NE Oncology Issue – September 2012

Teresa Petrella, MD, FRCPC;1 Scott Ernst, MD, FRCPC;2 Alan Spatz, MD;3 Joel Claveau, MD, FRCPC;4 Ralph Wong, BSc, MD, FRCPC;5 Michael Smylie, MD, FRCPC6

1Division of Medical Oncology/Hematology, Odette Cancer Centre, Toronto, Ontario; 2Division of Medical Oncology, London Regional Cancer Program, London, Ontario; 3Department of Pathology, Jewish General Hospital, Montreal, Quebec; 4Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec and Hotel-Dieu de Quebec, Quebec City, Quebec; 5Cancer Care Manitoba, Winnipeg, Manitoba; 6Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta

Medical Writer: Diana Stempak, MSc, PhD, New Evidence

Corresponding Author: Dr. Teresa Petrella, Division of Medical Oncology/Hematology, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, T2-041, Toronto, ON, M4N 3M5 Telephone: 416-480-5248 • Fax: 416-480-6002 • Email: teresa.petrella@sunnybrook.ca

Metastatic melanoma is almost invariably incurable and the prognosis for patients with this disease is quite dismal. Historically, the median survival time for a patient with metastatic melanoma is six to nine months and the five-year overall survival (OS) rate is less than 5%. Until recently, there were few treatment options available for metastatic melanoma and those available demonstrated low efficacy and significant toxicity. The discovery, development and recent approval of novel agents such as vemurafenib (a selective BRAF inhibitor) and ipilimumab (a novel immunotherapeutic agent) has resulted in patients experiencing prolonged survival with manageable adverse events. In the case of vemurafenib, the importance of selecting patients in this new era of personalized medicine has been underscored. While challenges exist to implementing rapid, efficient biomarker testing, this is an essential component of therapy that will improve outcomes in this traditionally difficult-to-treat population. The recent approval of these new agents necessitates a shift in the treatment paradigm and in attitude. As a result, a renewed sense of hope now exists in a therapeutic area that was previously burdened by poor outcomes.

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Background

In 2012, 5,800 new cases of melanoma will have been diagnosed in Canada and 970 deaths will have been attributed to this disease.1 In the past several decades, the incidence rates for melanoma have significantly increased, particularly in males.2,3 The lifetime probability of developing melanoma is one in 85 for females and one in 67 for males and the five-year relative survival for melanoma is 90%.4

Melanoma, if detected early, is highly curable by appropriate surgery,5 but in patients with high-risk features (tumour thickness [depth greater than 4 mm], ulceration, high mitotic rate or regional node involvement) the risk of developing metastases can be very high (30% to 80%).6 Of these patients, 10% to 40% will present with metastases to the central nervous system (CNS) including the brain.7 Melanoma can metastasize to almost every major organ and tissue. (Table 1) The most common initial sites of distant metastases are the skin and soft tissue, and lymph nodes.8 The most common sites of visceral metastases are the lung, brain, liver, gastrointestinal tract, and bone.9 The prognosis for patients with metastatic melanoma is quite dismal as the disease is almost invariably incurable.5,10 Historically, the median survival time for patients with metastatic melanoma is six to nine months and the fiveyear overall survival (OS) rate is less than 5%.10 Until recently, there were few treatment options available for metastatic melanoma and those available demonstrated low efficacy and significant toxicity. Without question, metastatic melanoma is a devastating disease with a need for novel treatment strategies that has been unmet until the discovery and development of novel agents such as BRAF (v-raf murine sarcoma viral oncogene homologue B1) inhibitors (vemurafenib and dabrafenib) and novel immunotherapies (ipilimumab).

The purpose of this paper is to present a general discussion and summary on the clinical management of metastatic melanoma in Canada. New therapies such as vemurafenib and ipilimumab will be discussed, as well as promising new agents and/or combinations that are being explored in clinical trials. The goal is to raise awareness in the oncology community about new treatment approaches to metastatic melanoma, and to highlight the importance of rapid coordination and testing for biomarkers that are the targets for a more personalized approach to cancer therapy. With recent notable improvements in outcomes in patients with metastatic melanoma, the prognosis of this disease may not be as dismal as it was in the past. While this paper is evidence-based, it does not reflect a systematic literature review and is not meant to be used as a consensus guideline.

The Evolution of Cancer Therapy: From Chemotherapy to Personalized Medicine

Systemic chemotherapy was introduced well over 60 years ago as an approach to treating cancer by directly killing tumour cells. These agents function by varying mechanisms such as damaging deoxyribonucleic acid (DNA), impairing DNA repair, inhibiting microtubule formation and acting as alkylating agents. However, the cytotoxic effects are not limited to tumour cells alone, they also target any rapidly dividing cell in the body including bone marrow cells, hair follicles, and gut mucosal cells resulting in the classic side effects of myelosuppression, mucositis, alopecia, nausea, and vomiting.

The last decade has seen an emergence of therapies targeting the molecular and cellular changes specific to cancer such as specific cell signals and receptors, rather than all rapidly dividing cells. Used as monotherapy or in combination with other agents, these targeted therapies have significantly improved patient outcomes and the safety of treatment over previously accepted standards.11 Almost every malignancy can be divided into molecular subsets that vary in prognosis, natural history, and response to treatment. Research has now yielded an increasing number of available targeted therapies that are uniquely effective in small subpopulations of each tumour type.12

With these recent advances, the term personalized medicine has been coined and there has been a prominent shift in the general healthcare field as well as in oncology. The goal is to understand the relevant characteristics underlying a particular individual’s disease, which include both disease and host factors, and tailor therapy to that individual or disease. In other words, it is the use of the right drug, at the right dose, for the right patient, at the right time.13 While significant advances have been made in a number of tumour types, little change has been realized in the treatment of metastatic melanoma until very recently. Today, metastatic melanoma is at the forefront of the movement toward personalized medicine. To better understand how these new treatments fit into the treatment paradigm, it is important to look at how melanoma can be classified.

Classification of Melanoma

Different approaches can be taken to classify melanoma based on clinical, histological, and epidemiological characteristics.14 Historical classification by histologic subtypes included superficial spreading, nodular, lentigo maligna, and acral lentiginous.15 Melanoma can also be studied based on non-cutaneous sites (e.g., uveal tract of the eye and mucosal surfaces).16,17 In the past, efforts to classify melanoma into biological subtypes have had little impact on the clinical management of the disease and, in particular, on the management of metastatic melanoma. Cytotoxic and immunological therapies that have been available to date did not target specific pathways in cells, and most were not effective in controlling the disease regardless of the primary origin of the disease. In spite of the identification of a wide variety of genetic abnormalities and potential molecular targets in melanoma, effective targeted agents are required in order to advance patient outcomes.

In more recent years, emerging molecular data have provided strong genetic support for the notion of biologically distinct melanoma subtypes as mutations in oncogenes, tumour suppressor genes, and others have been discovered.14 Mutated oncogenes include NRAS (neuroblastoma RAS (rat sarcoma) viral (v-ras) oncogene homologue), BRAF, c-KIT (v-kit Hardy- Zuckerman 4 feline sarcoma viral oncogene homologue), GNAQ (guanine nucleotide binding protein (G protein), q polypeptide), and GNA11 (guanine nucleotide-binding protein subunit alpha-11). Tumour suppressor genes that are mutated include PTEN (phosphatase and tensin homologue), P53, and others. Some of these molecular alterations appear to be linked to the degree of sun exposure, histology, and physical location of the primary melanoma.18,19 The incidence of some of these mutations is summarized in Table 2. While the prognostic importance of many of these markers has not yet been demonstrated, the prognostic significance of BRAF has recently been shown. The presence of a BRAF mutation may be associated with poorer survival in patients with metastatic melanoma.20 It is suggested that BRAF-targeted therapy may transform the more aggressive tumour biology conferred by BRAF mutations20 into a more favourable phenotype similar to patients with amplified human epidermal growth factor 2 (HER2) in breast cancer who are treated with HER2-targeted therapies.21

These mutations are emerging targets for therapy and because the mutations are generally mutually exclusive, melanoma can be molecularly classified into distinct subtypes which will differ in the response to therapy. Melanoma is a heterogeneous disease and should no longer be treated as homogenous entity.

Treating Metastatic Melanoma in the Past

Over the last three decades, there have been few developments in more effective treatment strategies for metastatic melanoma. Systemic approaches that have been evaluated to date for metastatic disease include cytotoxic chemotherapy as single agents and in multi-drug combinations including dacarbazine (DTIC), temozolomide and platinum agents (carboplatin, paclitaxel, and protein-bound paclitaxel) and immunotherapies including the cytokines interferon-α (IFN) and interleukin-2 (IL-2).5 Treatment with DTIC, alone or in combination, has resulted in low response rates, rare durable responses, and no impact on survival. Though response rates for single agent IL-2 have been low, treatment with IL-2 had attracted some attention because of reports of durable responses in complete responders.26 The combination of chemotherapy with immunotherapy (biochemotherapy) resulted in increased response rates as observed in numerous phase III trials,10,27 but survival benefit has not been demonstrated while toxicity was significantly increased.27 Treating metastatic melanoma in the past has largely involved the use of best supportive care measures due to the lack of effective and tolerable treatment options. Until recently, oncologists specializing in melanoma watched significant advances being made in other malignancies. The paradigm is now shifting and significant advances are beginning to be realized.10

A New Era for the Treatment of Metastatic Melanoma

The heterogeneity of melanoma underscores the need for patient-specific diagnostic and treatment approaches,28 and the recognition of the heterogeneity of the disease is precisely what has driven recent clinical advances. The two leading agents that are changing the landscape of melanoma therapy are the highly selective BRAF inhibitor, vemurafenib, and the anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody, ipilimumab. Additional targets and new agents against these targets are currently being studied in phase III trials. These will be briefly addressed later in this paper. Furthermore, molecules are under development in each of these two drug classes and various combinations remain to be explored as synergies may become evident between different classes of drugs as well as between agents within the same class.27 Even for patients whose melanomas contain mutant BRAF, decisions about therapy with an inhibitor versus ipilimumab will need to be individualized.29

The selection of the most appropriate course of treatment is dependent on a number of factors that include, but are not limited to, the presence of a molecular target, tumour burden, rapidly versus slowly progressing disease, presence of brain metastases, performance status, and the ability to tolerate treatment. The current standard of care for metastatic melanoma in Canada is clinical trials and this will continue to be the case as combination therapies are investigated to further improve outcomes. For example, the recent observation that ipilimumab improves survival in patients with metastatic melanoma suggests the possibility of combining CTLA-4 blockade with BRAF inhibition.29 BRAF inhibition seems to enhance antigen presentation that may potentiate activity when the two agents are used together.30

BRAF: A Key Target for the Treatment of Metastatic Melanoma

BRAF is a RAS-(guanine nucleotide binding protein) activated serine/threonine protein kinase. It plays a central role in regulating the MAPK (mitogen-activated protein kinase) signalling pathway that normally regulates cell growth, division, and differentiation.31,32 (Figure 1) The MAPK signalling pathway has long been associated with human cancers due to frequent oncogenic mutations identified in RAF (rapidly growing fibrosarcoma) family members. The V600E activating mutation in BRAF (substitution of a valine for glutamic acid at position 600) is the most common mutation accounting for over 90% of BRAF mutations although other activating mutations are known (e.g., BRAF V600K and BRAF V600R).33 It significantly increases the kinase activity of BRAF resulting in uncontrolled cell growth, reduced apoptosis, increased invasiveness, and increased metastatic potential.31 V600E inhibition leads to inhibition of MAPK activation and, therefore, to growth arrest, apoptosis, and reversal of the malignant phenotype,10 making this an ideal target on which to focus therapeutic strategies. In 2002, it was discovered that approximately 50% of human melanomas harbour an activating mutation in BRAF, raising the possibility that melanoma could be amenable to targeted therapy.34 While a number of agents with some BRAF inhibitory activity have been studied in oncology, recent efforts have been focusing on the highly selective BRAF inhibitors. Vemurafenib is one such agent that has recently been approved by Health Canada. Other selective BRAF inhibitors include dabrafenib (GSK2118436), which has been shown to be effective in phase II35 and phase III trials.36

Vemurafenib: A Novel Selective BRAF Inhibitor

The first selective BRAF inhibitor to be developed in the clinical setting is vemurafenib (PLX4032). Vemurafenib is a small molecule inhibitor that binds potently to and selectively inhibits the BRAF V600 oncogenic mutation.37,38 Preclinical studies of vemurafenib in cell lines that were positive for the BRAF mutation demonstrated vemurafenib’s ability to inhibit extracellular signal regulated kinase (ERK) activation, arrest the cell cycle,39,40 selectively inhibit cell growth41 and proliferation,39 and induce apoptosis leading to cell death.40

In a phase I dose escalation study, vemurafenib was administered to 55 patients with solid tumours and to 32 patients with BRAF V600E mutation-positive metastatic melanoma in the extension phase of the study. All 32 patients in the extension phase received the recommended phase II dose of 960 mg twice daily. In the extension phase, vemurafenib was found to have high single-agent clinical activity with unprecedented response rates of 81% in patients, including those who had previously received multiple lines of chemotherapy, as well as at metastatic sites such as bone and liver that are typically refractory. A clear impact on progression-free survival (PFS) was also observed but these findings were only seen in patients with the V600E mutation. Patients who had wild-type BRAF had no evidence of tumour regression.42 As of August 2011, as presented at the ECCO/ESMO meeting, the OS estimate for the patients included in the extension phase was 13.8 months.43

The efficacy of vemurafenib in previously treated patients was confirmed in a phase II trial (BRIM-2) of 132 patients with BRAF V600E mutation-positive metastatic melanoma. The confirmed overall response rate (ORR) assessed by an independent review committee (IRC) was 53% (95% confidence interval [CI]: 44–62), with 6% achieving a complete response (CR) and 47% achieving a partial response (PR). Additionally, four of the 10 patients who had a BRAF V600K mutation had a PR to vemurafenib. The median PFS was 6.8 months (95% CI: 5.6–8.1) and the median OS was 15.9 months (95% CI: 11.6–18.3).44

In a phase III trial (BRIM-3) comparing first-line therapy of vemurafenib to DTIC, 675 patients with unresectable stage IIIC/ stage IV melanoma with the V600E BRAF mutation were treated. Vemurafenib was associated with statistically significantly improved OS and PFS compared with DTIC. (Figures 2 and 3) The key efficacy results for BRIM-3 are summarized in Table 3.

In the interim analysis (data cut-off December 20, 2010), vemurafenib was associated with a relative reduction of 63% in the risk of death (HR for death = 0.37 [95% CI: 0.26–0.55; p <0.001]) and with a relative reduction of 74% in the risk of tumour progression (HR for tumour progression = 0.26 [95% CI: 0.20–0.33; p <0.001]). The median time to response in the vemurafenib group was 1.45 months compared with 2.7 months in the DTIC group and the difference in the confirmed response rates was highly significant (p <0.001). In the vemurafenib group, 10 patients were later found to have BRAF V600K mutations; of these patients, four had a PR (40%). Benefit was observed in all subgroups studied including patients with poor prognosis including those with M1c disease or elevated lactate dehydrogenase (LDH). Vemurafenib consistently improved PFS, OS, and best ORR in this patient population.45

A total of 618 patients (92%) in the BRIM-3 study underwent at least one assessment for toxic effects. (Table 4) The most common adverse events (AEs) in the vemurafenib group were cutaneous events, arthralgia, and fatigue. Grade 2 or 3 photosensitivity skin reactions were observed in 12% of the patients and it was noted that grade 3 photosensitivity reactions characterized by blistering could have been prevented with the application of sunblock. As expected, the most common severe toxic effects in the DTIC group were fatigue, nausea, vomiting, and neutropenia. AEs resulted in dose modification or interruption in 129 of 336 patients (38%) in the vemurafenib group and in 44 of 282 patients (16%) in the DTIC group. In the vemurafenib group, 61 patients (18%) developed cutaneous AEs with a cutaneous squamous-cell carcinoma or kertoacanthoma, or both. All lesions were treated by simple excision.45

Vemurafenib has also shown promise in the treatment of patients with melanoma metastatic to the brain that harbours a BRAF mutation. Preliminary results suggest that vemurafenib is well tolerated and that it has activity in metastatic melanoma that has metastasized to the brain.47 A phase II study is currently ongoing to confirm these results. Furthermore, in a recent phase II trial, dabrafenib was also shown to have activity in melanoma that is metastatic to the brain, suggesting that there is a role for BRAF inhibition in the treatment of such patients.48

BRAF Resistance

It has become evident that metastatic melanoma can become resistant to BRAF inhibition and a number of mechanisms have been proposed. (Table 5)

Novel drug combinations, such as BRAF inhibitors plus MEK inhibitors or BRAF inhibitors plus PI3K/AKT inhibitors, are being evaluated in clinical trials with the hope of circumventing resistance mechanisms. It is also thought that combining BRAF and MEK inhibition may reduce the formation of squamouscell carcinomas.30

Immune Modulation to Treat Metastatic Melanoma

There are several examples of the successful use of monoclonal antibodies as targeted therapies in cancer including HER2 blockade by trastuzumab in breast cancer and CD20 blockade by rituximab in lymphomas. Extensive research efforts have focused on using antibodies to control immune checkpoints that diminish and extinguish anti-tumour immune responses.10 Immunological therapies for metastatic melanoma, including the use of cytokines, tumour vaccines, adoptive immunotherapy, and combinations, have been extensively studied but none have shown an impact on OS.49

Cytotoxic T-lymphocyte antigen 4, CD152 (CTLA-4) is a member of the immunoglobulin super-family. It is expressed on a subset of activated human T lymphocytes and regulatory T-cells, and plays a critical role in the control of activated T-cells. As a negative regulator of the immune system, it plays an important role in endogenous and vaccine-induced antitumour immunity. Resting lymphocytes do normally express CTLA-4 but expression is transiently up-regulated upon binding of the T-cell receptor. Up-regulation of CTLA-4 on the surface of cytotoxic T-cells results in inhibition of proliferation of these cells. Cytotoxic T lymphocytes (CTLs) are key to a melanoma-specific anti-tumour response.49 (Figure 4)

Ipilimumab: A Novel Anti-CTLA-4 Antibody

Host immune function has long been observed to play a role in the development and regulation of melanoma growth. In an effort to exploit this interaction, potential immunotherapies have been developed such as IL-2, IFN, and most recently, ipilimumab — a fully humanized monoclonal antibody which is specific against CTLA-4.49 Blocking CTLA-4 with monoclonal antibodies was initially shown to induce regression of established tumours in several mouse models.10 Phase I and II clinical trials showed long-lasting responses, prompting Hodi and colleagues to conduct a phase III clinical trial in patients with stage IV melanoma who were pretreated. Participants were randomized to receive ipilimumab (3 mg/kg), a glycoprotein 100 (gp100) peptide vaccine or both ipilimumab and gp100 once every three weeks for four treatments. Patients who were treated with ipilimumab experienced an improvement in OS, PFS, and ORR.51 The key efficacy results for this trial are summarized in Table 6.

Additionally, a phase III trial was conducted that compared DTIC plus ipilimumab versus DTIC plus placebo in previously untreated patients with metastatic melanoma. Patients received ipilimumab at a dose of 10 mg/kg plus DTIC at a dose of 850 mg/m2 or DTIC plus placebo every three weeks for four cycles followed by DTIC (850 mg/m2) alone every three weeks through week 22. At week 24, patients with stable disease or an objective response who did not have a dose-limiting AE were eligible for maintenance therapy consisting of placebo or ipilimumab every 12 weeks until progression, toxicity, or the end of the study.52 The OS results from this ongoing study are similar to the previous phase III trial and are summarized in Table 7 and Figure 5.

As the first assessment of progression occurred at week 12 after the true median, the median values for PFS were similar in the two groups. After the first tumour assessment, the Kaplan–Meier curves separated. (Figure 6) However, the PFS curves for the two groups subsequently became divergent as patients were followed. The best ORR was 15.2% in the DTIC plus ipilimumab group and 10.3% in the DTIC plus placebo group (p = 0.09). The median duration of response among all patients with a CR or PR was 19.3 months (95% CI: 12.1–26.1) in the DTIC plus ipilimumab group and 8.1 months (95% CI: 5.19–19.8) in the DTIC plus placebo group (p = 0.03).52 (Figure 7) However, it should be noted that the treatment arms of these first-line and second-line phase III trials were considerably different. Further research is warranted to identify and validate the optimal treatment regimen regarding ipilimumab dosing and scheduling as well as combinations.

A distinctive observation of ipilimumab is the variable response patterns, which include a slow, steady decline in baseline lesions, response after an initial increase in the number of lesions, and delayed response in index lesions accompanied by the appearance of new lesions. Although the first two types of responses would be captured using the standard Response Evaluation Criteria In Solid Tumours (RECIST), the last two atypical responses would likely be classified as progressive disease by RECIST. Patients being treated with ipilimumab may have delayed responses or durable stable disease even after apparent disease progression, therefore new immune-related response criteria have been proposed and may be necessary to avoid premature treatment withdrawal.53

While no specific molecular targets exist for ipilimumab, investigating predictive markers to identify patients who are most likely to benefit as long-term survivors should be a priority.49 Such markers could be useful in identifying responders despite early progression, providing clinicians and patients with the confidence to continue treatment.53

Immune-related adverse events (irAEs) are common in patients treated with ipilimumab and may occur in up to 60% of patients.51 The most common irAEs include dermatologic, gastrointestinal (diarrhea), endocrine, and hepatic toxicities. The majority of these irAEs are grade 1/2, non-life threatening, and easily managed. However, the more serious grade 3/4 irAEs can be difficult to manage by healthcare practitioners who lack experience with this drug. Prompt medical attention, early administration of corticosteroids, and close patient follow-up are critical to the management of irAEs.51 In the phase III firstline trial, early treatment discontinuation was primarily due to disease progression; however, significantly more patients discontinued treatment owing to drug-related AEs in the DTIC plus ipilimumab group (36%) than in the DTIC plus placebo group (4%).52

Positioning Vemurafenib and Ipilimumab in Clinical Practice

Over the past few years, there have been major advances in melanoma research and the clinical management of this disease will dramatically shift with the approvals of vemurafenib and ipilimumab. These drugs differ from one another by mechanism, treatment course, clinical outcomes, and AEs, as summarized in Table 8.

Data suggest a potentially synergistic benefit to combining vemurafenib and ipilimumab.30 It has been observed that non-specific inhibitors of the MAPK pathway, such as MEK inhibitors, may reduce T-cell function, and treatment with vemurafenib has been shown to increase melanoma differentiation, antigen expression, and improve antigen-specific T-cell recognition.30 A clinical trial exploring the synergism of these two agents has begun to accrue patients but until this trial is complete, the decision to use of vemurafenib versus ipilimumab should be determined by patient circumstance.30

Additionally, dual pathway blockade may be one way to circumvent resistance to vemurafenib. Evidence currently suggests that the MAPK pathway is activated in order to bypass the BRAF blockade. Targeting this pathway further downstream in the cascade can be achieved using MEK inhibitors such as GSK1120212 (trametinib). Using MEK inhibitors in combination with BRAF inhibitors could theoretically prolong response duration, and also possibly prevent some of the side-effects of the BRAF inhibitors.55 Phase I/II data suggest that combining the BRAF inhibitor GSK2118436 (dabrafenib) and the MEK inhibitor GSK1120212 (trametinib) is safe and has a lower incidence of adverse events associated with each agent alone. Long-term durability data are pending and are anxiously awaited.55 Results of phase III trials are anticipated.

Other Molecular Targets in Development for Metastatic Melanoma

A number of other molecular targets have been identified in melanoma patients. These include c-KIT, BRAF, MEK, NRAS, PI3K, Akt, mTOR, and GNAC. Several pharmacological inhibitors targeting mutated signal transduction molecules are being explored in clinical trials in genetically defined subgroups of patients with melanoma.27,56 (Table 9) Of these, the BRAF and c-KIT inhibitors are furthest in development at the moment.27

c-KIT (CD117) encodes a receptor tyrosine kinase whose ligand is stem cell factor (SCF). This interaction between the receptor and ligand and the resulting signalling drives melanoma differentiation, proliferation, survival, and migration.57 The c-KIT pathway activates downstream pathways including MAPK, PI3K, and Src.

Activating mutations and/or gene amplification of KIT have been reported in as many as 39% of mucosal, 36% of acral, and 28% of melanomas that arise in chronically sun damaged skin.18 In contrast, in a recent Canadian case series, 8.6% of mucosal and 4.2% of acral melanoma cases harboured KIT mutations.24 These activating KIT mutations initiate a series of signalling events that result in cellular proliferation and propagation of cancer.56 The finding of this oncogene is of clinical significance owing to the absence of the BRAF mutation in the majority of these subtypes of melanoma and, therefore, the lack of effective therapeutic options. Although limited in number thus far, clinical experiences confirm KIT as a melanoma therapeutic target and patients have experienced dramatic and durable responses to treatment with agents such as imatinib, nilotinib, and dasatinib. A phase II study of imatinib reported high response rates and prolonged PFS in c-KIT-positive patients,58 and a single agent trial has demonstrated responses59 and a phase II trial with nilotinib is ongoing.

Biomarker Screening

An important component of personalized medicine is the use of predictive biomarkers to aid in selecting patients who have a greater likelihood of responding to a given therapeutic modality. For metastatic melanoma specifically, this would lead to improved outcomes in this traditionally difficult-to-treat population while reducing the likelihood of exposing patients to potentially ineffective therapy and unnecessary side effects. In general terms, there are several criteria that should be met to successfully implement biomarker testing.

Adequate infrastructure is necessary to rapidly assess patients’ tumours for expression of these predictive biomarkers and quality-controlled validated assays with a rapid turnaround time need to be performed in appropriately credentialled laboratories with expertise in specific assay systems. This requires coordination between members of the multidisciplinary team, namely surgeons, pathologists, dermatologists, and medical oncologists. Additionally, educational programs that will update community oncologists on the rapidly evolving standard practice need to be implemented.33

While highly efficacious in a subset of patients, immunotherapy for melanoma currently lacks needed predictive biomarkers for efficacy and toxicities.30 However, it is known that vemurafenib therapy requires the identification of patients with the BRAF mutation much the same way as is now routinely being done for breast cancer (HER2) and chronic myeloid leukemia (BCR-ABL).37 The commercially available cobas® 4800 BRAF V600 Mutation Test was approved by Health Canada in November 2011. The cobas® test is a real-time polymerase chain reaction assay designed to detect the BRAF V600E mutation. It is highly selective for V600E; however, it also detects other BRAF V600 mutations with less sensitivity.30 The test is robust, rapid, and accurate providing a higher sensitivity in detecting the V600E mutation than Sanger sequencing.60 Health Canada recommends the use of a validated test to identify BRAF V600 mutation status.46

Vemurafenib and other BRAF-selective inhibitors should only be prescribed to patients who harbour the BRAF mutation. Recently, several studies have described the challenges of treating non-BRAF V600E melanoma cell lines with a BRAF inhibitor. These studies have demonstrated that BRAF inhibitors can paradoxically induce, rather than inhibit, RAF/MEK signalling in NRAS or wild-type BRAF tumours through the formation of RAF dimers, in a RAS-dependent manner thus stimulating cell proliferation.28,29 These studies underscore the need to carefully select the right patient population on the basis of BRAF mutational status before treating with BRAF selective inhibitors.28

Despite the clear need for mutation testing in metastatic melanoma, a number of challenges and barriers exist. Some of these are unique to metastatic melanoma and others are more general and apply to other therapeutic areas. These include funding of the molecular test, turnaround time, logistical issues surrounding sample collection and handling, and timing of the test amongst others. There are also different models for biomarker screening that ought to be considered including a central reference centre model that uses a single imposed platform versus a network of reference centres and different platforms. Funding and availability of the test will be governed provincially. It is likely that testing will require some centralization as not all treatment centres have a molecular or skin pathologist. Strategies will need to be implemented to allow for efficient testing in order to avoid treatment delays. Furthermore, multiplexing of tests for various biomarkers will be important particularly in melanoma because there is a limited amount of tissue available. This tissue may be limited to the original melanoma, which can be very small and it may be difficult to obtain more. Multiplexing allows for the screening of an array of mutations at once (BRAF, cKIT, NRAS, and GNAQ amongst others). This should be done for high-risk patients before they become metastatic. Given that the incidence of BRAF mutations is approximately 50%, fast and accurate testing is especially critical in order to initiate vemurafenib in a timely fashion, particularly in rapidly progressing disease.

A Foundation to Build On

Recently, melanoma has earned the designation as “an unlikely poster child for personalized cancer therapy.”29 As new agents transition from the clinical trial context to widespread clinical practice, their use, including the management of AEs, will require optimization. Furthermore, new strategies will be needed to treat patients in whom resistance to BRAF inhibitors develops. Rational combination with other agents including other targeted therapies and immune therapies is one approach to overcome drug resistance. It is very likely that within the next several years, melanoma patients will be routinely screened for the presence of a panel of specific markers to determine the most appropriate therapeutic approaches that will undoubtedly have a positive impact on outcomes.

The key message is that metastatic melanoma is no longer the dismal disease it once was. With the recent approval of these new agents, a shift in the treatment paradigm and in attitude is needed. There now exists a renewed sense of hope in a therapeutic area that was previously burdened by poor outcomes.

Acknowledgments

The authors acknowledge medical writing support from Diana Stempak MSc, PhD of New Evidence; this support was funded by Hoffman La-Roche.

Conflict of Interest Disclosures

Dr. Petrella is an advisor and consultant for Bristol-Meyers Squibb, Glaxo SmithKline, Hoffmann-La Roche, and Merck. Dr. Ernst is an advisory board member for Bristol-Meyers Squibb and Hoffmann-La Roche. Dr. Claveau is a consultant and investigator for Bristol-Meyers Squibb, Glaxo SmithKline, Hoffmann-La Roche, Merck, and Novartis. Dr. Spatz and Dr. Wong do not have any conflicts of interest to disclose.

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Canadian Perspectives

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Sunil Verma, MD, MSEd, FRCPC

Dr. Sunil Verma is a medical oncologist and the Chair of Breast Medical Oncology at the Sunnybrook Odette Cancer Centre in Toronto, Ontario. He is also an Associate Professor at the University of Toronto. Dr. Verma completed his medical degree and postgraduate training in internal medicine and medical oncology at the University of Alberta. He completed a fellowship in breast cancer at the University of Toronto and a master’s degree in medical education at the University of Southern California. Dr. Verma is internationally recognized for his educational leadership and research in breast and lung cancers. He has led and created numerous innovative educational projects in oncology and won several teaching and mentoring awards. Dr. Verma’s research interests include reducing the toxicity of systemic treatment, developing novel therapies for breast and lung cancers, and medical education. He is the principal inves - tigator for many clinical trials in breast and lung cancers, including an international phase III trial in breast cancer, and has authored or co-authored articles appearing in publications such as the Journal of Clinical Oncology, Cancer, The Oncologist, and Lancet Oncology.

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Douglas A. Stewart, BMSc, MD, FRCPC
Dr. Douglas A. Stewart is currently a pro - fessor in the Departments of Oncology and Medicine, and Chief of the Division of Hematology and Hematological Ma - lignancies at the University of Calgary. Since July 1994, he has been practising medical oncology at the Tom Baker Cancer Centre in Calgary, where he is a member of the Breast Cancer and Hematology Tumour Groups, Leader of the Hematology/Blood and Marrow Transplant Program, and Provincial Leader of the Hematology Tumour Team for the Alberta Health Services Cancer Care Program. His research interests focus on clinical trials involving hematological malignancies and hematopoietic stem cell transplantation. Dr. Stewart has authored over 80 peer-reviewed manuscripts and over 120 abstracts.

Investigator Commentaries

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Kimberly L. Blackwell, MD

Dr. Kimberly Blackwell is a medical oncologist, Professor of Medicine, and Assistant Professor of Radiation Oncology at Duke University Medical Center in Durham, North Carolina, U.S. She is the Director of the Breast Cancer Program at the Duke Cancer Institute and serves on the national Scientific Advisory Board of the Susan G. Komen for the Cure. She received her undergraduate degree in bioethics at Duke University, and her medical degree at Mayo Clinic Medical School. Afterwards, Dr. Blackwell completed an internal medicine internship and residency, and a hematology-oncology fellowship at Duke University Medical School. In addition to maintaining an active clinical practice, she has served as a principal investigator on many clinical trials in breast cancer. Her research interests include breast cancer angiogenesis, breast cancer in younger women, endocrine therapy, and HER2-targeted therapy. Dr. Blackwell has authored or co-authored over 40 articles or book chapters appearing in journals such as Clinical Cancer Research, the Journal of Clinical Oncology, Cancer, Radiation Research, and Molecular Cancer Therapeutics. In the past year, she has reviewed for several grant committees and peer-reviewed journals.

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Tony Mok, MD
Dr. Tony Mok studied medicine at the University of Alberta and subsequently completed his fellowship training at the Princess Margaret Hospital in Toronto. After practising oncology and internal medicine for seven years in Toronto, Dr. Mok became an Assistant Professor in the Department of Clinical Oncology at the Chinese University of Hong Kong in 1996. He became a full professor in 2007. He holds an honorary professorship at the Guangdong Provincial People’s Hospital in Guangdong, China, and a guest professorship at the Peking University School of Oncology. He is heavily involved in several professional societies and committees, including being President-elect of the International Association for the Study of Lung Cancer. Dr. Mok is the Associate Editor of several journals and has published over 130 articles in peer-reviewed journals.

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Mathias J. Rummel, MD, PhD
Mathias J. Rummel is the head of the Department for Hematology at the Clinic for Hematology and Medical Oncology at the Justus-Liebig University-Hospital, Giessen, Germany. Professor Rummel studied medicine at J.W. Goethe University Hospital in Frankfurt, Germany, obtaining his licence to practice medicine in 1995. Following this, he completed his doctoral degree and residency, obtained board certification in internal medicine, and was awarded his PhD from J.W. Goethe University Hospital. Professor Rummel’s current research focuses on novel treatment approaches in hematological malignancies, most notably follicular and other indolent lymphomas as well as hairy cell leukemia and also immune thrombocytopenic purpura (ITP). He is the chair of the Study group indolent Lymphomas (StiL) and principal investigator of several ongoing clinical trials in leukemias, lymphomas, and ITP. He is actively involved in a number of professional scientific societies, he is a reviewer for a number of journals, and has several published book chapters and papers to his credit.

dr-Eichhorst

Barbara F. Eichhorst, MD
Dr. Eichhorst graduated from the University of Munich School of Medicine in 1997, having completed a doctoral thesis in the field of hematology that focused on evaluating the signal transduction pathways of Hodgkin cells. She became a consultant in internal medicine after finishing an internship at Klinikum Grosshadern in the Department of Internal Medicine III at the University of Munich. Shortly after its founding, Dr. Eichhorst became a leading member of the German CLL Study Group and has served as the group’s secretary since 2005. She has published several papers on the treatment of chronic lymphocytic leukemia (CLL) and has acted as principal investigator for several phase II and III clinical trials that evaluated treatment optimization in CLL. Dr. Eichhorst is currently an Associate Professor at the University of Cologne and a consultant in hematology and internal oncology at the University Hospital of Cologne.

dr-Nagler

Arnon Nagler, MD, MSc
Arnon Nagler is Professor of Medicine at the Tel Aviv University, Tel Aviv, Israel, and the Director of both the Division of Hematology and the Bone Marrow Transplantation and Cord Blood Bank at the Chaim Sheba Medical Center, Tel Hashomer, Israel. Dr. Nagler received his medical training at the Hebrew University-Hadassah Medical School, Jerusalem, Israel, specializing in hematology at the Rambam Medical Center, Haifa, Israel. He carried out a postdoctoral research fellowship in hematology and bone marrow transplantation at Stanford University Hospital in Palo Alto, California, U.S. Dr. Nagler has been working in the fields of bone marrow transplantation for hematological malignancies, including non-Hodgkin lymphoma, and hemato-oncology, for the last 20 years. In Israel, Dr. Nagler established the first public cord blood bank and performed the first cord blood transplantations from related and unrelated donors in genetic and malignant hematological disease. His main clinical interests include stem cells, bone marrow transplantation, hematological malignancies, cord blood biology, and adoptive cell-mediated immunotherapy. Dr. Nagler has written numerous articles, reviews, and chapters for peer-reviewed journals, and is the principal investigator for a number of clinical studies. He serves on the Editorial Board of several journals and is a Section Editor for Leukemia.

dr-Hallek

Michael Hallek, MD
Dr. Michael Hallek is Professor of Medicine, and Director and Chair of the Department of Internal Medicine I at the University of Cologne in Cologne, Germany, where he oversees internal medicine, hematology, hemostaseology, oncology, intensive care, infectious diseases, and immunology. From 1994–2005, Dr. Hallek was head of the Gene Therapy Program at the Gene Center of the University of Munich and of the Clinical Cooperation Group for Gene Therapy at the National Centre for Research on Environment and Health (GSF) in Munich. In 2007, Dr. Hallek was appointed Director of the Center of Integrated Oncology (CIO), the joint comprehensive cancer centre of the Universities of Cologne and Bonn. Since 1994, he has been Chair of the German CLL Study Group. Dr. Hallek is the principal investigator for the CLL-8 clinical trial.