Pharmacotherapy

Targeted therapies in melanoma

J-F. Baurain, P. Manlow, F. Cornelis

The incidence of melanoma has increased continuously these last decades. Fortunately, cure is possible in most cases thanks to diagnosis at an early stage. Nevertheless, in some instances, melanoma is diagnosed at later stages and in other cases relapses occur. Moreover, melanoma is the deadliest cutaneous cancer and more importantly the most common origin of death due to cancer in young people. Thankfully though, hope for these patients has been increasing during the past three decades with the increased insight in the underlying oncogenic mutations. This progress has opened up new per- spectives for etiological targeted therapies. This review will focus on the recent advances in melanoma treatment. (Belg J Med Oncol 2012;6:194-200)

Introduction and activation of melanocytes stop. The prolifera- Recent progress in genetic, molecular and cellular tion of melanocytes is therefore tightly controlled. biology has made possible the characterisation of Melanocytes proliferate in response to various exoge- abnormalities leading to malignant transformation nous factors produced by other cells such as «fibro- of a melanocyte into a melanoma cell. The complete blast growth factor» (FGF), «hepatocyte growth genome sequencing of a melanoma cell line led to factor» (HGF) and «stem cell factor» (SCF). These the identification of 33,345 somatic base substitu- factors then bind to transmembrane receptors lo- tions.1 Among these, 292 were located in protein- cated at the cell surface. This fixation activates the coding sequences resulting in 187 amino acid changes. receptor that transmits the signal via a cascade of Some of these modifications are present in proteins cytoplasmic proteins. At the end of this cascade, involved in cell proliferation or differentiation. This activated transcription factors bind to gene promotors progress has opened up new perspectives for targeted which activate or repress the expression of genes therapies for advanced melanoma patients. leading for example to cell proliferation. The mecha- Melanocytes are located in the basal layer of the epi- nism used to activate a downstream partner is dermis. Their function is to produce melanin, a natural phosphorylation. On the other hand, the mechanism pigment that absords ultraviolet light (UV). This used to deactivate the signal transduction is the pigment is transferred to neighbouring keratino- removal of phosphates by phosphatases. cytes whereby protecting melanocytes and other cells from damages caused by UV. During a high Genetic alterations in melanoma UV exposure, melanocytes produce more pigment Some mutations in oncogenes involved in signal and their number increases by cell division. This transduction lead to their permanent activation proliferation also occurs within injured skin. After independently of the above signal (Figure 1). For healing or decrease of UV exposure, the proliferation example, 50% of melanoma cells harbour a mutation

Author: J-F. Baurain, MD, PhD, P. Manlow, F. Cornelis, Service d’Oncologie Médicale, Centre du cancer, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium, Please send all correspondence to: J-F. Baurain, MD, PhD, Service d’Oncologie Médicale, Centre du cancer, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium, [email protected]. Conflict of interest: the author has nothing to disclose and indicates no potential conflicts of interest. Keywords: melanoma, genetic alterations, BRAF, c-KIT, nilotinib, vemurafenib, dabrafenib, MEK, trametinib.

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Growth Factors Percentages of Melanoma with mutations Activating mutations of c-KIT gene or gene ampli cation in 30% of mucosal or acro-lentiginous melanoma 0 50 100 Receptors ISE

RAS-GTP RAS-GDP PIP2 Actif Inactif P P PIP3K CSE Activating mutations of NRAS gene P P in 20% of melanoma

P PTEN PIP3 RAF Mutations or deletions of PTEN gene Activating mutations of BRAF gene in 50% of melanoma P in 50% of melanoma Acral AKT Activating mutations of AKT gene P or gene ampli cation MEK in 60% of melanoma Mucosal P P mTOR ERK

p16 Ocular BRAF c-KIT PROLIFERATION SURVIVAL

Figure 1. The two major transduction signal pathways and Figure 2. Percentages of c-KIT and BRAF mutations in frequency of mutations in melanoma. The proteins of the melanoma according to its origin. Melanoma are divided MAPK (Mitogen-Activated Protein Kinases) pathway are in into 5 categories: arising from an Intermittent Sun Exposure grey and those of the PIP3 kinases are in purple. Proteins (ISE), arising from Chronic Sun Exposure (CSE), not arising inhibiting these pathways are depicted in red. Some genes from sun exposure such as acro-lentiginous melanoma, encoding proteins involved in these two pathways are mucosal melanoma and ocular melanoma. mutated in melanoma cells. The frequency of these mutations is indicated in red.

in BRAF. BRAF is one of the three isoforms of the mechanism has been acquired to prevent uncon- RAF kinases. No mutations have been seen in trolled melanocyte proliferation.4 Interestingly, if on ARAF or CRAF. In a healthy melanocyte, only RAF top of introducing BRAFV600E, the PIP3 kinase dimers can transduce the signal. On the other hand, pathway is activated concomitantly through the loss mutated BRAF can, as a monomer, activate MEK of PTEN for example, a malignant transformation is independently of RAS signalling. Eighty percent of seen. Therefore, it is important to remember that one BRAF mutations consist of the substitution of a valine mutation is not enough to transform a melanocyte for a glutamic acid at position 600 (BRAFV600E).2 into a melanoma cell. Activating mutations in NRAS are found in 20 % of As such, a succession of mutations in several genes melanoma. c-KIT, a receptor of SCF, is mutated in involved in different pathways is required for a malig- 1% of all melanoma. Nevertheless mutations in this nant transformation. Moreover, the genetic alterations receptor reach 30% in the subgroup of acro-lentigi- in the melanoma of one patient can be different nous and mucosal melanoma. Other mutations from another. In the near future, melanoma will be were observed in genes coding for proteins involved analysed in depth in order to identify these genetic in another signal transduction pathway such as alterations. This in turn will enable us to adapt the PTEN or AKT. Interestingly, there is a link between treatment to every individual by combining different the type of sun exposure leading to melanoma and drugs that block key activated pathways. the types of mutations which are present (Figure 2).3 Mutations in BRAF alone are however not sufficient Inhibition of c-KIT to lead to cancerous cell transformation. When a Several mutations in c-KIT have been reported in mutated form of BRAF is introduced in melanocytes melanoma (Figure 3). Some of which were also report- in vitro, rapid senescence of the cells is observed. ed in Gastro-Intestinal Stromal Tumours (GIST). This observation suggests that this mutational These mutations modify the kinase activity of the

Belgian Journal of Medical Oncology volume 6, issue 6, 2012 195 receptor leading to its permanent activation. In other melanoma cases, most frequently of the acrolentigi- EXON nous subtype, gene amplification of the c-KIT gene 1 Ligand 2 has been observed. c-KIT is therefore an ideal thera- binding 3 peutic target in melanoma cases harbouring a gene domain 4 amplification or mutations of c-KIT. As acrolentiginous 5 melanoma is the most common subtype in Asian 6 Dimerization and African populations, c-KIT targeted therapy for domain 7 c-KIT mutant melanoma may be more relevant for 8 these populations. 9 10 Transmembrane Imatinib was the first Tyrosine Kinase Inhibitor V599C segment 11 V560G (TKI) approved for therapeutic use. It has revolu- L576P tionised the treatment of chronic myeloid leukaemia 12 13 V642E and GIST and is an oral drug that is able to inhibit Proximal a wide variety of kinases including c-KIT. Forty- kinase 14 domain three patients with metastatic melanoma harbouring 15 16 c-KIT gene mutations or amplification were treated in Distal 17 E816V a phase II study with imatinib at a dose of 400mg/d.5 kinase N822K domain 18 The most commonly observed side-effects were 19 fatigue, oedema, anorexia, elevation of transaminases 20 and neutropenia. Ten patients responded (Response 21 Rate: 23%) and amongst them 9 had mutations in exon 11 or 13. These responses appeared rapidly within the first month of treatment. Moreover, more than half of the patients showed disease control Figure 3. Genetic structure of c-KIT and mutations observed with imatinib. The progression-free survival (PFS) at in melanoma. The protein structure of c-KIT is indicated in 6 months was 36.6%. These results are encouraging green. This protein contains 5 immunoglobulin domains. since there was doubling of the PFS at 6 months. Some of them are dedicated to ligand binding and the more Meanwhile, another phase II study was published.6 proximal to dimerization. This protein contains two kinase Amongst the 25 evaluable patients, six patients domains. The exons where mutations are frequently observed showed a response (RR : 24%). All of them harboured are indicated in red. The most frequent mutations are also frequently found mutations in c-KIT (V559C, L576P, depicted. V642E or N822K). patients harbouring c-KIT mutations. However, due Nilotinib is a new inhibitor of BCR-ABL, c-KIT and to slow recruitment this trial was amended to a PDGFR kinases. This oral drug has shown similar phase II study. efficacy to imatinib in GIST patients. Eleven patients with metastatic melanoma harbouring c-KIT gene Dasatinib is an orally administered inhibitor of the mutations or amplifications were treated with nilo- src family kinases, c-KIT and PDGF receptor. Several tinib at a dose of 400 mg twice daily.7 The toxicity investigators have reported a high src kinase activity was moderate with grade 1 nausea and dry-eyes. in melanoma through aberrant expression of FGF Amongst the 9 evaluable patients, two patients receptors. This formed the rational to test inhibitors showed a partial response (RR: 22%) and 56% of of src kinases in a phase II trial including 36 meta- the patients showed disease control. The best re- static melanoma patients.8 Half of the patients sponder had a melanoma with a mutation in c-KIT received dasatinib at a dose of 100mg twice daily, (L576P). These results support imatinib treatment and while the others received a dose of 70mg twice daily formed the rationale for a randomised phase III trial due to toxicity. The most commonly observed toxici- comparing nilotinib to dacarbazine in melanoma ties were fatigue, dyspnea and pleural effusion.

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day 1 day 29 day 57 day 115 day 170

Figure 4. Clinical activity of Vemurafenib: A 35 year old patient received Vemurafenib for a stage IIIc melanoma. The pictures on the top part of the figure (A) show the evolution of in transit metastases on the left thigh. The pictures on the bottom part (B) show the evolution of the lesions located in the left popliteal area. At day 29, a fast response was observed which con- tinued at first to improve with time. At day 170, new lesions (red arrows) appeared and showed secondary resistance to Vemurafinib. The patient then received ipilimumab and is still under treatment.

Only two patients showed a partial response (RR: 5%). Inhibition of the NRAS/BRAF/MEK One of them had a mutation in exon 13 of the c-KIT pathway gene. The PFS at 6 months was 13%. In a case-report, a More than half of all melanoma cases harbour genetic partial response in one patient with a L576P mutation abnormalities in the NRAS/BRAF/MEK pathway, in c-KIT was described.9 Overall, the lower efficacy making it an attractive therapeutic target. Vemurafenib, and the higher toxicity of dasatinib refrain its use in formerly known as PLX4032 or RG7204, is the first melanoma treatment. However, a promising approach V600E BRAF inhibitor to be approved for melanoma could be to combine dasatinib with chemotherapy. treatment. Its development was tremendously fast A recent phase I trial has shown synergistic effects with the publication of phase I result in august 2010 with this approach.10 and its FDA/EMA approval in 2011.13 Metastatic Secondary resistance to these drugs may occur and melanoma patients receiving vemurafenib at are observed in 50% of patients suffering from 960mg/bid show dramatic responses, even with GIST. Different mechanisms have been described, high tumour burdens. These responses occur for example acquisition of secondary mutations quickly with tumour shrinkage within the first such as V654A or T670I. These patients could how- months (Figure 4). This fast response is very differ- ever respond to other TKI such as sunitinib or ent from the kinetic of responses seen with immu- sorafenib. In this light, a small study from Minor et notherapy, i.e. Ipilimumab.14 Around 90% of the pa- al indicates that sunitinib has activity in melanoma tients present a clinical benefit. This high response patients with KIT mutations.11 These data were con- rate was confirmed across all the different studies firmed in a Belgian academic multi-centre phase II (BRIM1, BRIM2, BRIM3). Interestimngly, it has trial including 36 patients with metastatic melanoma been shown that the non-responders have a tumour who failed at least one line of dacarbazine-based without a decrease in pERK expression (down- chemotherapy who were treated with sunitinib. stream partner of BRAF/MEK). The median time of This study met its primary endpoint (3 partial response was around 5.5 to 7 months. However, remissions) and demonstrated a clinical benefit rate most, if not all the patients progress under vemura- of 33% for sunitinib.12 fenib.15 The updated PFS analysis presented at

Belgian Journal of Medical Oncology volume 6, issue 6, 2012 197 ASCO 2012 confirmed the significantly longer PFS headache. However, these adverse events were rarely for patients treated with vemurafenib compared grade 3 or 4 in severity.19 to dacarbazine (6.9 vs. 1.6 months; HR[95%CI]: The use of MEK inhibitors in the management of 0.38[0.32-0.46]; p<0.001). This translated into a advanced melanoma has also been studied. Trame- significant survival benefit for patients treated with tinib is a reversible, highly selective allosteric inhibi- vemurafenib with an overall survival (OS) of 13.6 tor of MEK1/2 activation and kinase activity. In a months compared to 9.7 months for patients in the recently reported phase III study, 322 metastatic dacarbazine arm, representing a 30% reduction in melanoma patients with a V600E or V600K BRAF the risk of dying.16 The most common side effects seen mutation were randomised between trametinib with vemurafenib are photosensitivity, arthralgia, (2mg orally) once daily or intravenous dacarbazine fatigue, alopecia and elevation of liver enzymes. In (1,000mg/m2 of body-surface area) or paclitaxel the BRIM2 studies, it has been reported that up to (175mg /m 2) every 3 weeks. The median PFS was 45% of patients had their doses reduced. Dose inter- 4.8 months in the trametinib group compared to ruptions were required for 64% of patients.15 1.5 months in the chemotherapy group (HR[95%CI]: Other important vemurafenib side-effects include 0.45[0.33-0.63]; p<0.001). At 6 months, the OS rapid development of keratoacanthomas and squa- rate was 81% in the trametinib group and 67% in the mous skin cancer early on during treatment (20 to chemotherapy group despite crossover (HR[95%CI]: 30% of patients receiving Vemurafenib). These side 0.54[0.32-0.92]; p=0.01). Rash, diarrhea, and peri- affects seem to be the result of the paradoxical acti- pheral edema were the most common toxic effects vation of the MAPK pathways in these lesions.17,18 in the trametinib group and were managed with Molecular analysis of these lesions has shown that dose interruption and dose reduction. Asymptomatic most of them harbour HRAS mutation. Mutated and reversible reduction in the cardiac ejection frac- HRAS will preferably activate CRAF, leading to a direct tion and ocular toxic effects occurred infrequently. MEK activation. Therefore it is important that patients Secondary skin neoplasms were not observed.20 regularly consult a dermatologist. In addition to this, patients should undergo oropharyngeal and genital Unfortunately, resistance to BRAF inhibitors often examinations before starting and during vemu- occurs. Some patients present a primary resistance rafenib treatment. Another important concern is the to BRAF inhibitors, and do not respond to the drug possible onset of secondary lung or gastro-intestinal at all. In addition to this, nearly all patients who malignancy, a problem that will become even more initially respond to NRAF inhibitors progress within important in the adjuvant setting. less than one year due to acquisition of secondary resistance. The mechanisms of resistance are highly Dabrafenib is another specific BRAF inhibitor. It can variable and imply a reactivation, or a bypass of the block V600E BRAF but also other mutated forms of MAPK pathway. Some speculative scenarios are BRAF: V600K, V600D. The activity in preliminary possible thanks to the analysis of secondary malig- phase I and II studies is comparable to that of vemu- nancies such as cutaneous squamous carcinoma rafenib although the toxicity profile is slightly different disclosing a lot of information about tumour resis- with no photosensitivity or elevation of liver enzymes. tance.17 These events seems more to be a direct par- It seems that dabrafenib induces a kind of cytokine adoxical activation of the MAPK pathway. Interest- release syndrome that could only be treated with ingly, it has been observed that these lesions have corticosteroids. In the phase III BREAK-3 trial, 250 a mutation in HRAS. In V600E BRAF melanoma, patients with previously untreated, stage IV or unre- the BRAF homodimer is the preferred partner for sectable stage III, V600E BRAF mutation-positive downstream activation. In HRAS mutated tumours, melanoma were randomly assigned to receive dab- there is preferable formation of a heterodimer (BRAF/ rafenib or dacarbazine. Median PFS was 5.1 months CRAF) or the activation of a homodimer of CRAF. for dabrafenib compared to 2.7 months for dacarba- The activation of CRAF leads to the direct activation zine (HR[95%CI]: 0·30[0·18-0·51]; p<0·0001). The of MEK. Other mechanisms to activate the MAPK most common adverse events with dabrafenib were pathway could be to directly activate MEK through skin-related toxicity, fever, fatigue, arthralgia, and activated COT by a crosstalk with the PIP3 kinase

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pathway. Alternatively, mutations in MEK (ME- phase III trial. In addition to this, other trials are K1Q56P) could also activate the MAPK pathway underway where BRAF inhibitors are combined even if BRAF is blocked. Activation of alternative with PIP3K inhibitors or mTOR inhibitors. Results pathways could also occur by overexpression of of these studies are eagerly awaited. tyrosine receptors and activation of the PIP3k pathway. Interestingly, a recent report describes the Conclusion successful rechallenge in two patients with BRAF- During these last two years, melanoma treatment V600-mutant melanoma who experienced previous has dramatically changed with the development of progression during treatment with a selective BRAF targeted therapies and new immunotherapeutic inhibitor. These two case observations indicate agents. Targeted agents such as vemurafenib, dab- that resistance to BRAF-selective inhibitors can be rafenib, trametinib, nilotinib and imatinib give a reversible following treatment interruption.21 rapid clinical benefit in patients with mutated These putative resistance mechanisms form a strong BRAF/cKIT melanoma and prevent early death rationale to combine different targeted therapies in caused by rapid disease progression. The toxicity the management of advanced melanoma. During profiles of these agents are very different from con- ASCO 2011, a small phase I trial combining dab- ventional chemotherapy. Nowadays, patients with rafenib and trametinib showed promising clinical a melanoma showing mutations in c-KIT, BRAF or activity in patients with BRAFV600 mutant meta- NRAS should respectively receive nilotinib, vemu- static melanoma. More importantly, a major decrease rafinib or a MEK inhibitor. One definite concern is in the number of side effects was observed with the possible onset of secondary malignancies when the combination compared to both single agents using BRAF inhibitors. Unfortunately, primary respectively.22 At ASCO 2012, updated results of and secondary resistance to these targeted agents this study confirmed these preliminary data. The occurs frequently. Therefore, patients with a BRAF combination of dabrafenib with trametinib had an mutated metastatic melanoma should be included acceptable safety profile, with a lower incidence of in clinical trials that test combinations of BRAF MEKi-related rash and BRAFi-induced hyperprolifer- inhibitors with inhibitors targeting other kinases ative skin lesions compared with the single agents. in the MAP kinase or the PIP3 kinase pathways. Among the 77 patients in the study, a confirmed Indeed the preliminary results of such combinations ORR of 56% was reported.23 This encouraging show potential for increased clinical efficacy and activity is currently under investigation in a larger reduced side effects.

Key messages for clinical practice

• Over the last few years, treatment of advanced melanoma underwent a revolution. • Targeted agents such as vemurafenib, dabrafenib, trametinib, nilotinib and imatinib give a rapid clinical benefit in patients with mutated BRAF/cKIT melanoma and prevent early death caused by rapid disease progression. • Patients with a melanoma showing mutations in c-KIT, BRAF or NRAS should respectively receive nilotinib, vemurafinib or a MEK inhibitor. • Onset of secondary malignancies is a major concern when using BRAF inhibitors. • Primary and secondary resistance to BRAF inhibitors occurs frequently. • BRAF mutated metastatic melanoma should be included in clinical trials testing combinations of BRAF inhibitors with inhibitors of MAP kinase or the PIP3 kinase pathways.

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