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New therapeutic options for advanced non-resectable malignant melanoma
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ADVMS 72 1–6 Advances in Medical Sciences xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Advances in Medical Sciences journal homepage: www.elsevier.com/locate/advms 1 2
Review Article
New therapeutic options for advanced non-resectable malignant melanoma
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Stadler a,b, Kasia Weina a,b, Christoffer Gebhardt a,b, Jochen Utikal a,b,*
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Q1 Simone
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Q2 a Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany Q3 b Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 July 2014 Accepted 15 December 2014 Available online xxx
Melanoma is a malignant tumor which is inclined to metastasize promptly into the lymphatic system and other organs such as lung, liver, brain or bone. Therefore early diagnosis remains crucial for improving clinical outcome for melanoma patients. Current chemotherapy and chemo-immunotherapy regimes have shown little clinical benefit with no improvement in overall survival. However, new advances in melanoma biology such as the discovery of predisposed gene signatures and key somatic events have changed clinical practice. New therapeutic approaches are being tested or have been approved by the FDA/EMA recently including targeted therapies, such as BRAF- and MEK-inhibitors, and novel immunotherapies, such as anti-CTLA4 or anti-PD1 therapies. For these therapies an improvement of progression-free and overall survival has been seen in patients with advanced non-resectable melanoma. The following review summarizes recent therapeutic options after the ASCO and ESMO annual meetings 2014 for the treatment of malignant melanoma. ß 2014 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Medical University of Bialystok.
Keywords: Melanoma Metastasis Treatment Targeted therapy Immunotherapy
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Contents 1. 2.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inhibition of the RAS/RAF/MEK/ERK signaling pathway 2.1. Inhibition of c-kit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. 2.3. Novel immunotherapies . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
2. Review
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Recent biological research advances have changed therapeutic options of unresectable advanced malignant melanoma in the field of targeted therapies and immunotherapies and were introduced into clinical practice [1]. In the following review we give an overview of novelties in the treatment of melanoma after the ASCO2014 meeting.
2.1. Inhibition of the RAS/RAF/MEK/ERK signaling pathway
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40–60% of patients with advanced melanoma have mutations in the BRAF gene. The BRAF-MEK-ERK signaling pathway is critical for cell growth and survival which in the case of a BRAF mutation causes aberrant cell growth (Fig. 1). The so called V600E-mutation of the BRAF gene exists in approximately 90 percent of all BRAFmutated melanomas; other variations including V600K are rare. In 2011, Chapman et al. [2], showed improved survival of melanoma patients with BRAF mutations treated with the BRAF kinase inhibitor vemurafenib. Patient response rate was 48% for vemurafenib, and was compared to the chemotherapeutic agent
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* Corresponding author at: Skin Cancer Unit, German Cancer Research Center (DKFZ) and University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany. Tel.: +49 621 383 4461; fax: +49 621 383 3815. E-mail address: [email protected] (J. Utikal).
http://dx.doi.org/10.1016/j.advms.2014.12.002 1896-1126/ß 2014 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Medical University of Bialystok.
Please cite this article in press as: Stadler S, et al. New therapeutic options for advanced non-resectable malignant melanoma. Adv Med Sci (2014), http://dx.doi.org/10.1016/j.advms.2014.12.002
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Fig. 1. Schematic overview of the RAS/RAF/MEK/ERK signaling pathway.
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dacarbazine (response rate 5%). Vemurafenib had been approved by the Food and Drug Administration (FDA) and the European Medicines Regulatory Agency (EMA) for therapy of unresectable, metastasized melanoma. Another BRAF inhibitor, dabrafenib, showed similar response rates but had a different side effect profile [3]. Besides in mutated melanoma showing a BRAF V600E mutation, vemurafenib and dabrafenib were also effective in melanomas with rarer BRAF gene mutations such as V600K, V600R, D594G or p.T599del mutations [4]. Although targeted therapies are generally well tolerated and considered to be safe, side effects have been associated with their use. The most common adverse events included: arthralgia, fatigue, alopecia, diarrhea and nausea. Cutaneous toxicity such as maculopapulous exanthema, palmo-plantar erythro-dysaesthesia syndrome, hyperkeratosis, xerosis, pruritus, photosensitivity and paronychia has been observed with the use of vemurafenib. In addition, dabrafenib shows as side-effect pyrexia [2,3,5–7]. Moreover, vemurafenib and dabrafenib have a differential influence on patients’ lymphocytes despite similar clinical efficacy in melanoma [8,9]. Treatment with BRAF inhibitors alone was shown to promote cutaneous squamous cell carcinomas, keratoacanthomas or tumor progression via stimulating MAPK signaling in RAF wild-type cells [5,10,11]. In patients treated with selective BRAF inhibitors, malignant melanocytic tumors developed with increased frequency. Hence, careful clinical surveillance and examination of patients treated with BRAF inhibitors is essential during treatment [11].
Another therapeutic strategy to target the BRAF-MEK-ERK pathway is the downstream inhibition of MEK1 and MEK2. Trametinib is a selective, oral MEK1/2 inhibitor which was shown to benefit survival status in stage IV melanoma with a BRAF V600E or V600K mutation [12]. It was approved as a single-agent by the FDA for the treatment of patients with V600E mutated metastatic melanoma in May 2013. Recent data show that trametinib can be given safely in the combination with paclitaxel [13]. A further MEK1/2 inhibitor termed selumetinib had shown clinical activity in patients with BRAF-mutant cutaneous or unknown primary melanoma in combination with dacarbazine [14]. Interestingly, it was shown recently that upstream mitogen-activated protein kinase (MAPK) pathway inhibition with BRAF inhibition following MEK inhibition in MEK inhibitor resistant melanomas was still effective [15,16]. Apart from BRAF, NRAS is another mutation seen in about 20–30% of the patients [17]. In patients with melanoma harboring NRAS mutations treatment with MEK1/2 inhibitors can lead to a tumor regression. In a recent trial, six of 30 (20%) patients with NRASmutated melanoma had a partial response when treated with the MEK inhibitor binimetinib (MEK162) [18]. The most frequent adverse side effects with binimetinib included: acneiform dermatitis, peripheral edema, facial edema, diarrhea and creatine phosphokinase increases [18]. It is known that enhanced MAPK pathway signaling and cell cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma. Thus, simultaneous inhibition of MEK and
Please cite this article in press as: Stadler S, et al. New therapeutic options for advanced non-resectable malignant melanoma. Adv Med Sci (2014), http://dx.doi.org/10.1016/j.advms.2014.12.002
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CDK4/6 could further suppress pathway activation [19]. Recently, in a phase 1b/2 study of the selective CDK4/6 inhibitor LEE011 in combination with binimetinib (MEK162) in patients with NRASmutant melanoma results were observed. 6/14 patients achieved partial responses (43%; 1 confirmed, 5 unconfirmed) and 6 had stable disease [20]. The responses to BRAF inhibition are frequently short lived, due to selection pressure and in turn resistance develops. To date, many different resistance mechanisms have been described [21–23]. This has resulted in additional clinical studies where combinations of selective BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) with selective MEK1/2 inhibitors (trametinib, cobimetinib, binimetinib) were tested [24–27]. In a recent randomized, double-blinded Phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and placebo as first-line therapy in patients with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma (COMBI-d trial) an overall response rate of 67% for dabrafenib + trametinib and 51% for dabrafenib + placebo was seen. At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI: 0.42–0.94; P = 0.02). The median progression-free survival was 9.3 months in the dabrafenib + trametinib group and 8.8 months in the dabrafenib + placebo group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI]: 0.57–0.99; P = 0.03). Rates of adverse events were similar in the two groups. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2%vs. 9%), whereas pyrexia occurred in more patients (51%vs. 28%) [28]. Similar response rates were seen in another recent Phase III trial (CoBRIM) with the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P < 0.001) [29]. Another recent clinical trial with dabrafenib plus trametinib, as compared with vemurafenib monotherapy (COMBI-v trial), significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. The overall survival rate at 12 months was 72% (95% confidence interval [CI]: 67–77) in the combination-therapy group and 65% (95% CI: 59–70) in the vemurafenib group (hazard ratio for death in the combinationtherapy group, 0.69; 95% CI: 0.53–0.89; P = 0.005). Median progression-free survival was 11.4 months in the combinationtherapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI: 0.46–0.69; P < 0.001) [30]. This shows that a combination of a BRAF inhibitor with a MEK inhibitor, as compared with a BRAF inhibitor alone, improved the rate of progression-free and overall survival in previously untreated patients with BRAFmutated metastatic melanoma.
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2.2. Inhibition of c-kit
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Another target for non-resectable advanced melanoma is the KIT proto-oncogene in subsets of melanoma. About 1–2% of all melanomas have point mutations in the KIT receptor tyrosine kinase gene, which have been identified in mucosal and acral melanomas as well as in chronically sun-damaged melanomas. Therefore, melanomas that arise in such regions should be assessed for KIT mutations. Tyrosine-kinase inhibitors, such as imatinib show an overall response rate of 16% respect. 23.3% of patients when tumors harbor KIT mutations [31,32]. NRAS mutations and KIT copy number gain may be mechanisms responsible for therapeutic resistance to imatinib [33]. An effect of the tyrosinekinase inhibitor dasatinib against L576P KIT mutated melanoma has been reported by Woodman et al. [34]. However, dasatinib was
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poorly tolerated and did not meet the pre-specified endpoint of 30% response rate or 6-month PFS in a phase II trial [35]. Recently, in a Phase II multicentric uncontrolled national trial assessing the efficacy of the tyrosine kinase inhibitor nilotinib in the treatment of advanced melanomas with KIT mutation an ORR of 20% (95% CI: 6.8–40.7) was found in patients with KIT mutation [36].
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2.3. Novel immunotherapies
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Other new therapeutic options in melanoma involve the stimulation of the immune system. For example, ipilimumab is a human IgG1 monoclonal antibody that blocks the cytotoxic T lymphocyte associated antigen (CTLA-4) (Fig. 2). CTLA-4 negatively regulates previously activated T cells. By blocking CTLA-4, subsequently the activation and proliferation of T cells, autoimmunity and antitumor immunity is augmented. In a randomized clinical study, ipilimumab at a dose of 3 mg/kg demonstrated an overall survival benefit compared with a vaccine [37]. Ipilimumab not only has shown effectiveness in cutaneous melanoma but also in patients with rarer melanoma variants. A recent DECOG trial revealed overall response rates among 104 evaluable patients of 16% for cutaneous, 17% for mucosal, 9% for ocular melanomas and 11% for unknown primary melanoma (MUP) [38]. Other recent studies revealed similar results in patients with uveal melanoma [39,40] or with mucosal melanoma [41]. However, severe adverse events were observed. Yet, most of these were reversible after proper and early treatment. Recently, ipilimumab used at a dose of 10 mg/kg was shown to produce a better clinical benefit rate than at a dose of 3 mg/kg [42]. This benefit is largely due to marked improvement in complete response rates in the 10 mg/kg group, and lower rates of progressive disease. However, these findings are limited by the small sample size, retrospective nature and limited follow-up [42]. In addition to non-resectable melanoma, ipilimumab (10 mg/kg) has been used as adjuvant therapy in a placebocontrolled trial. It provided a clinically and statistically significant improvement in recurrence-free survival for patients with stage III melanoma at high risk of recurrence in a recent phase III trial [43]. In addition to the CTLA-4-inhibitor, a tumor-targeted monoclonal antibody against programmed death 1 (PD-1) receptor, which down-modulates the initial T cell activation, has been used in preclinical and clinical trials (Fig. 2). PD-1 scavenges the immunosuppressive ligand PD-L1, which is selectively expressed on tumor cells including melanoma cells. Blocking the interaction of PD-1 with PD-L1 disables T-cell activation, which in turn stimulates the immune system in vitro and results in an antitumor activity in preclinical models and also in the clinic. Moreover, the blockade of PD-1 is able to overcome immune resistance [44–47]. Anti-PD-1 antibody MK3475, pembrolizumab, was tested in clinical studies in patients with advanced melanoma. An overall median progression-free survival longer than seven months and a sustained tumor regression was reported [46]. Among 365 patients with measurable disease at baseline, overall response rate by RECIST was 40% (95% CI: 32–48%) in ipilimumab-naive and 28% (95% CI: 22–35%) in patients who received ipilimumab before [48]. Pembrolizumab (MK3475) granted accelerated approval by the FDA for treatment of patients with advanced or unresectable melanoma in September 2014. Another PD-1-inhibior, nivolumab, demonstrated favorable 2- and 3-year overall survival rates, durable responses and an acceptable safety profile [49]. A randomized blinded comparative Phase 3 study evaluating nivolumab versus chemotherapy in patients with previously untreated BRAF wild-type advanced melanoma was stopped early because an analysis conducted by the independent Data Monitoring Committee showed evidence of superior overall survival in patients receiving nivolumab compared to the control arm. Confirmed overall response rates in nivolumab and investigator’s
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Please cite this article in press as: Stadler S, et al. New therapeutic options for advanced non-resectable malignant melanoma. Adv Med Sci (2014), http://dx.doi.org/10.1016/j.advms.2014.12.002
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Fig. 2. Schematic overview of the immune synapse and therapeutic interventions.
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choice chemotherapy patients was 32% (95% CI: 24, 41) and 11% (95% CI: 3.5, 23), with median time to response of 2.1 months (range: 1.6, 7.4) and 3.5 months (range: 2.1, 6.1), respectively [50]. Fatigue, exanthema, pruritus, and diarrhea were common adverse events. Nevertheless these properties make PD-1 and PD-L1 promising targets for cancer immunotherapy [49]. On the basis of this immunologic mechanisms and preclinical data, Wolchock and colleagues, conducted a trial with ipilimumab in combination with nivolumab [47]. They reported a rapid tumor regression (tumor reduction of 80% or more) in an extensive part of patients in the concurrent-regimen group. Responses were observed regardless of BRAF mutational status and were durable in the majority of patients [51]. However, treatment-related severe adverse events of grade 3–4 were seen in 62% of patients. Another therapeutic strategy is the combination of immunotherapeutics with BRAF inhibitors since both have different mechanisms of action. However, both agents have skin and liver toxicities although they are rare and limit their use in patients. A phase 1 study was conducted where both groups received ipilimumab and different doses of vemurafenib. In both groups liver toxicity was dose limiting, which stayed clinically asymptomatic and reversible.
Other adverse events were temporal arteritis and exanthema. In conclusion the risks of concurrent administration of vemurafenib and impilimumab can be severe [52]. Another phase IB study combined ipilimumab with peginterferon alfa-2b in patients with unresectable stages IIIB/C/IV melanoma. Peginterferon alfa-2b added to ipilimumab resulted in an excellent response rate of 42.3% in this population. Peginterferon alpha-2b at 2 mcg/kg weekly with ipilimumab at 3 mg/kg every 3 weeks was tolerated well although 20% of patients treated at this dose experienced grade 3 exanthema. Based on a clinical benefit rate of 53.8%, this combination warrants further exploration [53]. New combination therapies where targeted therapies and immunotherapeutics are used in parallel could improve future treatment of melanoma, however potential increased side effects needs to be further investigated.
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3. Conclusions
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New therapeutic options in the treatment of malignant melanoma have been developed over the past decade. Encouraging clinical data sets of targeted therapies and immunotherapies have
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Please cite this article in press as: Stadler S, et al. New therapeutic options for advanced non-resectable malignant melanoma. Adv Med Sci (2014), http://dx.doi.org/10.1016/j.advms.2014.12.002
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been shown recently in malignant melanoma. However, further proof-of-principle studies and clinical trials are needed to further improve therapies in melanoma with lowest adverse side effect risk.
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Conflict of interests
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Q5
Financial disclosure
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All authors confirm that the manuscript has been read and approved by all named authors. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
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JU is on the advisory board or has received honoraria and travel
Q7 support from Roche, GlaxoSmithKline, Bristol-Myers Squibb, LEO
Pharma and Merck. CG has received honoraria and travel support from Roche, and Bristol-Myers Squibb.
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References
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[1] Pflugfelder A, Kochs C, Blum A, Capellaro M, Czeschik C, Dettenborn T, et al. Malignant melanoma S3-guideline ‘‘diagnosis, therapy and follow-up of melanoma’’. J Dtsch Dermatol Ges 2013;11(Suppl. 6):1–116. [2] Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al., BRIM3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–16. [3] Ascierto PA, Minor D, Ribas A, Lebbe C, O’Hagan A, Arya N, et al. Phase II trial (BREAK-2) of the braf inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol 2013;31:3205–11. [4] Hallmeyer S, Hamid O, Sorof TA, Mun Y, Liu S, Abhyankar S, et al. Phase II study of vemurafenib in patients with locally advanced, unresectable stage IIIc or metastatic melanoma and activating exon 15 BRAF mutations other than V600E. J Clin Oncol 2014;32(5s). suppl; abstract 9075. [5] Manousaridis I, Mavridou S, Goerdt S, Leverkus M, Utikal J. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereol 2013;27:11–8. [6] Ascierto PA, Minor DR, Ribas A, Lebbe C, O’Hagan A, Swann RS, et al. Long-term safety and overall survival update for BREAK-2, a phase 2, single-arm, openlabel study of dabrafenib in previously treated metastatic melanoma (NCT01153763). J Clin Oncol 2014;32(5s). suppl; abstract 9034. [7] McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014;15:323–32. [8] Schilling B, Sondermann W, Zhao F, Griewank KG, Livingstone E, Sucker A, et al. Differential influence of vemurafenib and dabrafenib on patients’ lymphocytes despite similar clinical efficacy in melanoma. Ann Oncol 2014;25:747–53. [9] Orouji E, Ziegler B, Umansky V, Gebhardt C, Utikal J. Leukocyte count restoration under dabrafenib treatment in a melanoma patient with vemurafenibinduced leukopenia: case report. Medicine (Baltimore) 2014;93(28):e161. [10] Oberholzer PA, Kee D, Dziunycz P, Sucker A, Kamsukom N, Jones R, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol 2012;30:316–21. [11] Zimmer L, Hillen U, Livingstone E, Lacouture ME, Busam K, Carvajal RD, et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol 2012;30:2375–83. [12] Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al., METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367:107–14. [13] Coupe N, Corrie P, Hategan M, Larkin J, Gore ME, Gupta A, et al. A phase 1, does escalation study of paclitaxel with GSK1120212 (Trametinib) for the treatment of advanced melanoma. Ann Oncol 2014;25(S4). abstract 1094PD. [14] Robert C, Dummer R, Gutzmer R, Lorigan P, Kim KB, Nyakas M, et al. Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study. Lancet Oncol 2013;14:733–40. [15] Bernhardt M, Orouji E, Larribere L, Gebhardt C, Utikal J. Efficacy of vemurafenib in a trametinib-resistant stage IV melanoma patient – letter. Clin Cancer Res 2014;20:2498–9. [16] Goldinger SM, Zimmer L, Schulz C, Ugurel S, Hoeller C, Kaehler KC, et al. Dermatology Cooperative Oncology Group (DeCOG). Upstream mitogen-activated protein kinase (MAPK) pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients. Eur J Cancer 2014;50:406–10.
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[17] Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. A landscape of driver mutations in melanoma. Cell 2012;150:251–63. [18] Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 2013;14:249–56. [19] Kwong LN, Costello JC, Liu H, Jiang S, Helms TL, Langsdorf AE, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med 2012;18:1503–10. [20] Sosman JA, Kittaneh M, Lolkema MPJK, Postow MA, Schwartz G, Franklin C, et al. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: Early encouraging clinical activity. J Clin Oncol 2014;32(5s). suppl; abstract 9009. [21] Trunzer K, Pavlick AC, Schuchter L, Gonzalez R, McArthur GA, Hutson TE, et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol 2013;31:1767–74. [22] Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 2013;494:251–5. [23] Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 2014;508: 118–22. [24] Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:1694–703. [25] Kefford R, Miller WH, Shao-Weng Tan D, Sullivan RJ, Long G, Dienstmann R, et al. Preliminary results from a phase Ib/II, open-label, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAFV600-dependent advanced solid tumors. J Clin Oncol 2013;31. suppl; abstract 9029. [26] Flaherty K, Daud A, Weber JS, Sosman JA, Kim K, Gonzalez R, et al. Updated overall survival (OS) for BRF113220, a phase 1-2 study of dabrafenib (D) alone versus combined dabrafenib and trametinib (D + T) in pts with BRAF V600 mutation-positive (+) metastatic melanoma (MM). J Clin Oncol 2014;32(5s). suppl; abstract 9010. [27] Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)mutated melanoma: a phase 1b study. Lancet Oncol 2014;15:954–65. [28] Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014;371:1877–88. [29] Larkin J, Ascierto PA, Dre´no B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014;371:1867–76. [30] Robert C1, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2014 [Epub ahead of print]. [31] Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011;305: 2327–34. [32] Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, et al. Phase II, open-label, singlearm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 2011;29:2904–9. [33] Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol 2013;31:3182–90. [34] Woodman SE, Trent JC, Stemke-Hale K, Lazar AJ, Pricl S, Pavan GM, et al. Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther 2009;8:2079–85. [35] Kluger HM, Dudek AZ, McCann C, Ritacco J, Southard N, Jilaveanu LB, et al. A phase 2 trial of dasatinib in advanced melanoma. Cancer 2011;117:2202–8. [36] Lebbe C, Chevret S, Jouary T, Dalac S, Dalle S, Guillot B, et al. Phase II multicentric uncontrolled national trial assessing the efficacy of nilotinib in the treatment of advanced melanomas with c-KIT mutation or amplification. J Clin Oncol 2014;32(5s). suppl; abstract 9032. [37] Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711–23. [38] Zimmer L, Eigentler TK, Vaubel JM, Mohr P, Jradi Z, Kiecker F, et al. Open-label, multicenter, single-arm phase II study (DeCOG-Trial) to further evaluate the efficacy and safety of ipilimumab in patients with cutaneous melanoma and rare subgroups. J Clin Oncol 2014;32(5s). suppl; abstract 9031. [39] Luke JJ, Callahan MK, Postow MA, Romano E, Ramaiya N, Bluth M, et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer 2013;119:3687–95. [40] Piulats Rodriguez JM, Ochoa de Olza M, Codes M, Lopez-Martin JA, Berrocal A, Garcı´a M, et al. Phase II study evaluating ipilimumab as a single agent in the first-line treatment of adult patients (Pts) with metastatic uveal melanoma (MUM): the GEM-1 trial. J Clin Oncol 2014;32(5s). suppl; abstract 9033. [41] Postow MA, Luke JJ, Bluth MJ, Ramaiya N, Panageas KS, Lawrence DP, et al. Ipilimumab for patients with advanced mucosal melanoma. Oncologist 2013;18:726–32.
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[42] Lee-Ying RM, Feng X, Smylie M, Monzon JG, Cheng T. Efficacy of two ipilimumab (IPI) doses (10 vs. 3 mg/kg) in Alberta, Canada, tertiary cancer centers. J Clin Oncol 2014;32(5s). suppl; abstract 9090. [43] Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Ipilimumab versus placebo after complete resection of stage III melanoma: initial efficacy and safety results from the EORTC 18071 phase III trial. J Clin Oncol 2014;32(5s). suppl; abstract LBA9008. [44] Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455–65. [45] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443–54. [46] Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013;369:134–44. [47] Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369:122–33. [48] Ribas A, Hodi FS, Kefford R, Hamid O, Daud A, Wolchok JD, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). J Clin Oncol 2014;32(5s). suppl; abstract LBA9000.
[49] Hodi FS, Sznol M, Kluger HM, McDermott DF, Carvajal RD, Lawrence DP, et al. Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS936558, ONO-4538) in a phase I trial. J Clin Oncol 2014;32(5s). suppl; abstract 9002. ´ Angelo SP, Hodie FS, Gutzmer R, Neyns B, et al. A phase [50] Weber JS, Minor DR, D 3 randomized, open-label study of nivolumab (anti-PD-1, BMS-936558, ONO4538) versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma and prior anti-CTLA-4 therapy. Ann Oncol 2014;25(S4). abstract LBA3. [51] Sznol M, Kluger HM, Callahan MK, Postow MA, Gordon RA, Segal NH, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol 2014;32(5s). suppl; abstract LBA9003. [52] Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 2013;368: 1365–6. [53] Kudchadkar RR, Gibney GT, Dorman D, Merek S, Ramadan H, Chen A, et al. A phase IB study of ipilimumab with peginterferon alfa-2b for patients with unresectable stages IIIB/C/IV melanoma. J Clin Oncol 2014;32(5s). suppl; abstract 9098.
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Contents lists available at ScienceDirect
Advances in Medical Sciences journal homepage: www.elsevier.com/locate/advms 1 2
Review Article
New therapeutic options for advanced non-resectable malignant melanoma
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Stadler a,b, Kasia Weina a,b, Christoffer Gebhardt a,b, Jochen Utikal a,b,*
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Q1 Simone
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Q2 a Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany Q3 b Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 July 2014 Accepted 15 December 2014 Available online xxx
Melanoma is a malignant tumor which is inclined to metastasize promptly into the lymphatic system and other organs such as lung, liver, brain or bone. Therefore early diagnosis remains crucial for improving clinical outcome for melanoma patients. Current chemotherapy and chemo-immunotherapy regimes have shown little clinical benefit with no improvement in overall survival. However, new advances in melanoma biology such as the discovery of predisposed gene signatures and key somatic events have changed clinical practice. New therapeutic approaches are being tested or have been approved by the FDA/EMA recently including targeted therapies, such as BRAF- and MEK-inhibitors, and novel immunotherapies, such as anti-CTLA4 or anti-PD1 therapies. For these therapies an improvement of progression-free and overall survival has been seen in patients with advanced non-resectable melanoma. The following review summarizes recent therapeutic options after the ASCO and ESMO annual meetings 2014 for the treatment of malignant melanoma. ß 2014 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Medical University of Bialystok.
Keywords: Melanoma Metastasis Treatment Targeted therapy Immunotherapy
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Contents 1. 2.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inhibition of the RAS/RAF/MEK/ERK signaling pathway 2.1. Inhibition of c-kit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. 2.3. Novel immunotherapies . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
2. Review
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Recent biological research advances have changed therapeutic options of unresectable advanced malignant melanoma in the field of targeted therapies and immunotherapies and were introduced into clinical practice [1]. In the following review we give an overview of novelties in the treatment of melanoma after the ASCO2014 meeting.
2.1. Inhibition of the RAS/RAF/MEK/ERK signaling pathway
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40–60% of patients with advanced melanoma have mutations in the BRAF gene. The BRAF-MEK-ERK signaling pathway is critical for cell growth and survival which in the case of a BRAF mutation causes aberrant cell growth (Fig. 1). The so called V600E-mutation of the BRAF gene exists in approximately 90 percent of all BRAFmutated melanomas; other variations including V600K are rare. In 2011, Chapman et al. [2], showed improved survival of melanoma patients with BRAF mutations treated with the BRAF kinase inhibitor vemurafenib. Patient response rate was 48% for vemurafenib, and was compared to the chemotherapeutic agent
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* Corresponding author at: Skin Cancer Unit, German Cancer Research Center (DKFZ) and University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany. Tel.: +49 621 383 4461; fax: +49 621 383 3815. E-mail address: [email protected] (J. Utikal).
http://dx.doi.org/10.1016/j.advms.2014.12.002 1896-1126/ß 2014 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Medical University of Bialystok.
Please cite this article in press as: Stadler S, et al. New therapeutic options for advanced non-resectable malignant melanoma. Adv Med Sci (2014), http://dx.doi.org/10.1016/j.advms.2014.12.002
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Fig. 1. Schematic overview of the RAS/RAF/MEK/ERK signaling pathway.
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dacarbazine (response rate 5%). Vemurafenib had been approved by the Food and Drug Administration (FDA) and the European Medicines Regulatory Agency (EMA) for therapy of unresectable, metastasized melanoma. Another BRAF inhibitor, dabrafenib, showed similar response rates but had a different side effect profile [3]. Besides in mutated melanoma showing a BRAF V600E mutation, vemurafenib and dabrafenib were also effective in melanomas with rarer BRAF gene mutations such as V600K, V600R, D594G or p.T599del mutations [4]. Although targeted therapies are generally well tolerated and considered to be safe, side effects have been associated with their use. The most common adverse events included: arthralgia, fatigue, alopecia, diarrhea and nausea. Cutaneous toxicity such as maculopapulous exanthema, palmo-plantar erythro-dysaesthesia syndrome, hyperkeratosis, xerosis, pruritus, photosensitivity and paronychia has been observed with the use of vemurafenib. In addition, dabrafenib shows as side-effect pyrexia [2,3,5–7]. Moreover, vemurafenib and dabrafenib have a differential influence on patients’ lymphocytes despite similar clinical efficacy in melanoma [8,9]. Treatment with BRAF inhibitors alone was shown to promote cutaneous squamous cell carcinomas, keratoacanthomas or tumor progression via stimulating MAPK signaling in RAF wild-type cells [5,10,11]. In patients treated with selective BRAF inhibitors, malignant melanocytic tumors developed with increased frequency. Hence, careful clinical surveillance and examination of patients treated with BRAF inhibitors is essential during treatment [11].
Another therapeutic strategy to target the BRAF-MEK-ERK pathway is the downstream inhibition of MEK1 and MEK2. Trametinib is a selective, oral MEK1/2 inhibitor which was shown to benefit survival status in stage IV melanoma with a BRAF V600E or V600K mutation [12]. It was approved as a single-agent by the FDA for the treatment of patients with V600E mutated metastatic melanoma in May 2013. Recent data show that trametinib can be given safely in the combination with paclitaxel [13]. A further MEK1/2 inhibitor termed selumetinib had shown clinical activity in patients with BRAF-mutant cutaneous or unknown primary melanoma in combination with dacarbazine [14]. Interestingly, it was shown recently that upstream mitogen-activated protein kinase (MAPK) pathway inhibition with BRAF inhibition following MEK inhibition in MEK inhibitor resistant melanomas was still effective [15,16]. Apart from BRAF, NRAS is another mutation seen in about 20–30% of the patients [17]. In patients with melanoma harboring NRAS mutations treatment with MEK1/2 inhibitors can lead to a tumor regression. In a recent trial, six of 30 (20%) patients with NRASmutated melanoma had a partial response when treated with the MEK inhibitor binimetinib (MEK162) [18]. The most frequent adverse side effects with binimetinib included: acneiform dermatitis, peripheral edema, facial edema, diarrhea and creatine phosphokinase increases [18]. It is known that enhanced MAPK pathway signaling and cell cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma. Thus, simultaneous inhibition of MEK and
Please cite this article in press as: Stadler S, et al. New therapeutic options for advanced non-resectable malignant melanoma. Adv Med Sci (2014), http://dx.doi.org/10.1016/j.advms.2014.12.002
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CDK4/6 could further suppress pathway activation [19]. Recently, in a phase 1b/2 study of the selective CDK4/6 inhibitor LEE011 in combination with binimetinib (MEK162) in patients with NRASmutant melanoma results were observed. 6/14 patients achieved partial responses (43%; 1 confirmed, 5 unconfirmed) and 6 had stable disease [20]. The responses to BRAF inhibition are frequently short lived, due to selection pressure and in turn resistance develops. To date, many different resistance mechanisms have been described [21–23]. This has resulted in additional clinical studies where combinations of selective BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) with selective MEK1/2 inhibitors (trametinib, cobimetinib, binimetinib) were tested [24–27]. In a recent randomized, double-blinded Phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and placebo as first-line therapy in patients with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma (COMBI-d trial) an overall response rate of 67% for dabrafenib + trametinib and 51% for dabrafenib + placebo was seen. At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI: 0.42–0.94; P = 0.02). The median progression-free survival was 9.3 months in the dabrafenib + trametinib group and 8.8 months in the dabrafenib + placebo group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI]: 0.57–0.99; P = 0.03). Rates of adverse events were similar in the two groups. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2%vs. 9%), whereas pyrexia occurred in more patients (51%vs. 28%) [28]. Similar response rates were seen in another recent Phase III trial (CoBRIM) with the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P < 0.001) [29]. Another recent clinical trial with dabrafenib plus trametinib, as compared with vemurafenib monotherapy (COMBI-v trial), significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. The overall survival rate at 12 months was 72% (95% confidence interval [CI]: 67–77) in the combination-therapy group and 65% (95% CI: 59–70) in the vemurafenib group (hazard ratio for death in the combinationtherapy group, 0.69; 95% CI: 0.53–0.89; P = 0.005). Median progression-free survival was 11.4 months in the combinationtherapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI: 0.46–0.69; P < 0.001) [30]. This shows that a combination of a BRAF inhibitor with a MEK inhibitor, as compared with a BRAF inhibitor alone, improved the rate of progression-free and overall survival in previously untreated patients with BRAFmutated metastatic melanoma.
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2.2. Inhibition of c-kit
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Another target for non-resectable advanced melanoma is the KIT proto-oncogene in subsets of melanoma. About 1–2% of all melanomas have point mutations in the KIT receptor tyrosine kinase gene, which have been identified in mucosal and acral melanomas as well as in chronically sun-damaged melanomas. Therefore, melanomas that arise in such regions should be assessed for KIT mutations. Tyrosine-kinase inhibitors, such as imatinib show an overall response rate of 16% respect. 23.3% of patients when tumors harbor KIT mutations [31,32]. NRAS mutations and KIT copy number gain may be mechanisms responsible for therapeutic resistance to imatinib [33]. An effect of the tyrosinekinase inhibitor dasatinib against L576P KIT mutated melanoma has been reported by Woodman et al. [34]. However, dasatinib was
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poorly tolerated and did not meet the pre-specified endpoint of 30% response rate or 6-month PFS in a phase II trial [35]. Recently, in a Phase II multicentric uncontrolled national trial assessing the efficacy of the tyrosine kinase inhibitor nilotinib in the treatment of advanced melanomas with KIT mutation an ORR of 20% (95% CI: 6.8–40.7) was found in patients with KIT mutation [36].
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2.3. Novel immunotherapies
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Other new therapeutic options in melanoma involve the stimulation of the immune system. For example, ipilimumab is a human IgG1 monoclonal antibody that blocks the cytotoxic T lymphocyte associated antigen (CTLA-4) (Fig. 2). CTLA-4 negatively regulates previously activated T cells. By blocking CTLA-4, subsequently the activation and proliferation of T cells, autoimmunity and antitumor immunity is augmented. In a randomized clinical study, ipilimumab at a dose of 3 mg/kg demonstrated an overall survival benefit compared with a vaccine [37]. Ipilimumab not only has shown effectiveness in cutaneous melanoma but also in patients with rarer melanoma variants. A recent DECOG trial revealed overall response rates among 104 evaluable patients of 16% for cutaneous, 17% for mucosal, 9% for ocular melanomas and 11% for unknown primary melanoma (MUP) [38]. Other recent studies revealed similar results in patients with uveal melanoma [39,40] or with mucosal melanoma [41]. However, severe adverse events were observed. Yet, most of these were reversible after proper and early treatment. Recently, ipilimumab used at a dose of 10 mg/kg was shown to produce a better clinical benefit rate than at a dose of 3 mg/kg [42]. This benefit is largely due to marked improvement in complete response rates in the 10 mg/kg group, and lower rates of progressive disease. However, these findings are limited by the small sample size, retrospective nature and limited follow-up [42]. In addition to non-resectable melanoma, ipilimumab (10 mg/kg) has been used as adjuvant therapy in a placebocontrolled trial. It provided a clinically and statistically significant improvement in recurrence-free survival for patients with stage III melanoma at high risk of recurrence in a recent phase III trial [43]. In addition to the CTLA-4-inhibitor, a tumor-targeted monoclonal antibody against programmed death 1 (PD-1) receptor, which down-modulates the initial T cell activation, has been used in preclinical and clinical trials (Fig. 2). PD-1 scavenges the immunosuppressive ligand PD-L1, which is selectively expressed on tumor cells including melanoma cells. Blocking the interaction of PD-1 with PD-L1 disables T-cell activation, which in turn stimulates the immune system in vitro and results in an antitumor activity in preclinical models and also in the clinic. Moreover, the blockade of PD-1 is able to overcome immune resistance [44–47]. Anti-PD-1 antibody MK3475, pembrolizumab, was tested in clinical studies in patients with advanced melanoma. An overall median progression-free survival longer than seven months and a sustained tumor regression was reported [46]. Among 365 patients with measurable disease at baseline, overall response rate by RECIST was 40% (95% CI: 32–48%) in ipilimumab-naive and 28% (95% CI: 22–35%) in patients who received ipilimumab before [48]. Pembrolizumab (MK3475) granted accelerated approval by the FDA for treatment of patients with advanced or unresectable melanoma in September 2014. Another PD-1-inhibior, nivolumab, demonstrated favorable 2- and 3-year overall survival rates, durable responses and an acceptable safety profile [49]. A randomized blinded comparative Phase 3 study evaluating nivolumab versus chemotherapy in patients with previously untreated BRAF wild-type advanced melanoma was stopped early because an analysis conducted by the independent Data Monitoring Committee showed evidence of superior overall survival in patients receiving nivolumab compared to the control arm. Confirmed overall response rates in nivolumab and investigator’s
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Fig. 2. Schematic overview of the immune synapse and therapeutic interventions.
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choice chemotherapy patients was 32% (95% CI: 24, 41) and 11% (95% CI: 3.5, 23), with median time to response of 2.1 months (range: 1.6, 7.4) and 3.5 months (range: 2.1, 6.1), respectively [50]. Fatigue, exanthema, pruritus, and diarrhea were common adverse events. Nevertheless these properties make PD-1 and PD-L1 promising targets for cancer immunotherapy [49]. On the basis of this immunologic mechanisms and preclinical data, Wolchock and colleagues, conducted a trial with ipilimumab in combination with nivolumab [47]. They reported a rapid tumor regression (tumor reduction of 80% or more) in an extensive part of patients in the concurrent-regimen group. Responses were observed regardless of BRAF mutational status and were durable in the majority of patients [51]. However, treatment-related severe adverse events of grade 3–4 were seen in 62% of patients. Another therapeutic strategy is the combination of immunotherapeutics with BRAF inhibitors since both have different mechanisms of action. However, both agents have skin and liver toxicities although they are rare and limit their use in patients. A phase 1 study was conducted where both groups received ipilimumab and different doses of vemurafenib. In both groups liver toxicity was dose limiting, which stayed clinically asymptomatic and reversible.
Other adverse events were temporal arteritis and exanthema. In conclusion the risks of concurrent administration of vemurafenib and impilimumab can be severe [52]. Another phase IB study combined ipilimumab with peginterferon alfa-2b in patients with unresectable stages IIIB/C/IV melanoma. Peginterferon alfa-2b added to ipilimumab resulted in an excellent response rate of 42.3% in this population. Peginterferon alpha-2b at 2 mcg/kg weekly with ipilimumab at 3 mg/kg every 3 weeks was tolerated well although 20% of patients treated at this dose experienced grade 3 exanthema. Based on a clinical benefit rate of 53.8%, this combination warrants further exploration [53]. New combination therapies where targeted therapies and immunotherapeutics are used in parallel could improve future treatment of melanoma, however potential increased side effects needs to be further investigated.
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3. Conclusions
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New therapeutic options in the treatment of malignant melanoma have been developed over the past decade. Encouraging clinical data sets of targeted therapies and immunotherapies have
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Please cite this article in press as: Stadler S, et al. New therapeutic options for advanced non-resectable malignant melanoma. Adv Med Sci (2014), http://dx.doi.org/10.1016/j.advms.2014.12.002
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been shown recently in malignant melanoma. However, further proof-of-principle studies and clinical trials are needed to further improve therapies in melanoma with lowest adverse side effect risk.
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Conflict of interests
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Financial disclosure
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All authors confirm that the manuscript has been read and approved by all named authors. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
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JU is on the advisory board or has received honoraria and travel
Q7 support from Roche, GlaxoSmithKline, Bristol-Myers Squibb, LEO
Pharma and Merck. CG has received honoraria and travel support from Roche, and Bristol-Myers Squibb.
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References
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[1] Pflugfelder A, Kochs C, Blum A, Capellaro M, Czeschik C, Dettenborn T, et al. Malignant melanoma S3-guideline ‘‘diagnosis, therapy and follow-up of melanoma’’. J Dtsch Dermatol Ges 2013;11(Suppl. 6):1–116. [2] Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al., BRIM3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–16. [3] Ascierto PA, Minor D, Ribas A, Lebbe C, O’Hagan A, Arya N, et al. Phase II trial (BREAK-2) of the braf inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol 2013;31:3205–11. [4] Hallmeyer S, Hamid O, Sorof TA, Mun Y, Liu S, Abhyankar S, et al. Phase II study of vemurafenib in patients with locally advanced, unresectable stage IIIc or metastatic melanoma and activating exon 15 BRAF mutations other than V600E. J Clin Oncol 2014;32(5s). suppl; abstract 9075. [5] Manousaridis I, Mavridou S, Goerdt S, Leverkus M, Utikal J. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereol 2013;27:11–8. [6] Ascierto PA, Minor DR, Ribas A, Lebbe C, O’Hagan A, Swann RS, et al. Long-term safety and overall survival update for BREAK-2, a phase 2, single-arm, openlabel study of dabrafenib in previously treated metastatic melanoma (NCT01153763). J Clin Oncol 2014;32(5s). suppl; abstract 9034. [7] McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014;15:323–32. [8] Schilling B, Sondermann W, Zhao F, Griewank KG, Livingstone E, Sucker A, et al. Differential influence of vemurafenib and dabrafenib on patients’ lymphocytes despite similar clinical efficacy in melanoma. Ann Oncol 2014;25:747–53. [9] Orouji E, Ziegler B, Umansky V, Gebhardt C, Utikal J. Leukocyte count restoration under dabrafenib treatment in a melanoma patient with vemurafenibinduced leukopenia: case report. Medicine (Baltimore) 2014;93(28):e161. [10] Oberholzer PA, Kee D, Dziunycz P, Sucker A, Kamsukom N, Jones R, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol 2012;30:316–21. [11] Zimmer L, Hillen U, Livingstone E, Lacouture ME, Busam K, Carvajal RD, et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol 2012;30:2375–83. [12] Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al., METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367:107–14. [13] Coupe N, Corrie P, Hategan M, Larkin J, Gore ME, Gupta A, et al. A phase 1, does escalation study of paclitaxel with GSK1120212 (Trametinib) for the treatment of advanced melanoma. Ann Oncol 2014;25(S4). abstract 1094PD. [14] Robert C, Dummer R, Gutzmer R, Lorigan P, Kim KB, Nyakas M, et al. Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study. Lancet Oncol 2013;14:733–40. [15] Bernhardt M, Orouji E, Larribere L, Gebhardt C, Utikal J. Efficacy of vemurafenib in a trametinib-resistant stage IV melanoma patient – letter. Clin Cancer Res 2014;20:2498–9. [16] Goldinger SM, Zimmer L, Schulz C, Ugurel S, Hoeller C, Kaehler KC, et al. Dermatology Cooperative Oncology Group (DeCOG). Upstream mitogen-activated protein kinase (MAPK) pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients. Eur J Cancer 2014;50:406–10.
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[17] Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. A landscape of driver mutations in melanoma. Cell 2012;150:251–63. [18] Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 2013;14:249–56. [19] Kwong LN, Costello JC, Liu H, Jiang S, Helms TL, Langsdorf AE, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med 2012;18:1503–10. [20] Sosman JA, Kittaneh M, Lolkema MPJK, Postow MA, Schwartz G, Franklin C, et al. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: Early encouraging clinical activity. J Clin Oncol 2014;32(5s). suppl; abstract 9009. [21] Trunzer K, Pavlick AC, Schuchter L, Gonzalez R, McArthur GA, Hutson TE, et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol 2013;31:1767–74. [22] Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 2013;494:251–5. [23] Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 2014;508: 118–22. [24] Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:1694–703. [25] Kefford R, Miller WH, Shao-Weng Tan D, Sullivan RJ, Long G, Dienstmann R, et al. Preliminary results from a phase Ib/II, open-label, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAFV600-dependent advanced solid tumors. J Clin Oncol 2013;31. suppl; abstract 9029. [26] Flaherty K, Daud A, Weber JS, Sosman JA, Kim K, Gonzalez R, et al. Updated overall survival (OS) for BRF113220, a phase 1-2 study of dabrafenib (D) alone versus combined dabrafenib and trametinib (D + T) in pts with BRAF V600 mutation-positive (+) metastatic melanoma (MM). J Clin Oncol 2014;32(5s). suppl; abstract 9010. [27] Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)mutated melanoma: a phase 1b study. Lancet Oncol 2014;15:954–65. [28] Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014;371:1877–88. [29] Larkin J, Ascierto PA, Dre´no B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014;371:1867–76. [30] Robert C1, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2014 [Epub ahead of print]. [31] Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011;305: 2327–34. [32] Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, et al. Phase II, open-label, singlearm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 2011;29:2904–9. [33] Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol 2013;31:3182–90. [34] Woodman SE, Trent JC, Stemke-Hale K, Lazar AJ, Pricl S, Pavan GM, et al. Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther 2009;8:2079–85. [35] Kluger HM, Dudek AZ, McCann C, Ritacco J, Southard N, Jilaveanu LB, et al. A phase 2 trial of dasatinib in advanced melanoma. Cancer 2011;117:2202–8. [36] Lebbe C, Chevret S, Jouary T, Dalac S, Dalle S, Guillot B, et al. Phase II multicentric uncontrolled national trial assessing the efficacy of nilotinib in the treatment of advanced melanomas with c-KIT mutation or amplification. J Clin Oncol 2014;32(5s). suppl; abstract 9032. [37] Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711–23. [38] Zimmer L, Eigentler TK, Vaubel JM, Mohr P, Jradi Z, Kiecker F, et al. Open-label, multicenter, single-arm phase II study (DeCOG-Trial) to further evaluate the efficacy and safety of ipilimumab in patients with cutaneous melanoma and rare subgroups. J Clin Oncol 2014;32(5s). suppl; abstract 9031. [39] Luke JJ, Callahan MK, Postow MA, Romano E, Ramaiya N, Bluth M, et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer 2013;119:3687–95. [40] Piulats Rodriguez JM, Ochoa de Olza M, Codes M, Lopez-Martin JA, Berrocal A, Garcı´a M, et al. Phase II study evaluating ipilimumab as a single agent in the first-line treatment of adult patients (Pts) with metastatic uveal melanoma (MUM): the GEM-1 trial. J Clin Oncol 2014;32(5s). suppl; abstract 9033. [41] Postow MA, Luke JJ, Bluth MJ, Ramaiya N, Panageas KS, Lawrence DP, et al. Ipilimumab for patients with advanced mucosal melanoma. Oncologist 2013;18:726–32.
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[42] Lee-Ying RM, Feng X, Smylie M, Monzon JG, Cheng T. Efficacy of two ipilimumab (IPI) doses (10 vs. 3 mg/kg) in Alberta, Canada, tertiary cancer centers. J Clin Oncol 2014;32(5s). suppl; abstract 9090. [43] Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Ipilimumab versus placebo after complete resection of stage III melanoma: initial efficacy and safety results from the EORTC 18071 phase III trial. J Clin Oncol 2014;32(5s). suppl; abstract LBA9008. [44] Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455–65. [45] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443–54. [46] Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013;369:134–44. [47] Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369:122–33. [48] Ribas A, Hodi FS, Kefford R, Hamid O, Daud A, Wolchok JD, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). J Clin Oncol 2014;32(5s). suppl; abstract LBA9000.
[49] Hodi FS, Sznol M, Kluger HM, McDermott DF, Carvajal RD, Lawrence DP, et al. Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS936558, ONO-4538) in a phase I trial. J Clin Oncol 2014;32(5s). suppl; abstract 9002. ´ Angelo SP, Hodie FS, Gutzmer R, Neyns B, et al. A phase [50] Weber JS, Minor DR, D 3 randomized, open-label study of nivolumab (anti-PD-1, BMS-936558, ONO4538) versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma and prior anti-CTLA-4 therapy. Ann Oncol 2014;25(S4). abstract LBA3. [51] Sznol M, Kluger HM, Callahan MK, Postow MA, Gordon RA, Segal NH, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol 2014;32(5s). suppl; abstract LBA9003. [52] Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 2013;368: 1365–6. [53] Kudchadkar RR, Gibney GT, Dorman D, Merek S, Ramadan H, Chen A, et al. A phase IB study of ipilimumab with peginterferon alfa-2b for patients with unresectable stages IIIB/C/IV melanoma. J Clin Oncol 2014;32(5s). suppl; abstract 9098.
Please cite this article in press as: Stadler S, et al. New therapeutic options for advanced non-resectable malignant melanoma. Adv Med Sci (2014), http://dx.doi.org/10.1016/j.advms.2014.12.002
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