy with high-dose interleukin-2 (HD IL-2) or interferon-&alpha; (IFN-&alpha;). Although considered standard-of-care treatment, DTIC has shown objective response rates as low as 15.3% for a total of 3356 patients enrolled in more than 20 studies. Additionally, most of these responses were partial. Despite significant toxicity, immunotherapy with high-dose IL-2 resulted in a substantial benefit for some patients, leading to a 27% survival rate at 2 years and 16% at 4 years, in a trial involving 684 patients. However, the efficacy of IFN-&alpha; remains controversial. Its significant toxicity, especially at high doses, has restricted its use. Due to its easier use and reduced side effects compared with unmodified IFN-&alpha;, pegylated IFN-&alpha; was approved by the FDA in the adjuvant setting in 2011 for patients with lymph node-positive resected melanoma. Trials remain ongoing to evaluate its optimal dosage, as well as the subset of patients that might benefit from this option.

Frontline treatment options for patients with advanced melanoma have recently improved with the 2011 FDA approval of vemurafenib and ipilimumab, both with indications for metastatic disease. Vemurafenib is an orally available, targeted agent that selectively inhibits the BRAF kinase. It has specificity for the V600E-mutated form of the protein, the oncogenically active variant in 90% of patients with BRAF-mutated melanoma.

In the randomized phase III BRIM-3 study, vemurafenib was compared with DTIC in 675 patients with previously treated, BRAF

-positive metastatic melanoma. The response rate was substantially improved in patients treated with vemurafenib versus DTIC (48% vs 5%). Patients in the vemurafenib arm also experienced a markedly improved 6-month overall survival (OS) compared with those in the DTIC arm (84% vs 64%). Vemurafenib was also associated with a relative reduction in risk of death (63%), and a 74% reduction in the risk of either death or disease progression compared with DTIC (

Ipilimumab is a fully human, monoclonal antibody directed against the T-cell antigen cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4). In a multicenter, single-arm, phase II clinical trial, ipilimumab was shown to be active in patients with relapsed metastatic melanoma, with 27% of patients achieving disease control, despite a low overall response rate (5.8%). The 1-year and 2-year survival rates were 47.2% and 32.8%, respectively.

Subsequently, in the randomized, prospective phase III MDX010-20 trial, ipilimumab significantly prolonged median OS when administered either as a single-agent (10.1 months) or combined with the gp100 vaccine (10.0 months), versus gp100 alone (6.4 months;

< .001 for each comparison, respectively).

Another phase III trial, Study 024, found that OS was significantly improved in patients in the DTIC plus ipilimumab combination group (11.2 vs 9.1 months;

< .001). Survival rates were higher in the ipilimumabDTIC group at 1 year (47.3% vs 36.3%), 2 years (28.5% vs 17.9%), and 3 years (20.8% vs 12.2%). Treatment with ipilimumab plus DTIC produced a two-fold improvement in the median duration of response compared with the DTIC plus placebo arm (19.3 vs 8.1 months;

Both vemurafenib and ipilimumab are recommended by the National Comprehensive Cancer Network (NCCN) as category 1 options for treatment of advanced melanoma. The choice of treatment is individualized: Since patients with less-aggressive, low-volume, or asymptomatic metastatic melanoma may have more time to allow an antitumor immune response to mount, they may be good candidates for ipilimumab therapy; patients with more-aggressive, BRAF mutation-positive advanced melanoma, however, may benefit more from first-line treatment with vemurafenib.

In late May 2013, dabrafenib, a BRAF inhibitor, received approval for the treatment of patients with unresectable or metastatic melanoma with BRAF

mutation. A multicenter, international, open-label, randomized, active-controlled phase III trial evaluated the efficacy and safety of dabrafenib compared with DTIC in 250 patients with previously untreated, histologically confirmed, unresectable stage 3 or 4 melanoma that has been determined to be BRAF

mutation- positive by centralized testing. Median progression-free survival (PFS) was significantly improved in patients in the dabrafenib arm compared to the DTIC arm (5.1 vs 2.7 months). The most common drug-related adverse events (AEs) were hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. Serious AEs involved development of new primary skin cancers (cutaneous squamous cell carcinomas [SCC], new primary melanomas, and keratoacanthomas), febrile drug reactions requiring hospitalization, hyperglycemia, and uveitis/iritis.

RTK=receptor tyrosine kinase signaling pathway, which includes

oncogenes. PI3K=phosphatidylinositol 3-kinase pathway activation also occurs in melanoma.

Also approved in May 2013, trametinib is a MEK inhibitor and first in its class to receive approval, and is indicated for use in patients with unresectable or metastatic melanoma with BRAF

mutation. A multicenter, international, open-label, randomized, active- controlled phase III trial evaluated the efficacy and safety of trametinib compared to chemotherapy with either DTIC or paclitaxel in 322 patients with histologically confirmed, stage 3c or 4 melanoma determined to be BRAF

mutation-positive by centralized testing. Patients were not permitted to have received more than one prior chemotherapy regimen, and those with previous exposure to BRAF inhibitors or MEK inhibitors were ineligible. Median PFS was significantly improved in patients in the trametinib arm, compared with those receiving chemotherapy (4.8 vs 1.5 months). Trametinib did not demonstrate antitumor activity in patients who had received prior BRAF inhibitor therapy. The most common drug-related AEs were rash, diarrhea, and lymphedema. Serious AEs included cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease, and serious skin toxicity.

There are currently numerous experimental therapeutic options in various phases of clinical development that may hold promise for patients with advanced melanoma.

In the MAPK pathway, MEK kinases are situated immediately downstream of the BRAF kinase; once activated, MEK kinases trigger activation of pathways responsible for tumorigenesis. GSK1120212 is one such small molecule that has now reached phase III trials for the treatment of melanoma. In a phase III study, this selective, allosteric inhibitor of MEK 1 and 2 induced an objective response in 22% of patients, and 74% experienced some degree of tumor regression. Most common AEs included diarrhea, rash, and peripheral edema. No cases of SCC occurred.

AZD6244 is another MEK inhibitor that selectively binds to MEK 1 and 2. This drug remains in phase II clinical trials to evaluate its efficacy in treating patients with stage III or IV melanoma.

Lenvatinib is an oral, multitargeted receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFR&beta;. In a recent phase II study in which lenvatinib was administered to 93 patients with advanced BRAF wildtype melanoma, some clinical benefits were seen, with confirmed partial responses in 9% of patients, and a 32% clinical benefit rate. Median PFS was 3.7 months, and median OS was 9.5 months. Dose reduction was required to manage toxicity in 46% of patients. Most frequent AEs included hypertension, fatigue, nausea, diarrhea, and reduced appetite.

-paclitaxel (Abraxane) is a nanoparticle formulation of paclitaxel bound to albumin for injectable suspension. In a randomized, international phase III study in chemotherapy-na&iuml;ve patients with metastatic melanoma,

-paclitaxel significantly improved PFS compared to patients receiving DTIC chemotherapy.

Darleukin is a fully-human vasculartargeting immunocytokine, a fusion protein containing interleukin-2 (IL-2), which increases the safety of administration of IL-2, and improves its antitumor activity. Darleukin is currently being tested in a randomized phase IIb study of its efficacy in combination with DTIC, compared to DTIC monotherapy, in patients with metastatic melanoma.

Allovectin is a plasmid-based immunotherapy expressing HLA-B7 and &beta;2 microglobulin genes, and is designed to stimulate local and systemic antitumor responses. In a phase II single-arm study to evaluate the efficacy of intralesional injection of Allovectin-7 in 127 patients, the overall response rate was 11.8% and median OS was 18.8 months. The median duration of response was 13.8 months, and all responses lasted for more than 6 months.

A phase III trial remains ongoing to compare the safety and efficacy of Allovectin-7 vs DTIC or temozolomide in patients with recurrent stage 3 or stage 4 melanoma.15 Patients in the phase II study with similar characteristics to those in the new phase III study (chemo-na&iuml;ve with a single lesion injected) had a 17% overall response rate, and a median OS of 22.5 months.

Data have demonstrated clinical benefit of cancer vaccines containing a specific cancer antigen, and a peptide vaccine for melanoma. Toll-like receptor (TLR) agonists have the potential to enhance antitumor T-cell responses, either in combination with incomplete Freund&rsquo;s adjuvant (IFA) or alone. CD40 ligation at the vaccine site microenvironment may also enhance adjuvant activity. A clinical trial is recruiting patients with resected stage 3B-4 melanoma, and is designed to evaluate the efficacy and safety of a multipeptide vaccine with TLR agonists and IFA.

Figure 3. Mechanism of Action of PD-1 Inhibitors

By binding PD-1 on the surface of T cells, cancer cells can evade the immune system. Therapies that block PD-1/PD-L1 can reactivate the immune system.

Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy (OI) designed to selectively replicate in tumors and produce granulocyte-macrophage colony-stimulating factor (GM-CSF) to increase systemic antitumor immune responses. It is the first OI to demonstrate therapeutic benefit against melanoma, and represents a novel treatment option for melanoma with regional or distant metastases. In the phase III, randomized trial (OPTiM), the efficacy of T-VEC was evaluated in 436 patients with unresected stage 3B, 3C, or 4 melanoma, compared to GM-CSF. Data revealed that the primary endpoint of durable response rate was met, demonstrating a significant difference in the T-VEC arm compared to the GM-CSF arm (16% vs 2%). Most frequent AEs included chills, fatigue, and pyrexia. Serious AEs occurred in 26% of patients in the T-VEC arm, and 13% in the GM-CSF arm.

PD-1 Blockers PD-1 is an inhibitory T-cell co-receptor that may result in suppression of antitumor immunity. Various antibodies are being developed to inhibit the PD-1 pathway.

Lambrolizumab is a humanized, monoclonal IgG4 antibody against PD-1. In an ongoing phase Ib study of 135 patients with advanced melanoma, with or without previous ipilimumab treatment, preliminary data showed that even the lowest dose of lambrolizumab administered intravenously resulted in a high rate of sustained tumor regression. In addition to its significant antitumor activity, lambrolizumab was well-tolerated with manageable AEs. The confirmed overall response rate pooled across all dose cohorts was greater than 35%, with 77% of patients demonstrating a reduction in tumor burden, including 8 who had stable disease for more than 24 weeks. The most common drug-related AEs to date include grade 1/2 fatigue, pruritus, and rash. The incidence of grade 3/4 AEs was 10%.

Nivolumab is another humanized, monoclonal IgG4 antibody against PD-1. In a phase I trial of 107 patients with

CTLA-4 Blockade and GM Secreting Tumor Vaccine Combinations

CTLA-4 Blockade and PD-1 Blockade Combination

melanoma, data showed that nivolumab produced durable OS and responses with an acceptable safety profile. Cohorts of patients received 0.1, 0.3, 1.3, and 10mg/kg. Median OS across all doses was 16.8 months, and 20.3 months at the 3 mg/kg dose that was selected for phase III trials; 44% and 40% of patients remained alive at 2 and 3 years respectively; and of 29 responders who had been treated for at least one year, 16 demonstrated responses lasting one year or more. Drug-related AEs occurred in 82% of patients, and included lymphopenia, fatigue, and elevated serum lipase levels. Grade 3/4 AEs occurred in 21% of patients, and included diarrhea, endocrine disorders, and hepatitis.

Clinical and preclinical studies have begun to demonstrate evidence to support the use of combination therapies as a therapeutic strategy in melanoma. Numerous combined regimens are being evaluated, and include:

These combinations have shown therapeutic synergy in preclinical studies. GM increases dendritic cell activation, enhances antitumor T and B cell responses, and may activate regulatory immune responses. It has shown benefit in various types of carcinoma, and is also being evaluated in phase III adjuvant trials for melanoma. In a randomized phase II trial involving 245 patients, ipilimumab plus GM significantly increased OS compared to ipilimumab alone (67.9% vs 51.2%), as well as improved OS (17.5 months vs 12.7 months), with no significant differences in toxicity. This combination of GM-CSF and ipilimumab therefore may hold promise for improving survival of patients with advanced melanoma.

This combination of drugs also appears to offer potential benefit for treatment of melanoma, compared with monotherapy. Combination immunotherapy with ipilimumab and nivolumab has also been demonstrated to produce durable tumor regression with a manageable safety profile. In a phase I trial involving 53 patients, intravenous doses of nivolumab and ipilimumab were administered every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses; the combined treatment was then administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab were treated with nivolumab every 2 weeks for up to 48 doses. Clinical activity was observed in 65% of patients, and at the maximum doses that were associated with an acceptable level of AEs, 53% of patients had an objective response, with tumor reduction of 80% or more. Drug-related grade 3/4 AEs occurred in 53% of patients in the concurrent-regimen group, but were typically reversible, and in 18% in the sequenced-regimen group. The objective response rate was increased in the concurrent-regimen group compared to the sequenced-regimen group (40% vs 20%).

Metastatic melanoma remains one of the most therapeutically challenging malignancies, and curative treatments remain elusive. However, for the first time in decades, new drugs have resulted in significant clinical responses. Advances in basic and clinical research have produced novel treatment strategies that target specific molecules and pathways expressed in cancer cells. And one of the major focuses in melanoma therapy continues to be the understanding and targeting of signal transduction pathways responsible for the tumor&rsquo;s capacity for growth and resistance to chemotherapy.2 Additionally, the molecular heterogeneity of melanoma, and the recognition of numerous mechanisms of resistance to targeted therapies, support the use of a combinatorial approach to treatment. Clinical management of melanoma is therefore improving with increased understanding of the molecular pathogenesis of the tumor.

Pretto F and Neri D. Pharmacotherapy of metatstatic melanoma: emerging trends and opportunities for a cure.

Nikolaou VA, Stratigos AJ, Flaherty KT, et al. Melanoma: new insights and new therapies.

Evans MS, Madhunapantula SV, Robertson GP, et al. Current and future trials of targeted therapies in cutaneous melanoma. WS El-Deiry (ed), In:

Impact of Genetic Targets on Cancer Therapy

. Advances in Experimental Medicine and Biology. 2013;223-255.

Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation.

O&rsquo;Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study.

Hodi FS, O&rsquo;Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma.

Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.

National Comprehensive Cancer Network. Melanoma. Clinical Practice Guidelines in Oncology. 2012. Available at: http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp#melanoma. Accessed June 16, 2013.

FDA. Darafenib. 2013. Available at: http:// www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ ucm354477.htm. Accessed June 16, 2013.

FDA. Trametinib. 2013. Available at: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ ucm354478.htm. Accessed June 16, 2013.

ClinicalTrials.gov. MEK inhibitor AZD6244 in treating patients with stage III or IV melanoma. Available at: http://clinicaltrials.gov/ct2/show/ study/NCT00866177. Accessed June 16, 2013.

O&rsquo;Day S, Gonzalez R, Kim K, et al. A phase II study of the multitargeted kinase inhibitor lenvatinib in patients with advanced BRAF wild-type melanoma.

Celgene Corporation. ABRAXANE meets primary endpoint of progression-free survival in phase III chemotherapy-na&iuml;ve metastatic melanoma study. Available at: http://ir.celgene. com/phoenix.zhtml?c=111960&p=irol-newsArticle& ID=1740496&highlight. Accessed June 16, 2013.

Kharkevitch DD, Chu A, Strause LR, et al. Association of response and survival in Allovectin melanoma trials.

ClinicalTrials.gov. A phase 3 pivotal trial comparing Allovectin-7 alone vs chemotherapy alone in patients with stage 3 or stage 4 melanoma. Available at: http://clinicaltrials.gov/show/ NCT00395070. Accessed June 16, 2013.

Slingluff CL, Petroni GR, Chianese-Bullock KA, et al. A multipeptide vaccine plus toll-like receptor agonists in melanoma patients, with evaluation of the vaccine site microenvironment and sentinel immunized node (Mel58; NCT01585350).

ClinicalTrials.gov. A multipeptide vaccine plus toll-like receptor agonists in melanoma patients. Available at: http://www.clinicaltrials.gov/ct2/ show/NCT01585350?term=NCT01585350& rank=1. Accessed June 16, 2013.

Andtbacka RHI, Collichio FA, Amatruda T, et al. OPTiM: a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma.

Ribas A, Robert C, Daud A, et al. Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma.

Sznol M, Kluger HM, Hodi S, et al. Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS- 936558; ONO-4538).

Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma.

Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. June 2, 2013 [Epub ahead of print].

Kwong LN, Davies MA. Targeted therapy for melanoma: rational combinatorial approaches.

Articles

Until recently, the cornerstone of therapy for metastatic melanoma had been chemotherapy with DTIC and immunotherapy with HD IL-2 or interferon-Î±. 

Emma Hitt, PhD | Authors

Articles

Targeted Advances in Melanoma