CME Article Submitted: 18.8.2015 Accepted: 23.10.2015 Conflict of interest None.
Ricarda Rauschenberg, Marlene Garzarolli, Ursula Dietrich, Stefan Beissert, Friedegund Meier Department of Dermatology, Carl Gustav Carus University Hospital at the Technical University Dresden, Dresden, Germany Section Editor Prof. Dr. D. Nashan, Dortmund
DOI: 10.1111/ddg.12891
Systemic therapy of metastatic melanoma
Summary For patients with metastatic melanoma, there are currently several effective therapeutic options. The BRAF inhibitors vemurafenib and dabrafenib are characterized by rapid tumor control and high response rates. In combination with one of the two MEK inhibitors trametinib and cobimetinib, they achieve response rates (CR + PR, complete plus partial remissions) of 70 %, while delaying the development of treatment resistance, as well as a median overall survival of > 2 years with tolerable side effects. Showing long-term survival rates of approximately 20 %, the anti-CTLA-4 antibody ipilimumab is the first substance that has led to a significant prolongation of overall survival in patients with metastatic melanoma. However, delayed treatment response and severe immune-mediated side effects may pose limitations to its therapeutic benefit. Usually well tolerated, anti-PD-1 antibody monotherapy using nivolumab and pembrolizumab has yielded response rates (CR + PR) of up to 45 % and one-year survival rates of > 70 %. The combination of ipilimumab and nivolumab has shown response rates of up to 58 % and a median progression-free survival of > 11 months. While this combination is expected to result in a rapid and long-lasting response, this potential benefit comes at the expense of a high level of toxicity. Strategies for treatment sequencing and treatment combinations are currently being investigated in clinical studies. Overall, the prognosis for patients with metastatic melanoma has significantly improved. With long-term survival a possibility, not only acute but also long-term therapeutic side effects must be taken into account.
Introduction and basic principles In Western industrialized nations, the incidence of melanoma has markedly increased since the 1980s [1, 2]. Relevant risk factors include changes in recreational and vacation-related habits in the past 50 years combined with increased intermittent UV exposure [3, 4]. Compared with other solid tumors, melanoma exhibits a large number of mutations [5], with the MAP kinase signaling pathway (RAS-RAF-MEK-ERK) being of particular importance (Figure 1). Thus, a BRAF mutation is found in
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Figure 1 MAPK signaling pathway – targeted therapy with BRAF and MEK inhibitors.
about 40–60 % of cutaneous melanomas, a NRAS mutation in 15–25 %, the prevalence varying with the histological subtype and tumor location [6]. Another pathway important for tumor progression is the PI3K-AKT-PTEN signaling pathway whose activation (among others, through RAS) may also play a part in the development of resistance to MAP kinase inhibitors [7, 8]. Until recently, the prognosis for melanoma patients with distant metastases had been poor. According to a study by Balch et al. from 2009, one-year survival rates range from 33 % (TNM classification M1c) to 62 % (TNM classification M1a) [9]. However, after decades of stagnation, recent advances in immunotherapy and targeted therapies have considerably improved the prognosis of stage IV melanoma.
Chemotherapy Monochemotherapy Until 2011, treatment with the alkylating agent dacarbazine (DTIC) was regarded as standard treatment for patients with inoperable metastatic melanoma. Up to that point, alternatives had been limited [10]. Administered intravenously, dacarbazine is given at a dose of 800–1200 mg/m² body surface area on day 1 every 3–4 weeks or at a dose of 250 mg/m² on day 1–5 every 3–4 weeks [11]. In several phase III studies, DTIC showed objective response rates between 5 % and 14 %, with a tolerable side effect profile but without a clinically significant impact on overall survival. The efficacy and toxicity of the alkylating agent temozolomide (150–200 mg/m² orally on day 1–5 every four weeks) and the nitrosourea fotemustine (100 mg/m² IV on day 1, 8, and 15, followed by a five-week interval and continuation every three weeks) are comparable to those of DTIC [12–14]. Common side effects include myelosuppression, nausea, vomiting, fatigue, and headache. Especially when using fotemustine, the nadir may be delayed and only
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set in after 4–6 weeks. Nausea and vomiting may usually be prevented by prophylactic antiemetic therapy according to guidelines [15, 16].
Combined chemotherapy Various combined chemotherapy regimens have failed to show any survival benefit compared to DTIC monochemotherapy [17]. Given their high toxicity and associated impairment of quality of life, they may be considered in patients with a high tumor load or rapid progression after failure of other systemic therapies [10, 17]. In such cases, combined chemotherapy with carboplatin and paclitaxel is frequently given, showing a progression-free survival of four months with acceptable toxicity in a randomized trial. Common side effects include intolerance reactions, myelosuppression, neuropathy, diarrhea, musculoskeletal pain, and fatigue [18]. In view of the treatment options currently available, it is safe to assume that chemotherapy is to be considered a “last-line therapy”.
Targeted therapy BRAF inhibitors The serine-threonine kinase BRAF is an integral part of the aforementioned MAP (mitogen-activated protein) kinase signaling pathway [19]. Activating mutations of the protooncogene BRAF result in uncontrolled tumor growth (Figure 1). A BRAFV600E mutation is present in approximately 70 % of BRAF-positive tumors, a BRAF-V600K mutation in approximately 20 % [20]. In Germany, the BRAF inhibitors vemurafenib (Zelboraf ®, Roche) and dabrafenib (Tafinlar ®, Novartis) are licensed for systemic treatment of melanoma. In a phase III study (BRIM-3), 675 treatment-naive, inoperable melanoma patients with a confirmed BRAF-V600E mutation (AJCC stage IIIC–IV, without brain metastases) were treated with vemurafenib or dacarbazine [21]. Response rates and median progression-free survival for vemurafenib vs. dacarbazine were 48 % vs. 5 % and 5.3 months vs. 1.6 months. Median overall survival was 13.6 months for vemurafenib and 9.7 months for dacarbazine [22]. Dabrafenib showed comparable results in a phase III study (BREAK-3) in 250 patients [23]. Vemurafenib is given at a dose of 960 mg twice daily (four film-coated tablets twice a day). The recommended dose for dabrafenib is 150 mg twice daily (two 75-mg hard capsules twice a day.). Another BRAF inhibitor, encorafenib (LGX818, Array BioPharma), is currently being investigated in a clinical study (COLUMBUS). In a safety study with 3,222 participants, the most common side effects of vemurafenib therapy were rashes, arthralgia, fatigue, photosensitivity, hair loss, and nausea [24]. Moreover, patients exhibited cutaneous squamous cell carcinomas and secondary melanomas, which may be attributed to a paradoxical activation of the MAP kinase signaling pathway in cells with the BRAF wild type [25, 26]. QT interval prolongation has been described especially in elderly individuals (> 75 years) with comorbidities [24]. Adverse drug effects most commonly reported in studies on dabrafenib include hyperkeratoses, headache, pyrexia, arthralgia, fatigue, nausea, papillomas, hair loss, rash, and vomiting [23, 27]. The BRAF inhibitors have a similar toxicity profile, with photosensitivity characteristically observed more often with vemurafenib and pyrexia more frequently with dabrafenib. Managing side effects may require dose reductions or a temporary discontinuation of treatment. Furthermore, potential interactions with other drugs that are substrates of CYP2C8 and CYP3A4 have to be taken into account (see Summaries of Product Characteristics).
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Both BRAF inhibitors have also been shown to be effective in the treatment of brain metastases [27, 28]. In patients with asymptomatic BRAF-V600E-mutated brain metastases, dabrafenib achieved response rates of 30–40 % and a median overall survival of 7–8 months. In patients with asymptomatic and symptomatic BRAF-mutated brain metastases, vemurafenib yielded response rates of 18–20 % and a median overall survival of > 6 months. While response rates were lower in the vemurafenib study, patients were at a more advanced stage, which is why the data available does not allow for a comparison of efficacy between vemurafenib and dabrafenib. Given the rapid onset of action and high response rates, targeted treatment may especially be considered in patients with rapid tumor progression and/or symptomatic metastases; patients with normal LDH levels prior to the start of treatment show significantly longer median overall survival than patients with elevated LDH levels [24].
MEK inhibitors MEK is another therapeutic target in the MAP kinase signaling pathway (Figure 1). In a phase III study, 322 patients with inoperable metastatic melanoma and BRAF-V600E/K mutation received treatment with the MEK inhibitor trametinib (Mekinist ®, Novartis; 2 mg orally once a day until tumor progression) or chemotherapy (DTIC or paclitaxel). Trametinib treatment resulted in a significant improvement in median progression-free survival of 4.8 months vs. 1.5 months. The most common side effects included rashes (in part papulopustular eruptions), diarrhea, peripheral edema, and fatigue. A reduction in ejection fraction or ventricular dysfunction and retinopathies were among the rare adverse effects [29]. Another MEK inhibitor, binimetinib (MEK162, Array BioPharma), is currently being investigated in studies (COLUMBUS, NEMO). These also include patients with NRAS mutations.
c-KIT kinase inhibitors Overall rare in melanoma, mutations of the receptor tyrosine kinase KIT are most commonly found in mucosal (21 %) and acrolentiginous (11 %) melanomas or in those arising on chronically sun-damaged skin (17 %) [30, 31]. In a phase II study, 16 % of patients with c-KIT aberrations responded to the c-KIT kinase inhibitor imatinib (Glivec®, Novartis) (400 mg orally twice a day) with partial or complete remission; the median time to progression was 12 weeks and the median overall survival was 46.3 weeks [32]. The – at best – moderate results were attributed to the fact that only a certain proportion of c-KIT mutations, most likely in exon 11 and 13, is of oncogenetic relevance [33]. In another phase II study with imatinib (400 mg orally once a day), 23.3 % of patients showed partial remission with a median progression-free survival of 3.5 months. The most common side effects were edema, fatigue, anorexia, nausea, neutropenia, and elevated liver enzymes (transaminases). A dose increase to 800 mg daily was associated with increased toxicity, especially with edema, nausea, and vomiting (NCI-CTCAE grade 3–4) [32, 33]. In view of the rarity of treatment-relevant c-KIT mutations and the approval of two PD-1 antibodies (see Immunotherapy, PD-1 antibodies), treatment with c-KIT kinase inhibitors will likely play an ancillary role in the future.
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Combined BRAF and MEK inhibition Occurring in the majority of patients over the course of treatment, development of resistance poses a limitation to monotherapy with one of the aforementioned BRAF inhibitors. Most resistance mechanisms described to date result in reactivation of the MAP kinase signaling pathway [34]. By combining a BRAF and a MEK inhibitor, one may expect a delay in the development of resistance and a prolongation of the therapeutic response. In a phase III study (COMBI-V), 704 treatment-naive patients with BRAFV600-mutated metastatic melanoma were given dabrafenib (150 mg orally twice a day) plus trametinib (2 mg orally once a day) or vemurafenib (960 mg orally twice a day). Compared to monotherapy, the combined treatment resulted in a significant improvement in the response rate (64 % vs. 51 %), median progression-free survival (11.4 months vs. 7.3 months), and overall survival after 12 months (72 % vs. 65 %) [35]. It is noteworthy that the rate of treatment discontinuation due to side effects was similar in both treatment arms (13 % and 12 %). Side effects that most frequently led to treatment discontinuation were pyrexia (3 %) and reduced ejection fraction (3 %) on dabrafenib plus trametinib, and arthralgia (2 %) on vemurafenib. Compared with BRAF inhibitor monotherapy, keratoacanthomas or squamous cell carcinomas occurred more rarely on combined therapy with a BRAF and a MEK inhibitor (1 % vs. 18 %). In another phase III study (COMBI-D), 423 treatment-naive patients with BRAFV600E/K-mutated metastatic melanoma were treated with dabrafenib plus trametinib or with dabrafenib plus placebo [36]. Here, too, the combined therapy was superior to monotherapy, with a response rate of 69 % vs. 53 %, median progression-free survival of 11 months vs. 8.8 months, and median overall survival of 25.1 months vs. 18.7 months [37]. The incidence of grade 3 or 4 side effects (NCI-CTCAE) was similar in both treatment arms (32 % vs. 31 %), with the exception of pyrexia, which was primarily seen on dabrafenib plus trametinib compared to dabrafenib plus placebo (52 % vs. 25 %). Here, too, hyperkeratoses, squamous cell carcinomas, new primary melanomas, and other malignancies occurred more rarely with the combination of dabrafenib plus trametinib compared to BRAF inhibitor monotherapy. Moreover, in comparison with BRAF inhibitor monotherapy, combined therapy resulted in a significant improvement in the quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30) [38]. In another phase III study (coBRIM), 495 patients with BRAF-V600-mutated metastatic melanoma without prior therapy received a combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib (Roche) or vemurafenib plus placebo [39]. Combined therapy again proved superior to monotherapy, with a response rate of 69.6 % vs. 50 % and a median progression-free survival of 12.25 months vs. 7.20 months [40]. Data on median overall survival in this phase III study is not yet available. However, the phase Ib study (BRIM7) with vemurafenib plus cobimetinib yielded a median overall survival of 28.5 months [41]. The following side effects were more common on vemurafenib plus cobimetinib compared to vemurafenib alone: diarrhea (56 % vs. 28 %), nausea (40 % vs. 24 %), elevated creatine kinase levels (31 % vs. 3 %), photosensitivity (28 % vs. 15 %), elevated aspartate aminotransferase levels (22 % vs. 12 %), vomiting (21 % vs. 13 %), retinopathy (12 % vs. 2 years.
In Germany, the combination of dabrafenib (Tafinlar ®, Novartis) plus trametinib (Mekinist ®, Novartis) is now licensed for the treatment of inoperable or metastatic melanoma. Cobimetinib in addition to the approved vemurafenib is currently available through a compassionate use program; approval for cobimetinib is expected in 2015. In the future, the combination of a BRAF inhibitor with a MEK inhibitor will replace monotherapy, as suggested by improved response rates, prolonged survival, and a tolerable side effect profile.
Immunotherapy CTLA-4 antibodies Immunotherapy strategies for the treatment of melanoma have been used or investigated for a long time (for example, interferon alpha, interleukin 2). They are based on the knowledge that, under certain conditions, the immune system is capable of controlling and combating tumor cells but also of “accepting” them [42]. Activation and proliferation of T-cells in lymph nodes requires recognition of the tumor antigen by the T-cells receptor via the main histocompatibility complex on antigen-presenting cells on the one hand, and, on the other hand, costimulatory signals through binding of CD28 on T-cells to its ligand B7 on antigen-presenting cells (Figure 2) [43, 44]. The cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) acts as a physiological brake on the immune response by binding to B7 and inhibiting CD28. Consequently, it plays an integral part as immune checkpoint [44, 45]. By blocking this negative regulation, CTLA-4 antibodies may help boost the immune response, thus leading to immune-mediated tumor regression [46]. The CTLA-4 antibody ipilimumab (Yervoy ®, BMS) was the first systemic therapeutic agent to achieve a significant prolongation of overall survival [47]. In a
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The CTLA-4 antibody ipilimumab achieves long-term survival rates of > 20 %.
Early diagnosis and adequate management of immune-mediated side effects are essential.
phase III study, previously treated patients with metastatic melanoma were treated with four doses of ipilimumab 3 mg/kg IV every three weeks or with a gp100 peptide vaccine (gp100) or with ipilimumab plus gp100. Disease control rates and median overall survival were 28.5 % and ten months respectively on ipilimumab, 11 % and six months on gp100, and 20.1 % and ten months on ipilimumab plus gp100. In the analysis of pooled survival data from phase II and III studies, a plateau in the survival curve was observed after three years, with a three-year survival rate of 20–26 % [48]. Ipilimumab is most commonly associated with side effects that result from increased immune activity. In particular, these include gastrointestinal side effects such as colitis, cutaneous side effects such as rashes, endocrinopathies such as hypophysitis, hepatitis, and neurological side effects [47]. Early diagnosis and adequate treatment of these sometimes life-threatening side effects are essential, possibly with the use of systemic corticosteroids, infliximab, and other immunosuppressive agents (see Summary of Product Characteristics and [49]).
PD-1 antibodies Another relevant immune checkpoint involves the PD-1 (programmed death 1) signaling pathway. This PD-1 receptor inhibits T-cells activity by interaction with its ligands PD-L1 (B7-H1) on tumor cells and antigen-presenting cells, and PD-L2 (B7-DC) on activated monocytes and dendritic cells [50]. This results in an immunosuppressive tumor environment (Figure 2) [44, 45]. Therapeutic use of blocking anti-PD-1 or anti-PD-L1 antibodies interrupts this immunosuppression and increases the antitumor T-cells response. Nivolumab (Opdivo®, Bristol-Myers Squibb) is the first PD-1 antibody licensed in Europe for the treatment of both treatment-naive and pretreated patients with advanced (unresectable or metastatic) melanoma. Nivolumab 3 mg/kg is given at two-week intervals, provided neither tumor progression nor unacceptable side effects have occurred. The treatment regimen (two-week intervals) allows for close patient monitoring, especially at the start of the treatment. The therapeutic response is initially assessed after nine weeks, then every six weeks in the first year and every 12 weeks in the second year until disease progression [51]. In a phase III study (CheckMate-066), in which 418 patients with advanced melanoma and BRAF wild type without prior therapy participated, nivolumab achieved a response rate of 40 % vs. 13.9 % and a one-year survival rate of 72.9 % vs. 42.1 % compared with dacarbazine [52]. Another phase III study (CheckMate-037) in patients pretreated with ipilimumab and possibly a BRAF inhibitor showed a response rate of 31.7 % vs. 10.6 % for nivolumab compared with chemotherapy (dacarbazine or (optionally) carboplatin plus paclitaxel), with a median duration of 2.1 months until the onset of a therapeutic response [53]. Five percent of patients experienced severe acute side effects (NCI-CTCAE grade 3–4) on nivolumab; 9 % on chemotherapy. The most common grade 3–4 side effects on nivolumab included fatigue, anemia, diarrhea, and vomiting, whereas fatigue, diarrhea, nausea, anemia, arthralgias, vomiting, constipation, and neutropenia were observed during chemotherapy. In a dose escalation study using 0.1 mg, 0.3 mg, 1.0 mg, 3.0 mg, or 10 mg/kg body weight, the one-year and two-year survival rate was 62 % and 43 % respectively. Patients with objective tumor regression showed a median response duration of two years. Cumulative long-term toxicity did not occur [54]. Nivolumab treatment is most frequently associated with immune-mediated side effects, the most common being fatigue (33 %), skin rash (20 %), pruritus
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Early diagnosis and adequate management of immune-mediated side effects are essential.
PD-1 antibodies will play a significant role in first-line treatment. Early diagnosis and adequate management of immune-mediated side effects are essential.
(18 %), diarrhea (16 %), and nausea (14 %). Here, too, early diagnosis and adequate treatment of the sometimes life-threatening side effects are pivotal, possibly with the use of systemic corticosteroids, infliximab, and other immunosuppressive agents (see Summary of Product Characteristics and [55]). With respect to efficacy and toxicity, pembrolizumab, another PD-1 antibody, showed similar results in studies conducted to date [56, 57]. Analysis of pooled data from 655 patients treated with pembrolizumab in the KEYNOTE-001 study yielded a response rate of > 30 % and a median overall survival of 23 months. For firstline therapy with pembrolizumab, the response rate was 45 % and the median overall survival was 31 months [58]. In a phase III study comparing pembrolizumab and ipilimumab in patients with inoperable metastatic melanoma, the former achieved longer overall survival with a 12-month survival rate of 68–74 % vs. 58 %, while also showing lower toxicity [59]. It may thus be assumed that PD-1 antibodies will play a significant role in the first-line treatment of inoperable metastatic melanoma. Pembrolizumab (Keytruda®, MSD) has by now also been approved for the treatment of advanced (unresectable or metastatic) melanoma. The recommended dose is 2 mg/kg body weight IV over 30 min every three weeks. Treatment should be continued until disease progression or until the occurrence of intolerable side effects. Detailed information regarding diagnosis as well as acute and subsequent management of immune-mediated adverse events during treatment with pembrolizumab (depending on their severity) is provided both in a guideline (available through [email protected]) and in the Summary of Product Characteristics.
Combined PD-1 and CTLA-4 inhibition Combined inhibition of PD-1 and CTLA-4 yields high response rates with high toxicity. Most immune-mediated side effects are reversible with adequate management. Early diagnosis and adequate management of immune-mediated side effects are essential.
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Combined inhibition of PD-1 and CTLA-4 allows inactivated tumor-specific T-cells to proliferate again and exert their effector functions, thus resulting in immune activation of the previously immunosuppressed tumor environment [60]. In a phase III study (CheckMate-067), 945 treatment-naive patients with metastatic melanoma received nivolumab plus ipilimumab or nivolumab or ipilimumab. Response rates were 58 % for the combination vs. 44 % for nivolumab vs. 19 % for ipilimumab, with a median progression-free survival of 11.5 months vs. 6.9 months vs. 2.9 months. NCI-CTCAE grade 3–4 side effects were observed in 55 % of patients on nivolumab plus ipilimumab, 16 % on nivolumab, and 27 % on ipilimumab. They most commonly included diarrhea and elevated liver enzymes both on nivolumab plus ipilimumab and on nivolumab monotherapy; rashes, colitis, and hypophysitis on ipilimumab monotherapy. Remarkably, most grade 3–4 side effects resolved on adequate immunosuppressive therapy. With respect to this study, it has to be noted that it was not sufficiently powered for a reliable comparative statistical analysis of nivolumab plus ipilimumab vs. nivolumab [61, 62]. Remarkably, 68 % of patients who had to discontinue nivolumab plus ipilimumab because of side effects subsequently showed a therapeutic response. In line with this observation is the recent report of a patient who exhibited complete resolution of a bulky melanoma mass below the left breast three weeks after administration of nivolumab plus ipilimumab [63]. Interestingly, the median progression-free survival for patients with PD-L1 expression of ≥ 5 % was 14 months both on nivolumab monotherapy and on combined therapy with nivolumab plus ipilimumab [61, 62]. Thus, patients with PD-L1 expression of ≥ 5 % possibly benefit just as much from nivolumab as from nivolumab plus ipilimumab, while experiencing markedly lower toxicity with the former. With regard to monotherapy with PD-1 antibodies, the PD-L1 expression status as a predictive marker for the therapeutic response is controversial. Data available
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to date suggests that the PD-L1 expression status is a correlation marker but not a reliable predictive marker for the response to PD-1 antibody therapy.
Treatment sequence and treatment combinations
Strategies with respect to treatment sequence and treatment combinations are being investigated in prospective studies.
Targeted therapy with BRAF inhibitors and BRAF plus MEK inhibitors is characterized by a rapid response and high response rates. Although possible, longterm response to BRAF inhibitor monotherapy is rather infrequent. Compared to targeted therapy, immunotherapy with CTLA-4 and/or PD-1 antibodies shows a delayed response and lower response rates, with a long-term response observed in 20–26 % of patients treated with the CTLA-4 antibody ipilimumab. Data on the long-term response to targeted combined therapy with BRAF plus MEK inhibitors or to immunotherapy with PD-1 antibodies or CTLA-4 plus PD-1 antibodies is still pending. Preclinical studies show that BRAF inhibitors and BRAF plus MEK inhibitors have immune-activating effects on the tumor environment by – among other things – increasing tumor antigen presentation, T-cells recognition, and T-cells effector functions [64]. This raises the question of the optimal treatment sequence and optimal treatment combination. Retrospective analyses indicate that immunotherapy with ipilimumab does not impair the response to subsequent BRAF inhibitor treatment. On the other hand, patients who had to discontinue BRAF inhibitor therapy due to progression tend to have a poorer prognosis. On subsequent treatment with ipilimumab, 94 % of these patients showed tumor progression, with a median progression-free survival of 2.7 months and a median overall survival of five months [65]. A prospective study is currently under way to investigate the treatment sequence of dabrafenib plus trametinib followed by ipilimumab plus nivolumab and vice versa (NCT02224781). The various dynamics involved in the response to targeted therapies and immunotherapy as well as the immune-sensitizing effects of BRAF and MEK inhibitors described above suggest a benefit in combining these two treatment strategies. The combination strategy of targeted therapy plus immunotherapy is currently being investigated in several studies [66]. With the same basic idea, triple therapy with the BRAF inhibitor dabrafenib, the MEK inhibitor trametinib, and the PD-1 antibody pembrolizumab is being examined in a dose escalation study (Keynote022) (NCT02130466).
Algorithm for systemic therapy of metastatic melanoma If systemic therapy is indicated, enrolment in a clinical study should first be considered.
If systemic therapy is indicated, enrolment in a clinical study should first be considered [13]. Outside studies, approved therapeutic agents currently available include the BRAF inhibitors vemurafenib and dabrafenib, the MEK inhibitor trametinib, the PD-1 antibodies nivolumab and pembrolizumab, the CTLA-4 antibody ipilimumab, and chemotherapeutic agents. The MEK inhibitor cobimetinib is currently available through a compassionate use program. Relevant decision criteria regarding first-line treatment, treatment combinations, and treatment sequence include the patient’s general condition and symptoms, dynamics of tumor progression, tumor load, and mutation status.
Outlook Several effective treatment options are currently available for patients with metastatic melanoma, either as approved drugs or in the context of a compassionate use
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For patients with metastatic melanoma, the prognosis has significantly improved.
program and clinical trials. For patients with metastatic melanoma, the prognosis has thus significantly improved, resulting in long-term survival of > 20 %. The systematic implementation of treatment regimens requires professional side effect management. In light of possible long-term survival, not only acute but also potential long-term side effects of treatment have to be taken into account. The choice of therapeutic agents and their sequence is subject to numerous variables that require further evaluation. Another focus is on the search for individual prognostic tumor and immune markers that may assist in the treatment decision-making process. References 1
Correspondence to Prof. Dr. med. Friedegund Meier Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden Klinik und Poliklinik für Dermatologie Fetscherstraße 74 01307 Dresden Germany E-mail: friedegund.meier@ uniklinikum-dresden.de
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Schadendorf D, Bernhard H. Medikamentöse Systemtherapie des Melanoms. nkologe 2014; 20(6): 568–76. O Menzies AM, Haydu LE, Visintin L et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res 2012; 18(12): 3242–9. Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364(26): 2507–16. McArthur GA, Chapman PB, Robert C et al. Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014; 15(3): 323–32. Hauschild A, Grobb JJ, Demidov LV et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380(9839): 358–65. Larkin J, Del Vecchio M, Ascierto PA et al. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol 2014; 15(4): 436–44. Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012; 366(3): 207–15. Zimmer L, Hillen U, Livingstone E et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol 2012; 30(19): 2375–83. Long GV, Trefzer U, Davies MA et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13(11): 1087–95. Dummer R, Goldinger SM, Turtschi CP et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer 2014; 50(3): 611–21. Flaherty KT, Robert C, Hersey P et al. Improved survival with MEK inhibition in BRAFmutated melanoma. N Engl J Med 2012; 367(2): 107–14. Curtin JA, Busam K, Pinkel D et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006; 24(26): 4340–6. Garrido MC, Bastian BC. KIT as a Therapeutic Target in Melanoma. J Invest Dermatol 2010; 130(6): 20–7. Carvajal RD, Antonescu CR, Wolchok JD et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011; 305(22): 2327–34. Guo J, Si L, Kong Y et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 2011; 29(21): 2904–9. Solit DB, Rosen N. Resistance to BRAF inhibition in melanomas. N Engl J Med 2011; 364(8): 772–4. Robert C, Karaszewska B, Schachter J et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372(1): 30–9. Long GV, Stroyakovskiy D, Gogas H et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014; 371(20): 1877–88. Long GV, Stroyakovskiy D, Gogas H et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015; 386(9992): 444–51. Schadendorf D, Amonkar MM, Stroyakovskiy D et al. Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. Eur J Cancer 2015; 51(7): 833–40. Larkin J, Ascierto PA, Dréno B et al. Combined Vemurafenib and Cobimetinib in BRAFMutated Melanoma. N Engl J Med 2014; 371: 1867–76. Larkin MG, Yan Y, McArthur GA et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol 2015; 33 (suppl): abstr. 9006.
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65 Ackerman A, Klein O, McDermott DF et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer 2014; 120: 1695–701. 66 Wargo JA, Reuben A, Cooper ZA et al. Immune Effects of Chemotherapy, Radiation, and Targeted Therapy and Opportunities for Combination With Immunotherapy. Semin Oncol 2015; 42(4): 601–16.
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Fragen zur Zertifizierung durch die DDA 1.
Welche Mutation ist am
häufigsten beim malignen Melanom zu finden? a) BRAF-V600E b) BRAF-V600K c) BRAF-V600R d) NRAS-Q61R e) cKIT
2. Welches Systemtherapeutikum ist zur Behandlung des fortgeschrittenen malignen Melanoms in Deutschland bisher nicht zugelassen? a) Ipilimumab b) Vemurafenib c) Imatinib d) Dabrafenib e) Dacarbazin
3.
Welches Medikament kommt
nicht zur Behandlung einer immunvermittelten Enterokolitis infolge einer Therapie mit Ipilimumab in Betracht? a) Loperamid b) Prednison c) Methylprednisolon d) Infliximab e) Nivolumab
4. a) b) c) d) e)
5.
Welche Aussage ist richtig? Ipilimumab ist ein BRAF-Inhibitor. Vemurafenib ist ein MEK-Inhibitor. Dabrafenib ist ein BRAF-Inhibitor. Dacarbazin ist ein CTLA-4- Antikörper. Pembrolizumab ist ein PD-L1- Antikörper.
Welche Nebenwirkung tritt am
häufigsten unter einer Therapie mit Dabrafenib auf? a) Phototoxizität b) Pyrexie
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c) Exanthem d) Diarrhoe e) Dyspnoe
6. Welche Aussage ist falsch? a) Häufige Nebenwirkungen einer Therapie mit Vemurafenib sind Phototoxizität und Arthralgien. b) Die empfohlene Dosis für Dabrafenib beträgt 150 mg 2 x t äglich. c) Kutane Plattenepithelkarzinome und Zweitmelanome können sich unter einer Therapie mit Vemurafenib oder Dabrafenib aufgrund der paradoxen Aktivierung des MAP-Kinase-Signalwegs in Zellen mit BRAF-Wildtyp entwickeln. d) Als Nebenwirkungen einer Therapie mit Trametinib können papulopustulöse Exantheme und Retinopathien auftreten. e) Die Gesamttoxizität ist bei der Kombination eines BRAF- und eines MEK-Inhibitors erhöht.
Welche Aussage ist richtig? Dacarbazin konnte als erstes Systemtherapeutikum eine signifikante Verlängerung des Gesamtüberlebens bei Patienten mit inoperablem Melanom im AJCC-Stadium III–IV nachweisen. b) Für die Kombinationschemotherapie Carboplatin/Paclitaxel konnte in Studien ein Überlebensvorteil im Vergleich zu Dacarbazin demonstriert werden. c) Todesfälle infolge einer Behandlung mit Ipilimumab sind bisher nicht aufgetreten. d) Nivolumab konnte bei therapienaiven Patienten mit fortgeschrittenem malignem Melanom eine 1-Jahres-Überlebensrate von 72,9 % und eine Ansprechrate von 40 % erzielen. 7. a)
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1312
e)
Ipilimumab ist Pembrolizumab hinsichtlich des progressionsfreien Überlebens und der Ansprechrate überlegen.
8. Welche ist keine zu erwartende Nebenwirkung eines PD-1-Antikörpers? a) Hyperthyreose b) Hypothyreose c) Hepatitis d) Pneumonitis e) Photosensitivität
9. Welche Aussage ist falsch? a) Temozolomid und Dacarbazin sind in ihrer Toxizität und Wirksamkeit bei Patienten mit metastasiertem Melanom vergleichbar. b) Der BRAF-Inhibitor Encorafenib und der MEK-Inhibitor Binimetinib werden derzeit in klinischen Studien zur Systemtherapie des malignen Melanoms geprüft. c) Die PD-1-Antikörper Pembrolizumab und Nivolumab sind in Europa nur nach Vortherapie mit Ipilimumab zur Behandlung des fortgeschrittenen Melanoms zugelassen. d) Pembrolizumab und Nivolumab haben ein ähnliches Nebenwirkungsprofil. e) Dabrafenib und Vemurafenib haben zum Teil unterschiedliche Nebenwirkungen.
10. Welche Aussage ist falsch? a) Ipilimumab blockiert die CTLA-4-B7-Interaktion. b) Ipilimumab wird mit einer Dosis von 3 mg/kg Körpergewicht intravenös viermal im Abstand von drei Wochen eingesetzt. c) Die meisten Ipilimumab-induzierten immunvermittelten Nebenwirkungen sind unter leitliniengerechter immunsuppressiver Therapie reversibel.
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d) Ipilimumab ist in Kombination mit Nivolumab zur Behandlung des metastasierten malignen Melanoms in Deutschland zugelassen.
e)
Immunvermittelte Nebenwirkungen einer Therapie mit Ipilimumab sind unter anderem eine Hypophysitis und Hepatitis.
Liebe Leserinnen und Leser, der Einsendeschluss an die DDA für diese Ausgabe ist der 18. January 2015. Die richtige Lösung zum Thema „Current diagnosis and treatment of basal cell carcinoma“ in Heft 9 (September 2015) ist: (1a, 2b, 3d, 4a, 5c, 6d, 7e, 8a, 9d, 10e).
Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg. akademie-dda.de ein.
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Ricarda Rauschenberg, Marlene Garzarolli, Ursula Dietrich, Stefan Beissert, Friedegund Meier Department of Dermatology, Carl Gustav Carus University Hospital at the Technical University Dresden, Dresden, Germany Section Editor Prof. Dr. D. Nashan, Dortmund
DOI: 10.1111/ddg.12891
Systemic therapy of metastatic melanoma
Summary For patients with metastatic melanoma, there are currently several effective therapeutic options. The BRAF inhibitors vemurafenib and dabrafenib are characterized by rapid tumor control and high response rates. In combination with one of the two MEK inhibitors trametinib and cobimetinib, they achieve response rates (CR + PR, complete plus partial remissions) of 70 %, while delaying the development of treatment resistance, as well as a median overall survival of > 2 years with tolerable side effects. Showing long-term survival rates of approximately 20 %, the anti-CTLA-4 antibody ipilimumab is the first substance that has led to a significant prolongation of overall survival in patients with metastatic melanoma. However, delayed treatment response and severe immune-mediated side effects may pose limitations to its therapeutic benefit. Usually well tolerated, anti-PD-1 antibody monotherapy using nivolumab and pembrolizumab has yielded response rates (CR + PR) of up to 45 % and one-year survival rates of > 70 %. The combination of ipilimumab and nivolumab has shown response rates of up to 58 % and a median progression-free survival of > 11 months. While this combination is expected to result in a rapid and long-lasting response, this potential benefit comes at the expense of a high level of toxicity. Strategies for treatment sequencing and treatment combinations are currently being investigated in clinical studies. Overall, the prognosis for patients with metastatic melanoma has significantly improved. With long-term survival a possibility, not only acute but also long-term therapeutic side effects must be taken into account.
Introduction and basic principles In Western industrialized nations, the incidence of melanoma has markedly increased since the 1980s [1, 2]. Relevant risk factors include changes in recreational and vacation-related habits in the past 50 years combined with increased intermittent UV exposure [3, 4]. Compared with other solid tumors, melanoma exhibits a large number of mutations [5], with the MAP kinase signaling pathway (RAS-RAF-MEK-ERK) being of particular importance (Figure 1). Thus, a BRAF mutation is found in
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Figure 1 MAPK signaling pathway – targeted therapy with BRAF and MEK inhibitors.
about 40–60 % of cutaneous melanomas, a NRAS mutation in 15–25 %, the prevalence varying with the histological subtype and tumor location [6]. Another pathway important for tumor progression is the PI3K-AKT-PTEN signaling pathway whose activation (among others, through RAS) may also play a part in the development of resistance to MAP kinase inhibitors [7, 8]. Until recently, the prognosis for melanoma patients with distant metastases had been poor. According to a study by Balch et al. from 2009, one-year survival rates range from 33 % (TNM classification M1c) to 62 % (TNM classification M1a) [9]. However, after decades of stagnation, recent advances in immunotherapy and targeted therapies have considerably improved the prognosis of stage IV melanoma.
Chemotherapy Monochemotherapy Until 2011, treatment with the alkylating agent dacarbazine (DTIC) was regarded as standard treatment for patients with inoperable metastatic melanoma. Up to that point, alternatives had been limited [10]. Administered intravenously, dacarbazine is given at a dose of 800–1200 mg/m² body surface area on day 1 every 3–4 weeks or at a dose of 250 mg/m² on day 1–5 every 3–4 weeks [11]. In several phase III studies, DTIC showed objective response rates between 5 % and 14 %, with a tolerable side effect profile but without a clinically significant impact on overall survival. The efficacy and toxicity of the alkylating agent temozolomide (150–200 mg/m² orally on day 1–5 every four weeks) and the nitrosourea fotemustine (100 mg/m² IV on day 1, 8, and 15, followed by a five-week interval and continuation every three weeks) are comparable to those of DTIC [12–14]. Common side effects include myelosuppression, nausea, vomiting, fatigue, and headache. Especially when using fotemustine, the nadir may be delayed and only
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set in after 4–6 weeks. Nausea and vomiting may usually be prevented by prophylactic antiemetic therapy according to guidelines [15, 16].
Combined chemotherapy Various combined chemotherapy regimens have failed to show any survival benefit compared to DTIC monochemotherapy [17]. Given their high toxicity and associated impairment of quality of life, they may be considered in patients with a high tumor load or rapid progression after failure of other systemic therapies [10, 17]. In such cases, combined chemotherapy with carboplatin and paclitaxel is frequently given, showing a progression-free survival of four months with acceptable toxicity in a randomized trial. Common side effects include intolerance reactions, myelosuppression, neuropathy, diarrhea, musculoskeletal pain, and fatigue [18]. In view of the treatment options currently available, it is safe to assume that chemotherapy is to be considered a “last-line therapy”.
Targeted therapy BRAF inhibitors The serine-threonine kinase BRAF is an integral part of the aforementioned MAP (mitogen-activated protein) kinase signaling pathway [19]. Activating mutations of the protooncogene BRAF result in uncontrolled tumor growth (Figure 1). A BRAFV600E mutation is present in approximately 70 % of BRAF-positive tumors, a BRAF-V600K mutation in approximately 20 % [20]. In Germany, the BRAF inhibitors vemurafenib (Zelboraf ®, Roche) and dabrafenib (Tafinlar ®, Novartis) are licensed for systemic treatment of melanoma. In a phase III study (BRIM-3), 675 treatment-naive, inoperable melanoma patients with a confirmed BRAF-V600E mutation (AJCC stage IIIC–IV, without brain metastases) were treated with vemurafenib or dacarbazine [21]. Response rates and median progression-free survival for vemurafenib vs. dacarbazine were 48 % vs. 5 % and 5.3 months vs. 1.6 months. Median overall survival was 13.6 months for vemurafenib and 9.7 months for dacarbazine [22]. Dabrafenib showed comparable results in a phase III study (BREAK-3) in 250 patients [23]. Vemurafenib is given at a dose of 960 mg twice daily (four film-coated tablets twice a day). The recommended dose for dabrafenib is 150 mg twice daily (two 75-mg hard capsules twice a day.). Another BRAF inhibitor, encorafenib (LGX818, Array BioPharma), is currently being investigated in a clinical study (COLUMBUS). In a safety study with 3,222 participants, the most common side effects of vemurafenib therapy were rashes, arthralgia, fatigue, photosensitivity, hair loss, and nausea [24]. Moreover, patients exhibited cutaneous squamous cell carcinomas and secondary melanomas, which may be attributed to a paradoxical activation of the MAP kinase signaling pathway in cells with the BRAF wild type [25, 26]. QT interval prolongation has been described especially in elderly individuals (> 75 years) with comorbidities [24]. Adverse drug effects most commonly reported in studies on dabrafenib include hyperkeratoses, headache, pyrexia, arthralgia, fatigue, nausea, papillomas, hair loss, rash, and vomiting [23, 27]. The BRAF inhibitors have a similar toxicity profile, with photosensitivity characteristically observed more often with vemurafenib and pyrexia more frequently with dabrafenib. Managing side effects may require dose reductions or a temporary discontinuation of treatment. Furthermore, potential interactions with other drugs that are substrates of CYP2C8 and CYP3A4 have to be taken into account (see Summaries of Product Characteristics).
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Both BRAF inhibitors have also been shown to be effective in the treatment of brain metastases [27, 28]. In patients with asymptomatic BRAF-V600E-mutated brain metastases, dabrafenib achieved response rates of 30–40 % and a median overall survival of 7–8 months. In patients with asymptomatic and symptomatic BRAF-mutated brain metastases, vemurafenib yielded response rates of 18–20 % and a median overall survival of > 6 months. While response rates were lower in the vemurafenib study, patients were at a more advanced stage, which is why the data available does not allow for a comparison of efficacy between vemurafenib and dabrafenib. Given the rapid onset of action and high response rates, targeted treatment may especially be considered in patients with rapid tumor progression and/or symptomatic metastases; patients with normal LDH levels prior to the start of treatment show significantly longer median overall survival than patients with elevated LDH levels [24].
MEK inhibitors MEK is another therapeutic target in the MAP kinase signaling pathway (Figure 1). In a phase III study, 322 patients with inoperable metastatic melanoma and BRAF-V600E/K mutation received treatment with the MEK inhibitor trametinib (Mekinist ®, Novartis; 2 mg orally once a day until tumor progression) or chemotherapy (DTIC or paclitaxel). Trametinib treatment resulted in a significant improvement in median progression-free survival of 4.8 months vs. 1.5 months. The most common side effects included rashes (in part papulopustular eruptions), diarrhea, peripheral edema, and fatigue. A reduction in ejection fraction or ventricular dysfunction and retinopathies were among the rare adverse effects [29]. Another MEK inhibitor, binimetinib (MEK162, Array BioPharma), is currently being investigated in studies (COLUMBUS, NEMO). These also include patients with NRAS mutations.
c-KIT kinase inhibitors Overall rare in melanoma, mutations of the receptor tyrosine kinase KIT are most commonly found in mucosal (21 %) and acrolentiginous (11 %) melanomas or in those arising on chronically sun-damaged skin (17 %) [30, 31]. In a phase II study, 16 % of patients with c-KIT aberrations responded to the c-KIT kinase inhibitor imatinib (Glivec®, Novartis) (400 mg orally twice a day) with partial or complete remission; the median time to progression was 12 weeks and the median overall survival was 46.3 weeks [32]. The – at best – moderate results were attributed to the fact that only a certain proportion of c-KIT mutations, most likely in exon 11 and 13, is of oncogenetic relevance [33]. In another phase II study with imatinib (400 mg orally once a day), 23.3 % of patients showed partial remission with a median progression-free survival of 3.5 months. The most common side effects were edema, fatigue, anorexia, nausea, neutropenia, and elevated liver enzymes (transaminases). A dose increase to 800 mg daily was associated with increased toxicity, especially with edema, nausea, and vomiting (NCI-CTCAE grade 3–4) [32, 33]. In view of the rarity of treatment-relevant c-KIT mutations and the approval of two PD-1 antibodies (see Immunotherapy, PD-1 antibodies), treatment with c-KIT kinase inhibitors will likely play an ancillary role in the future.
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Combined BRAF and MEK inhibition Occurring in the majority of patients over the course of treatment, development of resistance poses a limitation to monotherapy with one of the aforementioned BRAF inhibitors. Most resistance mechanisms described to date result in reactivation of the MAP kinase signaling pathway [34]. By combining a BRAF and a MEK inhibitor, one may expect a delay in the development of resistance and a prolongation of the therapeutic response. In a phase III study (COMBI-V), 704 treatment-naive patients with BRAFV600-mutated metastatic melanoma were given dabrafenib (150 mg orally twice a day) plus trametinib (2 mg orally once a day) or vemurafenib (960 mg orally twice a day). Compared to monotherapy, the combined treatment resulted in a significant improvement in the response rate (64 % vs. 51 %), median progression-free survival (11.4 months vs. 7.3 months), and overall survival after 12 months (72 % vs. 65 %) [35]. It is noteworthy that the rate of treatment discontinuation due to side effects was similar in both treatment arms (13 % and 12 %). Side effects that most frequently led to treatment discontinuation were pyrexia (3 %) and reduced ejection fraction (3 %) on dabrafenib plus trametinib, and arthralgia (2 %) on vemurafenib. Compared with BRAF inhibitor monotherapy, keratoacanthomas or squamous cell carcinomas occurred more rarely on combined therapy with a BRAF and a MEK inhibitor (1 % vs. 18 %). In another phase III study (COMBI-D), 423 treatment-naive patients with BRAFV600E/K-mutated metastatic melanoma were treated with dabrafenib plus trametinib or with dabrafenib plus placebo [36]. Here, too, the combined therapy was superior to monotherapy, with a response rate of 69 % vs. 53 %, median progression-free survival of 11 months vs. 8.8 months, and median overall survival of 25.1 months vs. 18.7 months [37]. The incidence of grade 3 or 4 side effects (NCI-CTCAE) was similar in both treatment arms (32 % vs. 31 %), with the exception of pyrexia, which was primarily seen on dabrafenib plus trametinib compared to dabrafenib plus placebo (52 % vs. 25 %). Here, too, hyperkeratoses, squamous cell carcinomas, new primary melanomas, and other malignancies occurred more rarely with the combination of dabrafenib plus trametinib compared to BRAF inhibitor monotherapy. Moreover, in comparison with BRAF inhibitor monotherapy, combined therapy resulted in a significant improvement in the quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30) [38]. In another phase III study (coBRIM), 495 patients with BRAF-V600-mutated metastatic melanoma without prior therapy received a combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib (Roche) or vemurafenib plus placebo [39]. Combined therapy again proved superior to monotherapy, with a response rate of 69.6 % vs. 50 % and a median progression-free survival of 12.25 months vs. 7.20 months [40]. Data on median overall survival in this phase III study is not yet available. However, the phase Ib study (BRIM7) with vemurafenib plus cobimetinib yielded a median overall survival of 28.5 months [41]. The following side effects were more common on vemurafenib plus cobimetinib compared to vemurafenib alone: diarrhea (56 % vs. 28 %), nausea (40 % vs. 24 %), elevated creatine kinase levels (31 % vs. 3 %), photosensitivity (28 % vs. 15 %), elevated aspartate aminotransferase levels (22 % vs. 12 %), vomiting (21 % vs. 13 %), retinopathy (12 % vs. 2 years.
In Germany, the combination of dabrafenib (Tafinlar ®, Novartis) plus trametinib (Mekinist ®, Novartis) is now licensed for the treatment of inoperable or metastatic melanoma. Cobimetinib in addition to the approved vemurafenib is currently available through a compassionate use program; approval for cobimetinib is expected in 2015. In the future, the combination of a BRAF inhibitor with a MEK inhibitor will replace monotherapy, as suggested by improved response rates, prolonged survival, and a tolerable side effect profile.
Immunotherapy CTLA-4 antibodies Immunotherapy strategies for the treatment of melanoma have been used or investigated for a long time (for example, interferon alpha, interleukin 2). They are based on the knowledge that, under certain conditions, the immune system is capable of controlling and combating tumor cells but also of “accepting” them [42]. Activation and proliferation of T-cells in lymph nodes requires recognition of the tumor antigen by the T-cells receptor via the main histocompatibility complex on antigen-presenting cells on the one hand, and, on the other hand, costimulatory signals through binding of CD28 on T-cells to its ligand B7 on antigen-presenting cells (Figure 2) [43, 44]. The cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) acts as a physiological brake on the immune response by binding to B7 and inhibiting CD28. Consequently, it plays an integral part as immune checkpoint [44, 45]. By blocking this negative regulation, CTLA-4 antibodies may help boost the immune response, thus leading to immune-mediated tumor regression [46]. The CTLA-4 antibody ipilimumab (Yervoy ®, BMS) was the first systemic therapeutic agent to achieve a significant prolongation of overall survival [47]. In a
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The CTLA-4 antibody ipilimumab achieves long-term survival rates of > 20 %.
Early diagnosis and adequate management of immune-mediated side effects are essential.
phase III study, previously treated patients with metastatic melanoma were treated with four doses of ipilimumab 3 mg/kg IV every three weeks or with a gp100 peptide vaccine (gp100) or with ipilimumab plus gp100. Disease control rates and median overall survival were 28.5 % and ten months respectively on ipilimumab, 11 % and six months on gp100, and 20.1 % and ten months on ipilimumab plus gp100. In the analysis of pooled survival data from phase II and III studies, a plateau in the survival curve was observed after three years, with a three-year survival rate of 20–26 % [48]. Ipilimumab is most commonly associated with side effects that result from increased immune activity. In particular, these include gastrointestinal side effects such as colitis, cutaneous side effects such as rashes, endocrinopathies such as hypophysitis, hepatitis, and neurological side effects [47]. Early diagnosis and adequate treatment of these sometimes life-threatening side effects are essential, possibly with the use of systemic corticosteroids, infliximab, and other immunosuppressive agents (see Summary of Product Characteristics and [49]).
PD-1 antibodies Another relevant immune checkpoint involves the PD-1 (programmed death 1) signaling pathway. This PD-1 receptor inhibits T-cells activity by interaction with its ligands PD-L1 (B7-H1) on tumor cells and antigen-presenting cells, and PD-L2 (B7-DC) on activated monocytes and dendritic cells [50]. This results in an immunosuppressive tumor environment (Figure 2) [44, 45]. Therapeutic use of blocking anti-PD-1 or anti-PD-L1 antibodies interrupts this immunosuppression and increases the antitumor T-cells response. Nivolumab (Opdivo®, Bristol-Myers Squibb) is the first PD-1 antibody licensed in Europe for the treatment of both treatment-naive and pretreated patients with advanced (unresectable or metastatic) melanoma. Nivolumab 3 mg/kg is given at two-week intervals, provided neither tumor progression nor unacceptable side effects have occurred. The treatment regimen (two-week intervals) allows for close patient monitoring, especially at the start of the treatment. The therapeutic response is initially assessed after nine weeks, then every six weeks in the first year and every 12 weeks in the second year until disease progression [51]. In a phase III study (CheckMate-066), in which 418 patients with advanced melanoma and BRAF wild type without prior therapy participated, nivolumab achieved a response rate of 40 % vs. 13.9 % and a one-year survival rate of 72.9 % vs. 42.1 % compared with dacarbazine [52]. Another phase III study (CheckMate-037) in patients pretreated with ipilimumab and possibly a BRAF inhibitor showed a response rate of 31.7 % vs. 10.6 % for nivolumab compared with chemotherapy (dacarbazine or (optionally) carboplatin plus paclitaxel), with a median duration of 2.1 months until the onset of a therapeutic response [53]. Five percent of patients experienced severe acute side effects (NCI-CTCAE grade 3–4) on nivolumab; 9 % on chemotherapy. The most common grade 3–4 side effects on nivolumab included fatigue, anemia, diarrhea, and vomiting, whereas fatigue, diarrhea, nausea, anemia, arthralgias, vomiting, constipation, and neutropenia were observed during chemotherapy. In a dose escalation study using 0.1 mg, 0.3 mg, 1.0 mg, 3.0 mg, or 10 mg/kg body weight, the one-year and two-year survival rate was 62 % and 43 % respectively. Patients with objective tumor regression showed a median response duration of two years. Cumulative long-term toxicity did not occur [54]. Nivolumab treatment is most frequently associated with immune-mediated side effects, the most common being fatigue (33 %), skin rash (20 %), pruritus
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Early diagnosis and adequate management of immune-mediated side effects are essential.
PD-1 antibodies will play a significant role in first-line treatment. Early diagnosis and adequate management of immune-mediated side effects are essential.
(18 %), diarrhea (16 %), and nausea (14 %). Here, too, early diagnosis and adequate treatment of the sometimes life-threatening side effects are pivotal, possibly with the use of systemic corticosteroids, infliximab, and other immunosuppressive agents (see Summary of Product Characteristics and [55]). With respect to efficacy and toxicity, pembrolizumab, another PD-1 antibody, showed similar results in studies conducted to date [56, 57]. Analysis of pooled data from 655 patients treated with pembrolizumab in the KEYNOTE-001 study yielded a response rate of > 30 % and a median overall survival of 23 months. For firstline therapy with pembrolizumab, the response rate was 45 % and the median overall survival was 31 months [58]. In a phase III study comparing pembrolizumab and ipilimumab in patients with inoperable metastatic melanoma, the former achieved longer overall survival with a 12-month survival rate of 68–74 % vs. 58 %, while also showing lower toxicity [59]. It may thus be assumed that PD-1 antibodies will play a significant role in the first-line treatment of inoperable metastatic melanoma. Pembrolizumab (Keytruda®, MSD) has by now also been approved for the treatment of advanced (unresectable or metastatic) melanoma. The recommended dose is 2 mg/kg body weight IV over 30 min every three weeks. Treatment should be continued until disease progression or until the occurrence of intolerable side effects. Detailed information regarding diagnosis as well as acute and subsequent management of immune-mediated adverse events during treatment with pembrolizumab (depending on their severity) is provided both in a guideline (available through [email protected]) and in the Summary of Product Characteristics.
Combined PD-1 and CTLA-4 inhibition Combined inhibition of PD-1 and CTLA-4 yields high response rates with high toxicity. Most immune-mediated side effects are reversible with adequate management. Early diagnosis and adequate management of immune-mediated side effects are essential.
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Combined inhibition of PD-1 and CTLA-4 allows inactivated tumor-specific T-cells to proliferate again and exert their effector functions, thus resulting in immune activation of the previously immunosuppressed tumor environment [60]. In a phase III study (CheckMate-067), 945 treatment-naive patients with metastatic melanoma received nivolumab plus ipilimumab or nivolumab or ipilimumab. Response rates were 58 % for the combination vs. 44 % for nivolumab vs. 19 % for ipilimumab, with a median progression-free survival of 11.5 months vs. 6.9 months vs. 2.9 months. NCI-CTCAE grade 3–4 side effects were observed in 55 % of patients on nivolumab plus ipilimumab, 16 % on nivolumab, and 27 % on ipilimumab. They most commonly included diarrhea and elevated liver enzymes both on nivolumab plus ipilimumab and on nivolumab monotherapy; rashes, colitis, and hypophysitis on ipilimumab monotherapy. Remarkably, most grade 3–4 side effects resolved on adequate immunosuppressive therapy. With respect to this study, it has to be noted that it was not sufficiently powered for a reliable comparative statistical analysis of nivolumab plus ipilimumab vs. nivolumab [61, 62]. Remarkably, 68 % of patients who had to discontinue nivolumab plus ipilimumab because of side effects subsequently showed a therapeutic response. In line with this observation is the recent report of a patient who exhibited complete resolution of a bulky melanoma mass below the left breast three weeks after administration of nivolumab plus ipilimumab [63]. Interestingly, the median progression-free survival for patients with PD-L1 expression of ≥ 5 % was 14 months both on nivolumab monotherapy and on combined therapy with nivolumab plus ipilimumab [61, 62]. Thus, patients with PD-L1 expression of ≥ 5 % possibly benefit just as much from nivolumab as from nivolumab plus ipilimumab, while experiencing markedly lower toxicity with the former. With regard to monotherapy with PD-1 antibodies, the PD-L1 expression status as a predictive marker for the therapeutic response is controversial. Data available
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to date suggests that the PD-L1 expression status is a correlation marker but not a reliable predictive marker for the response to PD-1 antibody therapy.
Treatment sequence and treatment combinations
Strategies with respect to treatment sequence and treatment combinations are being investigated in prospective studies.
Targeted therapy with BRAF inhibitors and BRAF plus MEK inhibitors is characterized by a rapid response and high response rates. Although possible, longterm response to BRAF inhibitor monotherapy is rather infrequent. Compared to targeted therapy, immunotherapy with CTLA-4 and/or PD-1 antibodies shows a delayed response and lower response rates, with a long-term response observed in 20–26 % of patients treated with the CTLA-4 antibody ipilimumab. Data on the long-term response to targeted combined therapy with BRAF plus MEK inhibitors or to immunotherapy with PD-1 antibodies or CTLA-4 plus PD-1 antibodies is still pending. Preclinical studies show that BRAF inhibitors and BRAF plus MEK inhibitors have immune-activating effects on the tumor environment by – among other things – increasing tumor antigen presentation, T-cells recognition, and T-cells effector functions [64]. This raises the question of the optimal treatment sequence and optimal treatment combination. Retrospective analyses indicate that immunotherapy with ipilimumab does not impair the response to subsequent BRAF inhibitor treatment. On the other hand, patients who had to discontinue BRAF inhibitor therapy due to progression tend to have a poorer prognosis. On subsequent treatment with ipilimumab, 94 % of these patients showed tumor progression, with a median progression-free survival of 2.7 months and a median overall survival of five months [65]. A prospective study is currently under way to investigate the treatment sequence of dabrafenib plus trametinib followed by ipilimumab plus nivolumab and vice versa (NCT02224781). The various dynamics involved in the response to targeted therapies and immunotherapy as well as the immune-sensitizing effects of BRAF and MEK inhibitors described above suggest a benefit in combining these two treatment strategies. The combination strategy of targeted therapy plus immunotherapy is currently being investigated in several studies [66]. With the same basic idea, triple therapy with the BRAF inhibitor dabrafenib, the MEK inhibitor trametinib, and the PD-1 antibody pembrolizumab is being examined in a dose escalation study (Keynote022) (NCT02130466).
Algorithm for systemic therapy of metastatic melanoma If systemic therapy is indicated, enrolment in a clinical study should first be considered.
If systemic therapy is indicated, enrolment in a clinical study should first be considered [13]. Outside studies, approved therapeutic agents currently available include the BRAF inhibitors vemurafenib and dabrafenib, the MEK inhibitor trametinib, the PD-1 antibodies nivolumab and pembrolizumab, the CTLA-4 antibody ipilimumab, and chemotherapeutic agents. The MEK inhibitor cobimetinib is currently available through a compassionate use program. Relevant decision criteria regarding first-line treatment, treatment combinations, and treatment sequence include the patient’s general condition and symptoms, dynamics of tumor progression, tumor load, and mutation status.
Outlook Several effective treatment options are currently available for patients with metastatic melanoma, either as approved drugs or in the context of a compassionate use
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For patients with metastatic melanoma, the prognosis has significantly improved.
program and clinical trials. For patients with metastatic melanoma, the prognosis has thus significantly improved, resulting in long-term survival of > 20 %. The systematic implementation of treatment regimens requires professional side effect management. In light of possible long-term survival, not only acute but also potential long-term side effects of treatment have to be taken into account. The choice of therapeutic agents and their sequence is subject to numerous variables that require further evaluation. Another focus is on the search for individual prognostic tumor and immune markers that may assist in the treatment decision-making process. References 1
Correspondence to Prof. Dr. med. Friedegund Meier Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden Klinik und Poliklinik für Dermatologie Fetscherstraße 74 01307 Dresden Germany E-mail: friedegund.meier@ uniklinikum-dresden.de
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Kaatsch P, Katalinic A, Hentschel S et al. Beiträge zur Gesundheitsberichterstattung des Bundes – Krebs in Deutschland 2007/2008, 8. Ausgabe, Robert Koch-Institut (Hrsg) und die Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (Hrsg), Berlin, 2012. 2 Erdmann F, Lortet-Tieulent J, Schüz J et al. International trends in the incidence of malignant melanoma 1953–2008 – are recent generations at higher or lower risk? Int J Cancer 2013; 132(2): 385–400. 3 Leiter U, Eigentler T, Garbe C. Epidemiology of skin cancer. Adv Exp Med Biol 2014; 810: 120–40. 4 Moan JE, Baturaite Z, Dahlback A, Porojnicu AC. Ultraviolet radiation and cutaneous malignant melanoma. Adv Exp Med Biol 2014; 810: 359–74. 5 Lawrence MS, Stojanov P, Polak P et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013; 499(7457): 214–8. 6 Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol 2011; 164(4): 776–84. 7 Chudnovsky Y, Khavari PA, Adams AE. Melanoma genetics and the development of rational therapeutics. J Clin Invest 2005; 115(4): 813–24. 8 Davies MA. The role of the PI3K-AKT pathway in melanoma. Cancer J 2012; 18(2): 142–7. 9 Balch CM, Gershenwald JE, Soong S et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27(36): 6199–206. 10 Kim T, Amaria RN, Spencer C et al. Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma. Cancer Biol Med 2014; 11(4): 237–46. 11 Pflugfelder A, Kochs C, Blum A et al. Malignant melanoma S3-guideline “diagnosis, therapy and follow-up of melanoma”. J Dtsch Dermatol Ges 2013; 11 (Suppl 6): 1–116, 1–126. 12 Middleton MR, Grob JJ, Aaronson N et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000; 18(1): 158–66. 13 Patel PM, Suciu S, Mortier L et al. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer 2011; 47(10): 1476–83. 14 Avril MF, Aamdal S, Grob JJ et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 2004; 22(6): 1118–25. 15 http://www.mascc.org (Stand: 13.10.2015). 16 MASCC Antiemetic Guidelines©. http://www.mascc.org/antiemetic-guidelines (Stand: 13.10.2015). 17 Eigentler TK, Caroli UM, Radny P et al. Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials. Lancet Oncol 2003; 4(12): 748–59. 18 Hauschild A, Agarwala SS, Trefzer U et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 2009; 27(17): 2823–30.
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Fragen zur Zertifizierung durch die DDA 1.
Welche Mutation ist am
häufigsten beim malignen Melanom zu finden? a) BRAF-V600E b) BRAF-V600K c) BRAF-V600R d) NRAS-Q61R e) cKIT
2. Welches Systemtherapeutikum ist zur Behandlung des fortgeschrittenen malignen Melanoms in Deutschland bisher nicht zugelassen? a) Ipilimumab b) Vemurafenib c) Imatinib d) Dabrafenib e) Dacarbazin
3.
Welches Medikament kommt
nicht zur Behandlung einer immunvermittelten Enterokolitis infolge einer Therapie mit Ipilimumab in Betracht? a) Loperamid b) Prednison c) Methylprednisolon d) Infliximab e) Nivolumab
4. a) b) c) d) e)
5.
Welche Aussage ist richtig? Ipilimumab ist ein BRAF-Inhibitor. Vemurafenib ist ein MEK-Inhibitor. Dabrafenib ist ein BRAF-Inhibitor. Dacarbazin ist ein CTLA-4- Antikörper. Pembrolizumab ist ein PD-L1- Antikörper.
Welche Nebenwirkung tritt am
häufigsten unter einer Therapie mit Dabrafenib auf? a) Phototoxizität b) Pyrexie
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c) Exanthem d) Diarrhoe e) Dyspnoe
6. Welche Aussage ist falsch? a) Häufige Nebenwirkungen einer Therapie mit Vemurafenib sind Phototoxizität und Arthralgien. b) Die empfohlene Dosis für Dabrafenib beträgt 150 mg 2 x t äglich. c) Kutane Plattenepithelkarzinome und Zweitmelanome können sich unter einer Therapie mit Vemurafenib oder Dabrafenib aufgrund der paradoxen Aktivierung des MAP-Kinase-Signalwegs in Zellen mit BRAF-Wildtyp entwickeln. d) Als Nebenwirkungen einer Therapie mit Trametinib können papulopustulöse Exantheme und Retinopathien auftreten. e) Die Gesamttoxizität ist bei der Kombination eines BRAF- und eines MEK-Inhibitors erhöht.
Welche Aussage ist richtig? Dacarbazin konnte als erstes Systemtherapeutikum eine signifikante Verlängerung des Gesamtüberlebens bei Patienten mit inoperablem Melanom im AJCC-Stadium III–IV nachweisen. b) Für die Kombinationschemotherapie Carboplatin/Paclitaxel konnte in Studien ein Überlebensvorteil im Vergleich zu Dacarbazin demonstriert werden. c) Todesfälle infolge einer Behandlung mit Ipilimumab sind bisher nicht aufgetreten. d) Nivolumab konnte bei therapienaiven Patienten mit fortgeschrittenem malignem Melanom eine 1-Jahres-Überlebensrate von 72,9 % und eine Ansprechrate von 40 % erzielen. 7. a)
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1312
e)
Ipilimumab ist Pembrolizumab hinsichtlich des progressionsfreien Überlebens und der Ansprechrate überlegen.
8. Welche ist keine zu erwartende Nebenwirkung eines PD-1-Antikörpers? a) Hyperthyreose b) Hypothyreose c) Hepatitis d) Pneumonitis e) Photosensitivität
9. Welche Aussage ist falsch? a) Temozolomid und Dacarbazin sind in ihrer Toxizität und Wirksamkeit bei Patienten mit metastasiertem Melanom vergleichbar. b) Der BRAF-Inhibitor Encorafenib und der MEK-Inhibitor Binimetinib werden derzeit in klinischen Studien zur Systemtherapie des malignen Melanoms geprüft. c) Die PD-1-Antikörper Pembrolizumab und Nivolumab sind in Europa nur nach Vortherapie mit Ipilimumab zur Behandlung des fortgeschrittenen Melanoms zugelassen. d) Pembrolizumab und Nivolumab haben ein ähnliches Nebenwirkungsprofil. e) Dabrafenib und Vemurafenib haben zum Teil unterschiedliche Nebenwirkungen.
10. Welche Aussage ist falsch? a) Ipilimumab blockiert die CTLA-4-B7-Interaktion. b) Ipilimumab wird mit einer Dosis von 3 mg/kg Körpergewicht intravenös viermal im Abstand von drei Wochen eingesetzt. c) Die meisten Ipilimumab-induzierten immunvermittelten Nebenwirkungen sind unter leitliniengerechter immunsuppressiver Therapie reversibel.
CME Article
d) Ipilimumab ist in Kombination mit Nivolumab zur Behandlung des metastasierten malignen Melanoms in Deutschland zugelassen.
e)
Immunvermittelte Nebenwirkungen einer Therapie mit Ipilimumab sind unter anderem eine Hypophysitis und Hepatitis.
Liebe Leserinnen und Leser, der Einsendeschluss an die DDA für diese Ausgabe ist der 18. January 2015. Die richtige Lösung zum Thema „Current diagnosis and treatment of basal cell carcinoma“ in Heft 9 (September 2015) ist: (1a, 2b, 3d, 4a, 5c, 6d, 7e, 8a, 9d, 10e).
Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg. akademie-dda.de ein.
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1312
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