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Latest Approved Therapies for Metastatic Melanoma: What Comes Next?

Latest Approved Therapies for Metastatic Melanoma: What Comes Next? Hindawi Publishing Corporation Journal of Skin Cancer Volume 2013, Article ID 735282, 10 pages http://dx.doi.org/10.1155/2013/735282 Review Article Latest Approved Therapies for Metastatic Melanoma: What Comes Next? Farid Menaa Department of Oncology, Stem Cells and Nanomedicine, Fluorotronics, Inc., 2453 Cades Way, Building C, San Diego, CA 92081, USA Correspondence should be addressed to Farid Menaa; dr.fmenaa@gmail.com Received 10 August 2012; Revised 16 January 2013; Accepted 18 January 2013 Academic Editor:M.Lebwohl Copyright © 2013 Farid Menaa. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Nowadays, oncogene-directed therapy and immunotherapy represent the two most promising avenues for patients with metastatic melanoma. eTh recent oncogene-directed therapeutic, vemurafen ib, usually produces high level of tumor shrinkage and survival V600E benetfi sinmanypatientswith B-RA𝐹 mutant melanomas, although the fast and high degrees of responses are likely short-lived. Conversely, the newly-approved immunotherapeutic, ipilimumab, produces durable responses in patients presenting CTLA-4 T- cell surface protein. Nevertheless, the possible synergy in combining these two therapeutic strategies primarily rely on the rational design of medical protocols (e.g., sequence and timing of agent administration; drug selectivity; compatibility of combined therapies i.e., adoptive T cell or agents, i.e., MEK inhibitor trametinib, PD-1 and PDL-1 blockers). Improved therapeutic protocols shall overcome therapeutic limitations such as the (i) tolerability and safety (i.e., minimal toxic side-effects); (ii) progression free survival (e.g., reduced relapse disease frequency); (iii) duration response (i.e., decreased drug resistance). Eventually, multidisciplinary approaches are still requested (e.g., genomics for personalized medicine, nanomedicine to overcome low free-drug bioavailability and targeting, systematic search of “melanoma stem cells” to enhance the prognosis and develop more valuable theranostics). In this paper, I will mainly present and discuss the latest and promising treatments for advanced cutaneous melanomas. 1. Introduction suspicious lesion. eTh biopsy permits to establish not only an accurate diagnosis but also to define the optimal staging and Melanoma (from Greek—melas: “dark”) is a tumor originated proceed earlier with the appropriate therapy (e.g., surgery, from malignant transformation of melanocytes (i.e., melanin chemotherapy, and/or radiotherapy). pigment-producing cells) that can be found in the skin, Metastatic melanoma (i.e., advanced malignant bowel, and eye [1]. melanoma) is the most aggressive form of skin cancer According to the estimations provided by the American with a median overall survival (OS) of only few months (8 Cancer Society (ACS) in 2010, 68.130 new cases of melanomas to 18 months) [2]. This fact could be mainly explained by the were diagnosed and approximately 8.700 people died from modest results obtained with dacarbazine (DITC) and high- this cancer [2]. The incidence of melanoma in the US has dose interleukin 2 (HD IL-2), the two unique FDA-approved increased of about three folds between the last three decades therapies for metastatic melanoma until 2011 [7–9]. Indeed, (i.e., from 7.89 per 100.000 in 1975 to 22.52 per 100.000 in DITC is limited by a low response rate (RR of 5% to 15%) 2008) [3]. Clinical and epidemiological data suggest that and an insufficient OS (about 8 months) [7]. Besides, HD several risk factors can contribute to the increased inci- IL-2 is also limited by a low RR (6% to 10%), a short duration dence: (i) extensive or repeated exposure to sunlight [4]; (ii) of responses in most patients as well as a severe toxicity individuals with family history of melanoma (5–12% of all [8, 9]. Since 2011, 3 new agents have been approved for the reported cases) [5]; (iii) high nevi count and dysplastic nevus treatment of advanced melanoma by the Food and Drug [6], thereby suggesting the need to perform a biopsy of the Administration (FDA) [10–12]: (i) vemurafenib, a mutant 2 Journal of Skin Cancer V600E 𝐵 - inhibitor, recommended for unresectable or Currently, both HDI and PEG-IFN are considered as category metastatic melanoma [10]; (ii) ipilimumab, an anti-CTLA-4 2B due to their limited benefits, and so will not be further monoclonal antibody, also preconized for the treatment of detailed in this paper. unresectable or metastatic melanoma [11]; (iii) pegylated Eventually, in one hand, these new exciting chemother- interferon alpha-2b (PEG-IFN), a covalent conjugate of apies represent a great hope for the physicians and patients the polyethylene glycol (PEG) with the recombinant𝛼 -2b with advanced melanoma. In the other hand, their respec- interferon (IFN), long-time used to treat chronic hepatitis tive limitations clearly emphasize the importance of devel- patients infected with hepatitis c virus [12], and currently oping novel treatment strategies (e.g., cell-based ther- recommended as adjuvant treatment for stage III melanoma apies, advanced and rational combinatorial therapeutic [13]. approaches, nanodrug formulations). es Th e alternative ther- apeutic options might help to improve OS, PFS, RFS, RR, Vemurafenib has emerged as a highly selective mutant V600E and MDR while minimizing toxic adverse events, thereby 𝐵 - inhibitor with little effect on wild type B-RAF, contributing in fine to the quality of the patient’s life. thereby demonstrating significant tumor regression ( >40%) In this paper, most recent FDA-approved treatments while minimizing side eeff cts in a large number of patients against advanced cutaneous melanoma (stage III and IV) with metastatic melanoma [14–16]. Nevertheless, the single are highlighted, and possible enhanced therapeutic strategies use of this oncogene-targeted agent presents the following to overcome their respective associated limitations are dis- main disadvantages: (i) short median duration of response cussed. (MDR) and progression-free survival (PFS) (i.e., about 6 months only) [16]; (ii) low RR in patients who harbor mutations other than V E. eTh proportion of these patients 2. Latest FDA-Approved Drugs for ranges between 10% and 30% (e.g., V Kispresent in 5% to Advanced/Metastatic Melanoma 20% of patients with melanoma) [17, 18]. Ipilimumab was designed and developed to block the Most patients with unresectable stage III or stage IV disease cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), require systemic treatment rather than metastasectomy. thereby increasing the T-cell activity and promoting antitu- mor activity in patients with cancers [19]. er Th eby, in patients 2.1. Oncogene-Directed er Th apy: Mutant B-RAF Inhibitors. with unresectable or metastatic melanoma, ipilimumab plus Melanoma is a molecularly heterogeneous disease with DITC versus DITC alone signicfi antly improved the OS approximately half (40%–60%) of the cutaneous melanoma (about 11 months versus 9 months, resp.) and RR (about 15% cells harboring an activating mutation in the B-RAF gene, versus 10%, resp.) [20, 21]. which encodes a serine/threonine kinase protein kinase, and PEG-IFN, similarly to high-dose interferon (HDI or most of the mutations (>70%) are V E(i.e.,substitutionof Intron A) [1,22],has been approved forthe adjuvant valine for glutamate at amino acid position 600) [17, 26–28]. treatment (aer ft surgical resection) of stage III melanoma Because mutated B-RAF leads to constitutive activation of patients. This approval was mainly based on final results the mitogen-activated protein kinase pathway (MAPK) that, of a recent randomized phase III trial organized by the in turn, increases the cellular proliferation and drives the European Organization for Research and Treatment of Can- oncogenic activity [29, 30], intensive research has consisted to cer (EORTC) 18991 that showed greater relapse-free sur- selectively inhibit mutated B-RAF in patients with melanoma vival (RFS of 45.6%) in comparison to observation (38.9%), (e.g., studies with sorafenib, a multitargeted kinase inhibitor), although no signicfi ant eeff ctonOSwas noticed[12,23]. butthe resultsweregloballydisappointing duetooff-target Previously,inanopen-labelphase 2study,the ecffi acy and side effects mainly induced through inhibition of wild type safety of PEG-IFN in combination with temozolomide were B-RAF [14, 31–35]. investigated in patients with metastatic melanoma without Among highly selective B-RAF inhibitors, only the recent brain metastases [24]. The RR of this combination reached FDA-approved vemurafenib (formerly PLX4032, currently 31% of the patients, the median OS was 12 months, and marketed as Zelboraf and initially developed by Genentech V600E no patient developed brain metastases while receiving study Roche) is capable of silencing mutant𝐵 - without treatment, which was besides well tolerated. Up to date, and interfering with wild type B-RAF.Indeed,inaphase2clinical in the best of my knowledge, it remains unknown whether trial involving patients with metastatic melanoma harboring PEG-IFN can provide better efficacy and safety results than V600E 𝐵 - mutation (𝑛=132 ), vemurafenib demonstrated the biochemotherapy combining cisplatin, vinblastine, DTIC substantial tumor regression in 81% of the cases, a RR of 52%, plus IL-2 (Proleukin), and interferon. Indeed, a recent phase and a MDR of 6.8 months [14–16]. Further, in a phase 3 clini- 3trial (SWOGS0008) only assessed theecffi acyand safety cal trial (BRIM3) involving previously untreated patients (𝑛= of this biochemotherapy versus HDI in patients with high- 675), vemurafenib was much better than DITC in terms of RR risk melanoma [25]. eTh results showed major improvement (48% versus 5%, resp.), PFS (5.3 months versus 1.6 months, in the median RFS in favor of biochemotherapy (4.3 years resp.), and percent of patients alive at six months (OS of versus 1.9 years with HDI). OS, however, was exactly the same 84% versus 64%, resp.) [10]. Also, in a recent open-label pilot (56% at 5 years), and acute grade 4 toxicity was more frequent study, it was stated that vemurafenib could be beneficial for with biochemotherapy. All together, the biochemotherapy previously treated metastatic melanoma patients with brain can be considered as a better adjuvant treatment than HDI. metastases [36]. Besides, common adverse events associated 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 Journal of Skin Cancer 3 with vemurafenib included accelerated growth of cutaneous the years were always significantly higher in the ipilimumab- squamous cell carcinomas (SCCs) and keratoacanthomas DITC groupthaninthe grouptreated with thesingleagent [10, 37–40], most probably through paradoxical activation DITC (at 1 year: 47.3% versus 36.3%; at 2 years: 28.5% of MAPK signaling(about20–25%ofthe patients with versus 17.9%; at 3 years: 20.8% versus 12.2%, resp.), clearly advanced melanoma) [37–40]. demonstrating that ipilimumab is able to confer a durable Eventually, vemurafenib represents an excellent model response (MDR of 19.3 months versus 8.1 months, resp.). for successful targeted anticancer therapy (i.e., high RR and Nevertheless, median PFS was barely improved (2.8 months V600E versus 2.6 months, resp.). Also, grade 3 or 4 adverse events low toxicity) in patients with 𝐵 - mutations [41]. (e.g., hepatitis) occurred more frequently in patients treated Nevertheless, these clinical benefits are counterbalanced by V600E with ipilimumab plus DITC than in patients treated with the relatively short MDR, high selectivity for the𝐵 - DITC (plus placebo) (56.3% versus 27.5%, resp.), although mutation, and related toxicities of the drug. Owing to con- V600E low rates of gastrointestinal events and no drug-related deaths sideration that 10% to 30% of patients have a non-𝐹𝐴 V600k occurred in the ipilimumab-DITC group [20, 21]. mutation (e.g.,𝐵 - mutation is present in 5% to 20% Eventually, although the OS and MDR noticed with ipili- of melanoma patients) [17, 18], further studies are required to mumab are higher than that one observed with vemurafenib, examine the efficacy of vemurafenib, alone or in combination, the most important limitation of this drug tested alone or in V600E in patients with a non-𝐹𝐴 mutation. es Th e studies are combination remains the modest RR. This strongly suggests a important to avoid useless administration of vemurafenib in need for rational combination between ipilimumab and other a subset of patients, who might otherwise become resistant to commercially available free- or nanoencapsulated drugs (e.g., the drug. Alternatively, rational combination of vemurafenib vemurafenib and bevacizumab, resp.) that might provide with other agents (e.g., ipilimumab) might circumvent an complementary clinical benefits. eventual drug resistance and/or further improve the clinical outcome of the patients (e.g., MDR, OS). 3. Therapeutic Perspectives for Improving the Effects of FDA-Approved Drugs 2.2. Immunotherapy: CTLA-4 Inhibitors. Melanoma is one 3.1. Promising Molecular Targets to Overcome the Resistance of the most immunogenic tumors due to the presence of Associated with B-RAF Inhibitors. Since approximately 50% tumor infiltrating lymphocytes (TIL) in resected melanoma, of patients with melanoma harbor B-RAF mutations and clinical responses to immune stimulation, and occasional might be then eligible for treatment with the novel B-RAF spontaneous regressions. CTLA-4 expression is necessary inhibitors, this means that another half of the patients with foractivationofself-regulation of Tcells,and so CTLA- advanced melanoma might not fully benefit from vemu- 4 inhibitors could represent serious therapeutic options to V600E rafenib (i.e., specific 𝐵 - targeting drug). eTh refore, generate T-cell hyperresponsiveness and overcome tumor it appearsreasonabletodevelop drugsthatspecicfi ally target immune escape [19]. V600k Up to date, ipilimumab (formerly MDX-010, MDX-101, gene mutations other than V E(e.g.,𝐵 - targeting or MDX-CTLA-4, currently marketed as Yervoy and initially agents). Also, at a larger extent, targeting any molecular alter- developed by Bristol-Myers Squibb) is a fully human IgG1 ations that occur (frequently or rarely) in specicfi melanoma monoclonal antibody that blocks CTLA-4, subsequently related pathways (including those which are involved in increasing the T-cell activity and promoting an antitumor “melanoma stem cells”) shall provide additive or synergistic activity and represents the only approved immunotherapeu- clinical benefits. For instance, molecules involved in the tic agent for systemic treatment [20]. In the rfi st phase 3 mitogen-activated protein kinase (MAPK) signaling could randomized trial involving patients with previously treated represent interesting targets to overcome the melanoma unresectable stage III or IV melanoma (𝑛=676 ), ipilimumab resistance. Indeed, it has been previously shown that MAPK activation by mutants B-RAF drives melanoma tumor pro- compared to the glycoprotein 100 peptide (gp100) vaccine demonstrated an improved median OS (10.1 months versus liferation, and that the resistance to B-RAF inhibitors— 6.4 months, resp.) and a much better RR (10.9% versus 1.5%, responsible for their short-duration response—can be (or resp.), albeit the occurrence of toxicities with ipilimumab, not) associated with reactivation of the MAPK pathway including grade 3 or 4 immune-related adverse events (“escape route”) [41–43]. Recent studies demonstrated that (e.g., enterocolitis, hepatitis, and dermatitis) and deaths, MAPK-dependent acquired resistance to B-RAF inhibition in was higher than with gp100 (10–15% versus 3%, resp.) [11]. melanomas can involve (i) upregulation of receptor tyrosine Ipilimumab plus gp100, compared to gp100, did not improve kinases (RTKs) and N-RAS [44]; (ii) elevated expression of the OS observed with ipilimumab alone (10.0 months versus COT kinase through MAPK pathway reactivation [45]; (iii) 10.1 months, resp.) [11]. In the second phase 3 randomized activation of MAPK kinase (MEK aka MAPK/ERK) [46, 47]; trial involving previously untreated patients with metastatic (iv) elevation of C-RAF [48]. Besides, MAPK-independent melanoma (𝑛 = 502 ), ipilimumab combined with DITC molecules involved in the melanoma resistance mechanism demonstrated a modest but statistically significant improve- include (i) upregulation of IGF-1R [49]; (ii) PI3K/AKT ment in OS compared to DITC plus placebo (11.2 months signaling through the activation of c-KIT (a RTK also known versus 9.1 months, resp.) as well as a better overall RR (15.2% as CD117) [50]; (iii) loss of PTEN through the suppression of versus 10.3%, resp.) [20, 21]. Interestingly, survival rates over BIM expression [51]. 𝑅𝐴𝐹 𝑅𝐴𝐹 𝐵𝑅 𝑅𝐴𝐹 𝐵𝑅 𝑅𝐴𝐹 𝑅𝐴𝐹 4 Journal of Skin Cancer Recent promising results from clinical trials mainly impli- melanoma in cohort B (𝑛=83 patients who had progressive cate MEK-1 and c-KIT inhibitors. Indeed, a recent phase III brain metastases aeft r previous local treatments) achieved trial (METRIC study) involving patients with advanced or an overall intracranial response with dabrafenib. Further, V600E/k the treatment-related adverse events of grade 3 or worse metastatic melanoma harboring𝐵 - mutant and occurred in 38 (22%) patients from the cohort A and in 51 without prior brain metastases (𝑛=332 )reportedthe great (30%) patients from the cohort B. eTh three most frequent efficacy of a reversible and highly selective allosteric inhibitor serious events were pyrexia (6%), intracranial hemorrhage of MEK1/2 activity, trametinib (formerly GSK 1120212), when (6%), and SCC (6%). To sum up, these impressive results compared with “chemotherapy” (DITC or paclitaxel, but not V600E were mainly obtained in patients with𝐵 - mutant vemurafenib) [52]. er Th eby, significant improvements have melanoma and brain metastases, irrespective of whether they been observed in favor of trametinib, mainly at the median were previously treated or untreated, clearly showing that PFS (4.8 months versus 1.4 months with chemotherapy) and dabrafenib is safe (e.g., lack of skin toxicity) and can confer the overall RR (24% versus 7% with chemotherapy). In spite of robust activity in intracranial disease, suggesting possible crossovers, at 6 months, OS was also significantly improved in elimination of whole brain radiotherapy in similar subsets favoroftrametinib(74%versus56% with “chemotherapy”). of patients. Further, in a randomized open-label multicenter Globally, trametinib was well tolerated and safe (e.g., most phase 3 trial (BREAK-3 study) involving previously untreated side effects included skin rash and hypertension), validating V600E patients with𝐵 - mutant melanoma (𝑛=250 )[63], that targeting the MEK pathway is a viable strategy. Besides, dabrafenib compared to DITC led to (i) a signicfi ant improve- ongoing trials are evaluating the safety and eca ffi cy of c-KIT ment of the median PFS (5.1 months versus 2.7 months, inhibitors (i.e., imatinib, nilotinib, and dasatinib) [53–55], resp.); (ii) a greater RR (53% versus 19%, resp.). eTh OS data and their combinations with B-RAF inhibitors are underway. were immature at the time of the study analysis. Further, Indeed, c-KIT is mutated in approximately 20% of sun- hyperkeratosis (37%), pyrexia (28%), and skin papillomas damaged skin [56] and, once its corresponding protein is (24%) were among the most frequent adverse events observed activated by its ligand called SCF (Stem Cell Factor), mediates in patients treated with dabrafenib, and interestingly, only few cell growth and cell survival signals through signaling path- cases of SCC (7%) and keratoacanthomas (3%) were noticed ways such as P13K-AKT-mTOR and RAS-RAF-MEK-ERK. [63]. Other recent results, obtained from an open-label study Thereby, c-KIT hasbeenimplicatedinthe pathogenesis of V600 involving patients with metastatic melanoma and𝐵 - several cancers including metastatic melanoma [57, 58], and mutations (𝑛=247 ), showed that dabrafenib and trametinib previous clinical trials demonstrated a durable overall RR canbesafelycombinedatfullmonotherapy doses(150mg (16–24%) as well as a median OS ranging from 11 to 14 months and2mg,resp.)[64–66].Indeed,for thecombo therapy [50, 53, 59]. group of patients, compared to the monotherapy group Eventually, rational combination of B-RAF inhibitors (dabrafenib only), the following end points were observed (e.g., vemurafenib, dabrafenib) with drugs that specifi- (i) the rate of pyrexia was increased (71% versus 26%, resp.); cally target one of the above-mentioned molecules (e.g., (ii) the rate of proliferative skin lesions (i.e., the incidence MEK, c-KIT, or CTLA-4) would further improve the of cutaneous SCC) was not significantly reduced (7% versus clinical outcome of the patients with advanced/metastatic 19%, resp.); according to me, this observation might be melanoma. A current nonrandomized open-label phase 1/2 explained by the presence of MEK-independent subsets trial (NCT01400451 study) that aims to evaluate the ecffi acy of mutant RAS, since MEK-dependent and -independent and safety of vemurafenib with ipilimumab in adult subjects V600 subsets of mutant RAS have been identified in tumor cell lines with𝐵 - mutation-positive metastatic melanoma is [67, 68]; (iii) PFS was significantly improved (9.4 months ongoing but is not recruiting participants, yet [60]. The versus 5.8months, resp.);(iv)RRwas signicfi antly improved results of this challenging study are expected for August 2015 (76% versus 54%, resp.); (v) the duration of response was [60]. Interestingly, the selective B-RAF inhibitor, dabrafenib also much better (10.5 months versus 5.6 months, resp.). (formerlyGSK2118436),previouslyshowedsimilar ecffi acy to However, OS could not be compared because of the relatively vemurafenib [35], and several clinical trials in patients with V600 short-term followup. es Th e overall exciting experimental 𝐵 - mutant melanoma showed promising results with results will need to be confirmed in ongoing phase 3 larger dabrafenib as a single agent [61–63] or in combo with trame- studies before combo therapy likely replaces monotherapy tinib [64–66]. er Th eby, a recent multicentre, open-label phase (i.e., B-RAF inhibitor as a single agent). Indeed, larger studies 1/2 trial (BREAK-MB study), investigated the efficacy and V600E/k might demonstrate whether B-RAF/MEK combo therapy can safety of oral dabrafenib in adult patients with𝐵 - (i)bothdelay andprevent onsetofresistancetotherapy; mutant melanoma metastatic to the brain (𝑛 = 172 )[61, V600E (ii) significantly reduce the incidence of SCC formation 62]. 29 of 74 (39.2%) patients with 𝐵 - mutant fevers, chills, and MEK inhibitor-induced dermatitis; (iii) V600k melanoma and only 1 of 15 (6.7%) patients with𝐵 - extend overall survival or if ipilimumab shall be implemented mutant melanoma in cohort A (𝑛=89 patients who had to confer a survival benefit in case of treatment failures not received previous local treatment for brain metastases) (e.g., disease progression, unacceptable adverse events); (iv) achieved an overall intracranial response with dabrafenib. recover patients that initially failed with monotherapy or V600k Comparatively, 20 of 65 (30.8%) patients with𝐵 - provide potential benefit to initial monotherapy in order to V600k mutant melanoma and 4 of 18 (22%) with𝐵 - mutant further improve PFS. 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 Journal of Skin Cancer 5 3.2. Promising Molecular Targets to Overcome Low-Response pointwas thesameseenwithBCP that ledthe US FDA Rate Associated with Immunotherapeutic Agents. Although to approve bevacizumab for lung cancer [75]. Therefore, a ipilimumab can induce long-term responses in a subset of trial of chemotherapy combining bevacizumab with the first- patients, the relatively low RR (10%–15%) observed with this line therapeutic agents for metastatic melanoma (e.g., ipili- immunotherapeutic agent limits its use. Possible ways to mumab, vemurafenib) might be beneficial. In this regard, the overcome this limitation would be (i) increase of the dose first combination study, a recent nonrandomized open-label (e.g., 3 to 10 mg/kg); (ii) selection/stratification of the patients phase 1 trial, did investigate potential synergies of ipilimumab (i.e., personalized medicine); (iii) rationale combination with and bevacizumab in a limited number of evaluable adult other treatment modalities (e.g., molecularly targeted ther- patients with unresectable stage III or stage IV melanoma apy, radiation therapy, adoptive T-cell therapy, melanoma (𝑛=21 ) [76]. This preliminary and promising study showed initiating/propagating cells). that ipilimumab plus bevacizumab could (i) display syner- The low response rate of ipilimumab is thought to be gistic effects and provide clinical benefit in a large number caused by melanoma immune escape, a mechanism that of patients as shown in 14/21 of the enrolled patients; (ii) involves the expression of programmed death ligand 1 (PD- be safely administered with management of noted toxicities, L1), which once bound to its ligand PD-1 (programmed which were mostly immune related (e.g., grade 3-4 hepatitis, death-1) of activated lymphocytes, would cause apoptosis of grade 2 colitis, arteritis, hypophysitis, thyroiditis, bilateral the activated lymphocytes and subsequent immune toler- uveitis,). Further, studies with the immunostimulator sar- ance [69–71]. Interestingly, a phase 1 study led on specific gramostim(Leukine/Prokine)showthatthisdrugmay help human anti-PD-1 antibody (formerly MDX-1106 aka BMS- the immune system recover from the side eeff cts of treatment 936558), a fully recombinant human immunoglobulin G4 in patients with metastatic melanoma and so could be tested [72], oeff red clinical benefits in a variety of previously treated as a combinatory agent with ipilimumab. Indeed, a previous refractory solid tumors including melanoma, without gen- investigation (NCCTG study) has consisted to perform a erating significant toxicities [72]. Thereby, a dose-escalation dose-escalation clinical trial with aerosolized sargramostim study of the combination of MDX-1106 with ipilimumab has in HLA-A2 patients with metastatic melanoma to the lung been started [53], and phase 1 trials of anti-PD-L1 are also (𝑛=40 ). eTh data showed that the toxicity was acceptable underway. Recently, the clinical activity and safety of MDX- for all tested doses and the greatest increase in antitumor 1106 intravenously administrated in escalating doses every T-cell immune responses was achieved at the highest doses two weeks in patients with advanced melanoma (𝑛=94 ), [77]. en, Th a hypothesis-generating study was conducted to have been reported [73]. eTh overall RR was 28%, and 6% evaluate the safety and efficacy of prolonged administration of patients achieved stable disease aeft r 24 weeks. Most side of sargramostim as surgical adjuvant therapy in patients eeff cts were immune related, though three treatment-related with melanoma at high risk of recurrence (𝑛=98 ) deaths occurred on study, including two due to pneumonitis. [78]. eTh prolonged administration of the drug was well Interestingly, a subanalysis of the data hinted that the PD- tolerated among patients, and the 5-year melanoma-specific L1 protein might serve as a biomarker of response. Indeed, survival rate was 60%, providing preliminary evidence that more than one-third of patients expressing PD-L1 responded sargramostim can be administered as adjuvant therapy for to immunotherapy, whereas responses were not observed patients with melanoma at high risk of recurrence. Inter- among patients lacking PD-L1 expression. Eventually, these estingly, an ongoing recent randomized open-label phase 2 preliminary data strongly suggest that blockage of the PD-1 longitudinal trial (NCT01134614) is studying how well giving pathway may represent a new immune therapy. ipilimumab with (arm I) or without (arm II) sargramostim Besides, pertinent clinical studies are assessing the com- works in treating adult patients with stage III or stage IV binatorial effects of ipilimumab with promising antiangio- melanoma without brain metastases (estimated enrollment genic drugs (e.g., bevacizumab, an antivascular endothelial 𝑛=220 ) [79]. However, the eeff cts (e.g., OS, PFS, RR, MDR, growth factor A (VEGF-A)), immunostimulators (e.g., sar- safety) of ipilimumab plus sargramostim versus ipilimumab gramostim, a recombinant human granulocyte macrophage alone, in treating patients with advanced melanoma, remain colony-stimulating factor (GM-CSF)), and/or anticancer unknown. Eventually, fotemustine (Muphoran), a non-FDA- agents (e.g., fotemustine, a nitrosourea alkylating agent, or approved drug available in Europe, is known to rapidly cross the B-RAF inhibitor vemurafenib) based on previous studies the blood-brain barrier and to display encouraging activity [74–76]. Indeed, a recent randomized phase 2 trial (BEAM in patients with brain metastases [80]. Also, in a phase 3 trial study) involving patients with previously untreated advanced involving patients with metastatic melanoma (𝑛=229 )[81], melanoma (𝑛 = 214 ) has evaluated the activity of the fotemustine compared to DITC was associated with (i) an FDA-approved drug bevacizumab (Avastin) combined with improved overall RR (15.5% versus 6.8%, resp.); (ii) a trend carboplatin plus paclitaxel (BCP) versus placebo carboplatin toward improved OS (7.3 versus 5.6 months, resp.); (iii) a plus paclitaxel (CP) [74]. Although the results were not as longer median time to development of brain metastases (22.7 good as expected (median PFS: 5.6 months with BCP versus months versus 7.2 months, resp.) in patients without brain 4.2 months with CP; overall RR: 25.5% with BCP versus metastases at inclusion; (iv) a similar MDR (5.8 months ver- 16.4%withCP; median OS:12.3monthswithBCP versus 8.6 sus 6.9 months); (v) a similar time to progression (1.8 months months with CP), the trial might be considered as positive. versus 1.9 months); (vi) a similar quality of life; (vii) more Further, no new safety signals were observed. Interestingly, adverse events such as myelosuppression (i.e., grade 3 to 4 the hazard rate (0.79) for improvement in OS at the last time neutropenia 51% versus 5%, resp. and thrombocytopenia 43% 6 Journal of Skin Cancer versus 6%, resp.) and alopecia. Interestingly, a recent open- antigen 4 (CTLA-4) in patients with unresectable or label, single-arm phase 2 trial (NIBIT-M1 study) is investi- metastatic melanoma. Interestingly, ipilimumab presents gating the efficacy and safety of ipilimumab plus fotemustine the opposite main advantage and disadvantage than in adult patients (𝑛=86 ) with metastatic melanoma and with vemurafenib. Several clinical trials are underway to address or without asymptomatic brain metastases [82]. As primarily the question of rational combination of those two approved results, this medicinal combination achieved disease control drugs, together and/or separately with other potential in 40 patients (46.5%) with metastatic melanoma, including therapeutic targets (PD-1, PD-L1, c-KIT, MEK1, VEGF- those with brain metastases. Nevertheless, the treatment- A...). Cell therapy such as adoptive T cell is encouraging. related adverse effects (e.g., grade 3 or 4 myelotoxicity and Nanoencapsulation of the recent FDA-approved free drugs hepatotoxicity) were present in 47 patients (55%). (e.g., vemurafenib, ipilimumab), using proper nanocarriers, Eventually, the use of nanomaterials to formulate nan- or rational combination of these free drugs with available odrugs (e.g., drug nanocarriers such as solid lipid nanopar- adjuvant nanotherapeutics might be beneficial as they ticles (SLN) or nanostructured lipid carriers (NLC)) might might enhance the overall pharmacological features (e.g., be useful to possibly enhance efficacy (e.g., systemic bioavail- bioavailability and targeting). eTh importance of direct ability, targeting), tolerability, and safety of free drugs pre- targeting of potential melanoma initiating/propagating cells senting clinical benefit for patients with metastatic melanoma within a given patient was not detailed in this paper but might (e.g., ipilimumab, vemurafenib). In general, it is well accepted be important in order to avoid immune resistance, immune that administration of appropriate nanodrug formulations escape, and disease relapse. Owing to consideration that the can contribute to enhance the duration response, the incidence of advanced/metastatic melanoma in the younger response rate, the OS, and PFS in patients with a given population is increasing, clinical trials in pediatric patients type of cancer [83, 84]. In this regard and based on a appear necessary. Eventually, the rational molecular or recent study announcing the preparation of nanoliposomes- cellular combo therapy is a key strategy, as it shall beneficiate encapsulated bevacizumab with beneficial effects in prolong- alargernumberofpatients. eTh recent resultsreportedin ing the residency of bevacizumab in the vitreous [85], it this paper are quite exciting and, undeniably, constitute a might be interesting to test ipilimumab plus nanoencapsu- newhopefor patients andhealthcareprofessionals. lated bevacizumab in patients with unresectable stage III or stage IV melanoma. Besides, “adoptive T-cell therapy” Abbreviations (ACT), which presents several conceptual similarities with hematopoietic stem-cell transplantations (HSCTs) in terms ACT: Adoptive T-cell therapy of advantages and disadvantages can constitute another ACS: American cancer society therapeutic option to overcome the low response asso- BCP: Bevacizumab/carboplatin/paclitaxel ciated with immunotherapeutic agents (e.g., ipilimumab). CTL-A4: Cytotoxic T-lymphocyte-associated Indeed, successful isolation-expansion-infusion of TIL has antigen 4 shown clinical benefits for the treatment of patients with DITC: Dacarbazine metastatic melanoma [86–91]. For instance, the RR (72%) FDA: Food and drug administration was higher when using nonmyeloablative lymphodepletion HDI: High-dose interferon with cytotoxic chemotherapy and with or without total body HSCT: Hematopoietic stem cell transplantation irradiation (TBI) than when ipilimumab was combined with IL-2: Interleukin-2 IL-2 [86–91]. Interestingly, preclinical work suggested that PD-1: Programmed death-1 V600E selective𝐵 - inhibition enhances T-cell recognition PEG-IFN: Pegylated interferon alpha-2b of melanoma without aeff cting lymphocyte function, provid- MAPK: Mitogen-activated protein kinase ing a rational for the combination of B-RAF inhibitors (e.g., MDR: Median duration response vemurafenib or dabrafenib) with stimulatory immune agents MEK: MAPK/extracellular signal-regulated (e.g., ipilimumab or PD-1/PD-L1) [92]. kinase (ERK) MEKi: MEK inhibitor OS: Overall survival 4. Conclusions PEG: Polyethylene glycol PFS: Progression-free survival The incidence of metastastic melanoma is increasing RAF: Ras-activating factor worldwide. Vemurafenib and ipilimumab, based on their RFS: Relapse/recurrence free survival respective success rates, are bringing hopes to physicians RR: Response rate and patients. Vemurafenib has emerged as a highly selective SCC: Squamous cell carcinoma V600E 𝐵 - mutant melanoma inhibitor and could display TBI: Total body irradiation good response rates in patients with unresectable or TIL: Tumor infiltrating lymphocytes. metastatic melanoma. Nevertheless, its main disadvantage remains the short median duration response as well as its limited use to patients who harbor mutations other than Conflict of Interests V600E V600k 𝐵 - (e.g., 𝐵 - ). Besides, ipilimumab was developed to block the cytotoxic T-lymphocyte-associated The author declares to have no conflict of interests. 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 Journal of Skin Cancer 7 Acknowledgments alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial,” The Lancet ,vol.372,no. The author would like to thank Dr. Abder Menaa, M. D. for 9633, pp. 117–126, 2008. his pertinent suggestions and critical review of this paper. [14] K. T. Flaherty, I. Puzanov, K. B. 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Latest Approved Therapies for Metastatic Melanoma: What Comes Next?

Menaa, Farid
Journal of Skin Cancer , Volume 2013 – Feb 24, 2013
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Hindawi Publishing Corporation
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Copyright © 2013 Farid Menaa. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2013/735282
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Hindawi Publishing Corporation Journal of Skin Cancer Volume 2013, Article ID 735282, 10 pages http://dx.doi.org/10.1155/2013/735282 Review Article Latest Approved Therapies for Metastatic Melanoma: What Comes Next? Farid Menaa Department of Oncology, Stem Cells and Nanomedicine, Fluorotronics, Inc., 2453 Cades Way, Building C, San Diego, CA 92081, USA Correspondence should be addressed to Farid Menaa; dr.fmenaa@gmail.com Received 10 August 2012; Revised 16 January 2013; Accepted 18 January 2013 Academic Editor:M.Lebwohl Copyright © 2013 Farid Menaa. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Nowadays, oncogene-directed therapy and immunotherapy represent the two most promising avenues for patients with metastatic melanoma. eTh recent oncogene-directed therapeutic, vemurafen ib, usually produces high level of tumor shrinkage and survival V600E benetfi sinmanypatientswith B-RA𝐹 mutant melanomas, although the fast and high degrees of responses are likely short-lived. Conversely, the newly-approved immunotherapeutic, ipilimumab, produces durable responses in patients presenting CTLA-4 T- cell surface protein. Nevertheless, the possible synergy in combining these two therapeutic strategies primarily rely on the rational design of medical protocols (e.g., sequence and timing of agent administration; drug selectivity; compatibility of combined therapies i.e., adoptive T cell or agents, i.e., MEK inhibitor trametinib, PD-1 and PDL-1 blockers). Improved therapeutic protocols shall overcome therapeutic limitations such as the (i) tolerability and safety (i.e., minimal toxic side-effects); (ii) progression free survival (e.g., reduced relapse disease frequency); (iii) duration response (i.e., decreased drug resistance). Eventually, multidisciplinary approaches are still requested (e.g., genomics for personalized medicine, nanomedicine to overcome low free-drug bioavailability and targeting, systematic search of “melanoma stem cells” to enhance the prognosis and develop more valuable theranostics). In this paper, I will mainly present and discuss the latest and promising treatments for advanced cutaneous melanomas. 1. Introduction suspicious lesion. eTh biopsy permits to establish not only an accurate diagnosis but also to define the optimal staging and Melanoma (from Greek—melas: “dark”) is a tumor originated proceed earlier with the appropriate therapy (e.g., surgery, from malignant transformation of melanocytes (i.e., melanin chemotherapy, and/or radiotherapy). pigment-producing cells) that can be found in the skin, Metastatic melanoma (i.e., advanced malignant bowel, and eye [1]. melanoma) is the most aggressive form of skin cancer According to the estimations provided by the American with a median overall survival (OS) of only few months (8 Cancer Society (ACS) in 2010, 68.130 new cases of melanomas to 18 months) [2]. This fact could be mainly explained by the were diagnosed and approximately 8.700 people died from modest results obtained with dacarbazine (DITC) and high- this cancer [2]. The incidence of melanoma in the US has dose interleukin 2 (HD IL-2), the two unique FDA-approved increased of about three folds between the last three decades therapies for metastatic melanoma until 2011 [7–9]. Indeed, (i.e., from 7.89 per 100.000 in 1975 to 22.52 per 100.000 in DITC is limited by a low response rate (RR of 5% to 15%) 2008) [3]. Clinical and epidemiological data suggest that and an insufficient OS (about 8 months) [7]. Besides, HD several risk factors can contribute to the increased inci- IL-2 is also limited by a low RR (6% to 10%), a short duration dence: (i) extensive or repeated exposure to sunlight [4]; (ii) of responses in most patients as well as a severe toxicity individuals with family history of melanoma (5–12% of all [8, 9]. Since 2011, 3 new agents have been approved for the reported cases) [5]; (iii) high nevi count and dysplastic nevus treatment of advanced melanoma by the Food and Drug [6], thereby suggesting the need to perform a biopsy of the Administration (FDA) [10–12]: (i) vemurafenib, a mutant 2 Journal of Skin Cancer V600E 𝐵 - inhibitor, recommended for unresectable or Currently, both HDI and PEG-IFN are considered as category metastatic melanoma [10]; (ii) ipilimumab, an anti-CTLA-4 2B due to their limited benefits, and so will not be further monoclonal antibody, also preconized for the treatment of detailed in this paper. unresectable or metastatic melanoma [11]; (iii) pegylated Eventually, in one hand, these new exciting chemother- interferon alpha-2b (PEG-IFN), a covalent conjugate of apies represent a great hope for the physicians and patients the polyethylene glycol (PEG) with the recombinant𝛼 -2b with advanced melanoma. In the other hand, their respec- interferon (IFN), long-time used to treat chronic hepatitis tive limitations clearly emphasize the importance of devel- patients infected with hepatitis c virus [12], and currently oping novel treatment strategies (e.g., cell-based ther- recommended as adjuvant treatment for stage III melanoma apies, advanced and rational combinatorial therapeutic [13]. approaches, nanodrug formulations). es Th e alternative ther- apeutic options might help to improve OS, PFS, RFS, RR, Vemurafenib has emerged as a highly selective mutant V600E and MDR while minimizing toxic adverse events, thereby 𝐵 - inhibitor with little effect on wild type B-RAF, contributing in fine to the quality of the patient’s life. thereby demonstrating significant tumor regression ( >40%) In this paper, most recent FDA-approved treatments while minimizing side eeff cts in a large number of patients against advanced cutaneous melanoma (stage III and IV) with metastatic melanoma [14–16]. Nevertheless, the single are highlighted, and possible enhanced therapeutic strategies use of this oncogene-targeted agent presents the following to overcome their respective associated limitations are dis- main disadvantages: (i) short median duration of response cussed. (MDR) and progression-free survival (PFS) (i.e., about 6 months only) [16]; (ii) low RR in patients who harbor mutations other than V E. eTh proportion of these patients 2. Latest FDA-Approved Drugs for ranges between 10% and 30% (e.g., V Kispresent in 5% to Advanced/Metastatic Melanoma 20% of patients with melanoma) [17, 18]. Ipilimumab was designed and developed to block the Most patients with unresectable stage III or stage IV disease cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), require systemic treatment rather than metastasectomy. thereby increasing the T-cell activity and promoting antitu- mor activity in patients with cancers [19]. er Th eby, in patients 2.1. Oncogene-Directed er Th apy: Mutant B-RAF Inhibitors. with unresectable or metastatic melanoma, ipilimumab plus Melanoma is a molecularly heterogeneous disease with DITC versus DITC alone signicfi antly improved the OS approximately half (40%–60%) of the cutaneous melanoma (about 11 months versus 9 months, resp.) and RR (about 15% cells harboring an activating mutation in the B-RAF gene, versus 10%, resp.) [20, 21]. which encodes a serine/threonine kinase protein kinase, and PEG-IFN, similarly to high-dose interferon (HDI or most of the mutations (>70%) are V E(i.e.,substitutionof Intron A) [1,22],has been approved forthe adjuvant valine for glutamate at amino acid position 600) [17, 26–28]. treatment (aer ft surgical resection) of stage III melanoma Because mutated B-RAF leads to constitutive activation of patients. This approval was mainly based on final results the mitogen-activated protein kinase pathway (MAPK) that, of a recent randomized phase III trial organized by the in turn, increases the cellular proliferation and drives the European Organization for Research and Treatment of Can- oncogenic activity [29, 30], intensive research has consisted to cer (EORTC) 18991 that showed greater relapse-free sur- selectively inhibit mutated B-RAF in patients with melanoma vival (RFS of 45.6%) in comparison to observation (38.9%), (e.g., studies with sorafenib, a multitargeted kinase inhibitor), although no signicfi ant eeff ctonOSwas noticed[12,23]. butthe resultsweregloballydisappointing duetooff-target Previously,inanopen-labelphase 2study,the ecffi acy and side effects mainly induced through inhibition of wild type safety of PEG-IFN in combination with temozolomide were B-RAF [14, 31–35]. investigated in patients with metastatic melanoma without Among highly selective B-RAF inhibitors, only the recent brain metastases [24]. The RR of this combination reached FDA-approved vemurafenib (formerly PLX4032, currently 31% of the patients, the median OS was 12 months, and marketed as Zelboraf and initially developed by Genentech V600E no patient developed brain metastases while receiving study Roche) is capable of silencing mutant𝐵 - without treatment, which was besides well tolerated. Up to date, and interfering with wild type B-RAF.Indeed,inaphase2clinical in the best of my knowledge, it remains unknown whether trial involving patients with metastatic melanoma harboring PEG-IFN can provide better efficacy and safety results than V600E 𝐵 - mutation (𝑛=132 ), vemurafenib demonstrated the biochemotherapy combining cisplatin, vinblastine, DTIC substantial tumor regression in 81% of the cases, a RR of 52%, plus IL-2 (Proleukin), and interferon. Indeed, a recent phase and a MDR of 6.8 months [14–16]. Further, in a phase 3 clini- 3trial (SWOGS0008) only assessed theecffi acyand safety cal trial (BRIM3) involving previously untreated patients (𝑛= of this biochemotherapy versus HDI in patients with high- 675), vemurafenib was much better than DITC in terms of RR risk melanoma [25]. eTh results showed major improvement (48% versus 5%, resp.), PFS (5.3 months versus 1.6 months, in the median RFS in favor of biochemotherapy (4.3 years resp.), and percent of patients alive at six months (OS of versus 1.9 years with HDI). OS, however, was exactly the same 84% versus 64%, resp.) [10]. Also, in a recent open-label pilot (56% at 5 years), and acute grade 4 toxicity was more frequent study, it was stated that vemurafenib could be beneficial for with biochemotherapy. All together, the biochemotherapy previously treated metastatic melanoma patients with brain can be considered as a better adjuvant treatment than HDI. metastases [36]. Besides, common adverse events associated 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 Journal of Skin Cancer 3 with vemurafenib included accelerated growth of cutaneous the years were always significantly higher in the ipilimumab- squamous cell carcinomas (SCCs) and keratoacanthomas DITC groupthaninthe grouptreated with thesingleagent [10, 37–40], most probably through paradoxical activation DITC (at 1 year: 47.3% versus 36.3%; at 2 years: 28.5% of MAPK signaling(about20–25%ofthe patients with versus 17.9%; at 3 years: 20.8% versus 12.2%, resp.), clearly advanced melanoma) [37–40]. demonstrating that ipilimumab is able to confer a durable Eventually, vemurafenib represents an excellent model response (MDR of 19.3 months versus 8.1 months, resp.). for successful targeted anticancer therapy (i.e., high RR and Nevertheless, median PFS was barely improved (2.8 months V600E versus 2.6 months, resp.). Also, grade 3 or 4 adverse events low toxicity) in patients with 𝐵 - mutations [41]. (e.g., hepatitis) occurred more frequently in patients treated Nevertheless, these clinical benefits are counterbalanced by V600E with ipilimumab plus DITC than in patients treated with the relatively short MDR, high selectivity for the𝐵 - DITC (plus placebo) (56.3% versus 27.5%, resp.), although mutation, and related toxicities of the drug. Owing to con- V600E low rates of gastrointestinal events and no drug-related deaths sideration that 10% to 30% of patients have a non-𝐹𝐴 V600k occurred in the ipilimumab-DITC group [20, 21]. mutation (e.g.,𝐵 - mutation is present in 5% to 20% Eventually, although the OS and MDR noticed with ipili- of melanoma patients) [17, 18], further studies are required to mumab are higher than that one observed with vemurafenib, examine the efficacy of vemurafenib, alone or in combination, the most important limitation of this drug tested alone or in V600E in patients with a non-𝐹𝐴 mutation. es Th e studies are combination remains the modest RR. This strongly suggests a important to avoid useless administration of vemurafenib in need for rational combination between ipilimumab and other a subset of patients, who might otherwise become resistant to commercially available free- or nanoencapsulated drugs (e.g., the drug. Alternatively, rational combination of vemurafenib vemurafenib and bevacizumab, resp.) that might provide with other agents (e.g., ipilimumab) might circumvent an complementary clinical benefits. eventual drug resistance and/or further improve the clinical outcome of the patients (e.g., MDR, OS). 3. Therapeutic Perspectives for Improving the Effects of FDA-Approved Drugs 2.2. Immunotherapy: CTLA-4 Inhibitors. Melanoma is one 3.1. Promising Molecular Targets to Overcome the Resistance of the most immunogenic tumors due to the presence of Associated with B-RAF Inhibitors. Since approximately 50% tumor infiltrating lymphocytes (TIL) in resected melanoma, of patients with melanoma harbor B-RAF mutations and clinical responses to immune stimulation, and occasional might be then eligible for treatment with the novel B-RAF spontaneous regressions. CTLA-4 expression is necessary inhibitors, this means that another half of the patients with foractivationofself-regulation of Tcells,and so CTLA- advanced melanoma might not fully benefit from vemu- 4 inhibitors could represent serious therapeutic options to V600E rafenib (i.e., specific 𝐵 - targeting drug). eTh refore, generate T-cell hyperresponsiveness and overcome tumor it appearsreasonabletodevelop drugsthatspecicfi ally target immune escape [19]. V600k Up to date, ipilimumab (formerly MDX-010, MDX-101, gene mutations other than V E(e.g.,𝐵 - targeting or MDX-CTLA-4, currently marketed as Yervoy and initially agents). Also, at a larger extent, targeting any molecular alter- developed by Bristol-Myers Squibb) is a fully human IgG1 ations that occur (frequently or rarely) in specicfi melanoma monoclonal antibody that blocks CTLA-4, subsequently related pathways (including those which are involved in increasing the T-cell activity and promoting an antitumor “melanoma stem cells”) shall provide additive or synergistic activity and represents the only approved immunotherapeu- clinical benefits. For instance, molecules involved in the tic agent for systemic treatment [20]. In the rfi st phase 3 mitogen-activated protein kinase (MAPK) signaling could randomized trial involving patients with previously treated represent interesting targets to overcome the melanoma unresectable stage III or IV melanoma (𝑛=676 ), ipilimumab resistance. Indeed, it has been previously shown that MAPK activation by mutants B-RAF drives melanoma tumor pro- compared to the glycoprotein 100 peptide (gp100) vaccine demonstrated an improved median OS (10.1 months versus liferation, and that the resistance to B-RAF inhibitors— 6.4 months, resp.) and a much better RR (10.9% versus 1.5%, responsible for their short-duration response—can be (or resp.), albeit the occurrence of toxicities with ipilimumab, not) associated with reactivation of the MAPK pathway including grade 3 or 4 immune-related adverse events (“escape route”) [41–43]. Recent studies demonstrated that (e.g., enterocolitis, hepatitis, and dermatitis) and deaths, MAPK-dependent acquired resistance to B-RAF inhibition in was higher than with gp100 (10–15% versus 3%, resp.) [11]. melanomas can involve (i) upregulation of receptor tyrosine Ipilimumab plus gp100, compared to gp100, did not improve kinases (RTKs) and N-RAS [44]; (ii) elevated expression of the OS observed with ipilimumab alone (10.0 months versus COT kinase through MAPK pathway reactivation [45]; (iii) 10.1 months, resp.) [11]. In the second phase 3 randomized activation of MAPK kinase (MEK aka MAPK/ERK) [46, 47]; trial involving previously untreated patients with metastatic (iv) elevation of C-RAF [48]. Besides, MAPK-independent melanoma (𝑛 = 502 ), ipilimumab combined with DITC molecules involved in the melanoma resistance mechanism demonstrated a modest but statistically significant improve- include (i) upregulation of IGF-1R [49]; (ii) PI3K/AKT ment in OS compared to DITC plus placebo (11.2 months signaling through the activation of c-KIT (a RTK also known versus 9.1 months, resp.) as well as a better overall RR (15.2% as CD117) [50]; (iii) loss of PTEN through the suppression of versus 10.3%, resp.) [20, 21]. Interestingly, survival rates over BIM expression [51]. 𝑅𝐴𝐹 𝑅𝐴𝐹 𝐵𝑅 𝑅𝐴𝐹 𝐵𝑅 𝑅𝐴𝐹 𝑅𝐴𝐹 4 Journal of Skin Cancer Recent promising results from clinical trials mainly impli- melanoma in cohort B (𝑛=83 patients who had progressive cate MEK-1 and c-KIT inhibitors. Indeed, a recent phase III brain metastases aeft r previous local treatments) achieved trial (METRIC study) involving patients with advanced or an overall intracranial response with dabrafenib. Further, V600E/k the treatment-related adverse events of grade 3 or worse metastatic melanoma harboring𝐵 - mutant and occurred in 38 (22%) patients from the cohort A and in 51 without prior brain metastases (𝑛=332 )reportedthe great (30%) patients from the cohort B. eTh three most frequent efficacy of a reversible and highly selective allosteric inhibitor serious events were pyrexia (6%), intracranial hemorrhage of MEK1/2 activity, trametinib (formerly GSK 1120212), when (6%), and SCC (6%). To sum up, these impressive results compared with “chemotherapy” (DITC or paclitaxel, but not V600E were mainly obtained in patients with𝐵 - mutant vemurafenib) [52]. er Th eby, significant improvements have melanoma and brain metastases, irrespective of whether they been observed in favor of trametinib, mainly at the median were previously treated or untreated, clearly showing that PFS (4.8 months versus 1.4 months with chemotherapy) and dabrafenib is safe (e.g., lack of skin toxicity) and can confer the overall RR (24% versus 7% with chemotherapy). In spite of robust activity in intracranial disease, suggesting possible crossovers, at 6 months, OS was also significantly improved in elimination of whole brain radiotherapy in similar subsets favoroftrametinib(74%versus56% with “chemotherapy”). of patients. Further, in a randomized open-label multicenter Globally, trametinib was well tolerated and safe (e.g., most phase 3 trial (BREAK-3 study) involving previously untreated side effects included skin rash and hypertension), validating V600E patients with𝐵 - mutant melanoma (𝑛=250 )[63], that targeting the MEK pathway is a viable strategy. Besides, dabrafenib compared to DITC led to (i) a signicfi ant improve- ongoing trials are evaluating the safety and eca ffi cy of c-KIT ment of the median PFS (5.1 months versus 2.7 months, inhibitors (i.e., imatinib, nilotinib, and dasatinib) [53–55], resp.); (ii) a greater RR (53% versus 19%, resp.). eTh OS data and their combinations with B-RAF inhibitors are underway. were immature at the time of the study analysis. Further, Indeed, c-KIT is mutated in approximately 20% of sun- hyperkeratosis (37%), pyrexia (28%), and skin papillomas damaged skin [56] and, once its corresponding protein is (24%) were among the most frequent adverse events observed activated by its ligand called SCF (Stem Cell Factor), mediates in patients treated with dabrafenib, and interestingly, only few cell growth and cell survival signals through signaling path- cases of SCC (7%) and keratoacanthomas (3%) were noticed ways such as P13K-AKT-mTOR and RAS-RAF-MEK-ERK. [63]. Other recent results, obtained from an open-label study Thereby, c-KIT hasbeenimplicatedinthe pathogenesis of V600 involving patients with metastatic melanoma and𝐵 - several cancers including metastatic melanoma [57, 58], and mutations (𝑛=247 ), showed that dabrafenib and trametinib previous clinical trials demonstrated a durable overall RR canbesafelycombinedatfullmonotherapy doses(150mg (16–24%) as well as a median OS ranging from 11 to 14 months and2mg,resp.)[64–66].Indeed,for thecombo therapy [50, 53, 59]. group of patients, compared to the monotherapy group Eventually, rational combination of B-RAF inhibitors (dabrafenib only), the following end points were observed (e.g., vemurafenib, dabrafenib) with drugs that specifi- (i) the rate of pyrexia was increased (71% versus 26%, resp.); cally target one of the above-mentioned molecules (e.g., (ii) the rate of proliferative skin lesions (i.e., the incidence MEK, c-KIT, or CTLA-4) would further improve the of cutaneous SCC) was not significantly reduced (7% versus clinical outcome of the patients with advanced/metastatic 19%, resp.); according to me, this observation might be melanoma. A current nonrandomized open-label phase 1/2 explained by the presence of MEK-independent subsets trial (NCT01400451 study) that aims to evaluate the ecffi acy of mutant RAS, since MEK-dependent and -independent and safety of vemurafenib with ipilimumab in adult subjects V600 subsets of mutant RAS have been identified in tumor cell lines with𝐵 - mutation-positive metastatic melanoma is [67, 68]; (iii) PFS was significantly improved (9.4 months ongoing but is not recruiting participants, yet [60]. The versus 5.8months, resp.);(iv)RRwas signicfi antly improved results of this challenging study are expected for August 2015 (76% versus 54%, resp.); (v) the duration of response was [60]. Interestingly, the selective B-RAF inhibitor, dabrafenib also much better (10.5 months versus 5.6 months, resp.). (formerlyGSK2118436),previouslyshowedsimilar ecffi acy to However, OS could not be compared because of the relatively vemurafenib [35], and several clinical trials in patients with V600 short-term followup. es Th e overall exciting experimental 𝐵 - mutant melanoma showed promising results with results will need to be confirmed in ongoing phase 3 larger dabrafenib as a single agent [61–63] or in combo with trame- studies before combo therapy likely replaces monotherapy tinib [64–66]. er Th eby, a recent multicentre, open-label phase (i.e., B-RAF inhibitor as a single agent). Indeed, larger studies 1/2 trial (BREAK-MB study), investigated the efficacy and V600E/k might demonstrate whether B-RAF/MEK combo therapy can safety of oral dabrafenib in adult patients with𝐵 - (i)bothdelay andprevent onsetofresistancetotherapy; mutant melanoma metastatic to the brain (𝑛 = 172 )[61, V600E (ii) significantly reduce the incidence of SCC formation 62]. 29 of 74 (39.2%) patients with 𝐵 - mutant fevers, chills, and MEK inhibitor-induced dermatitis; (iii) V600k melanoma and only 1 of 15 (6.7%) patients with𝐵 - extend overall survival or if ipilimumab shall be implemented mutant melanoma in cohort A (𝑛=89 patients who had to confer a survival benefit in case of treatment failures not received previous local treatment for brain metastases) (e.g., disease progression, unacceptable adverse events); (iv) achieved an overall intracranial response with dabrafenib. recover patients that initially failed with monotherapy or V600k Comparatively, 20 of 65 (30.8%) patients with𝐵 - provide potential benefit to initial monotherapy in order to V600k mutant melanoma and 4 of 18 (22%) with𝐵 - mutant further improve PFS. 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 Journal of Skin Cancer 5 3.2. Promising Molecular Targets to Overcome Low-Response pointwas thesameseenwithBCP that ledthe US FDA Rate Associated with Immunotherapeutic Agents. Although to approve bevacizumab for lung cancer [75]. Therefore, a ipilimumab can induce long-term responses in a subset of trial of chemotherapy combining bevacizumab with the first- patients, the relatively low RR (10%–15%) observed with this line therapeutic agents for metastatic melanoma (e.g., ipili- immunotherapeutic agent limits its use. Possible ways to mumab, vemurafenib) might be beneficial. In this regard, the overcome this limitation would be (i) increase of the dose first combination study, a recent nonrandomized open-label (e.g., 3 to 10 mg/kg); (ii) selection/stratification of the patients phase 1 trial, did investigate potential synergies of ipilimumab (i.e., personalized medicine); (iii) rationale combination with and bevacizumab in a limited number of evaluable adult other treatment modalities (e.g., molecularly targeted ther- patients with unresectable stage III or stage IV melanoma apy, radiation therapy, adoptive T-cell therapy, melanoma (𝑛=21 ) [76]. This preliminary and promising study showed initiating/propagating cells). that ipilimumab plus bevacizumab could (i) display syner- The low response rate of ipilimumab is thought to be gistic effects and provide clinical benefit in a large number caused by melanoma immune escape, a mechanism that of patients as shown in 14/21 of the enrolled patients; (ii) involves the expression of programmed death ligand 1 (PD- be safely administered with management of noted toxicities, L1), which once bound to its ligand PD-1 (programmed which were mostly immune related (e.g., grade 3-4 hepatitis, death-1) of activated lymphocytes, would cause apoptosis of grade 2 colitis, arteritis, hypophysitis, thyroiditis, bilateral the activated lymphocytes and subsequent immune toler- uveitis,). Further, studies with the immunostimulator sar- ance [69–71]. Interestingly, a phase 1 study led on specific gramostim(Leukine/Prokine)showthatthisdrugmay help human anti-PD-1 antibody (formerly MDX-1106 aka BMS- the immune system recover from the side eeff cts of treatment 936558), a fully recombinant human immunoglobulin G4 in patients with metastatic melanoma and so could be tested [72], oeff red clinical benefits in a variety of previously treated as a combinatory agent with ipilimumab. Indeed, a previous refractory solid tumors including melanoma, without gen- investigation (NCCTG study) has consisted to perform a erating significant toxicities [72]. Thereby, a dose-escalation dose-escalation clinical trial with aerosolized sargramostim study of the combination of MDX-1106 with ipilimumab has in HLA-A2 patients with metastatic melanoma to the lung been started [53], and phase 1 trials of anti-PD-L1 are also (𝑛=40 ). eTh data showed that the toxicity was acceptable underway. Recently, the clinical activity and safety of MDX- for all tested doses and the greatest increase in antitumor 1106 intravenously administrated in escalating doses every T-cell immune responses was achieved at the highest doses two weeks in patients with advanced melanoma (𝑛=94 ), [77]. en, Th a hypothesis-generating study was conducted to have been reported [73]. eTh overall RR was 28%, and 6% evaluate the safety and efficacy of prolonged administration of patients achieved stable disease aeft r 24 weeks. Most side of sargramostim as surgical adjuvant therapy in patients eeff cts were immune related, though three treatment-related with melanoma at high risk of recurrence (𝑛=98 ) deaths occurred on study, including two due to pneumonitis. [78]. eTh prolonged administration of the drug was well Interestingly, a subanalysis of the data hinted that the PD- tolerated among patients, and the 5-year melanoma-specific L1 protein might serve as a biomarker of response. Indeed, survival rate was 60%, providing preliminary evidence that more than one-third of patients expressing PD-L1 responded sargramostim can be administered as adjuvant therapy for to immunotherapy, whereas responses were not observed patients with melanoma at high risk of recurrence. Inter- among patients lacking PD-L1 expression. Eventually, these estingly, an ongoing recent randomized open-label phase 2 preliminary data strongly suggest that blockage of the PD-1 longitudinal trial (NCT01134614) is studying how well giving pathway may represent a new immune therapy. ipilimumab with (arm I) or without (arm II) sargramostim Besides, pertinent clinical studies are assessing the com- works in treating adult patients with stage III or stage IV binatorial effects of ipilimumab with promising antiangio- melanoma without brain metastases (estimated enrollment genic drugs (e.g., bevacizumab, an antivascular endothelial 𝑛=220 ) [79]. However, the eeff cts (e.g., OS, PFS, RR, MDR, growth factor A (VEGF-A)), immunostimulators (e.g., sar- safety) of ipilimumab plus sargramostim versus ipilimumab gramostim, a recombinant human granulocyte macrophage alone, in treating patients with advanced melanoma, remain colony-stimulating factor (GM-CSF)), and/or anticancer unknown. Eventually, fotemustine (Muphoran), a non-FDA- agents (e.g., fotemustine, a nitrosourea alkylating agent, or approved drug available in Europe, is known to rapidly cross the B-RAF inhibitor vemurafenib) based on previous studies the blood-brain barrier and to display encouraging activity [74–76]. Indeed, a recent randomized phase 2 trial (BEAM in patients with brain metastases [80]. Also, in a phase 3 trial study) involving patients with previously untreated advanced involving patients with metastatic melanoma (𝑛=229 )[81], melanoma (𝑛 = 214 ) has evaluated the activity of the fotemustine compared to DITC was associated with (i) an FDA-approved drug bevacizumab (Avastin) combined with improved overall RR (15.5% versus 6.8%, resp.); (ii) a trend carboplatin plus paclitaxel (BCP) versus placebo carboplatin toward improved OS (7.3 versus 5.6 months, resp.); (iii) a plus paclitaxel (CP) [74]. Although the results were not as longer median time to development of brain metastases (22.7 good as expected (median PFS: 5.6 months with BCP versus months versus 7.2 months, resp.) in patients without brain 4.2 months with CP; overall RR: 25.5% with BCP versus metastases at inclusion; (iv) a similar MDR (5.8 months ver- 16.4%withCP; median OS:12.3monthswithBCP versus 8.6 sus 6.9 months); (v) a similar time to progression (1.8 months months with CP), the trial might be considered as positive. versus 1.9 months); (vi) a similar quality of life; (vii) more Further, no new safety signals were observed. Interestingly, adverse events such as myelosuppression (i.e., grade 3 to 4 the hazard rate (0.79) for improvement in OS at the last time neutropenia 51% versus 5%, resp. and thrombocytopenia 43% 6 Journal of Skin Cancer versus 6%, resp.) and alopecia. Interestingly, a recent open- antigen 4 (CTLA-4) in patients with unresectable or label, single-arm phase 2 trial (NIBIT-M1 study) is investi- metastatic melanoma. Interestingly, ipilimumab presents gating the efficacy and safety of ipilimumab plus fotemustine the opposite main advantage and disadvantage than in adult patients (𝑛=86 ) with metastatic melanoma and with vemurafenib. Several clinical trials are underway to address or without asymptomatic brain metastases [82]. As primarily the question of rational combination of those two approved results, this medicinal combination achieved disease control drugs, together and/or separately with other potential in 40 patients (46.5%) with metastatic melanoma, including therapeutic targets (PD-1, PD-L1, c-KIT, MEK1, VEGF- those with brain metastases. Nevertheless, the treatment- A...). Cell therapy such as adoptive T cell is encouraging. related adverse effects (e.g., grade 3 or 4 myelotoxicity and Nanoencapsulation of the recent FDA-approved free drugs hepatotoxicity) were present in 47 patients (55%). (e.g., vemurafenib, ipilimumab), using proper nanocarriers, Eventually, the use of nanomaterials to formulate nan- or rational combination of these free drugs with available odrugs (e.g., drug nanocarriers such as solid lipid nanopar- adjuvant nanotherapeutics might be beneficial as they ticles (SLN) or nanostructured lipid carriers (NLC)) might might enhance the overall pharmacological features (e.g., be useful to possibly enhance efficacy (e.g., systemic bioavail- bioavailability and targeting). eTh importance of direct ability, targeting), tolerability, and safety of free drugs pre- targeting of potential melanoma initiating/propagating cells senting clinical benefit for patients with metastatic melanoma within a given patient was not detailed in this paper but might (e.g., ipilimumab, vemurafenib). In general, it is well accepted be important in order to avoid immune resistance, immune that administration of appropriate nanodrug formulations escape, and disease relapse. Owing to consideration that the can contribute to enhance the duration response, the incidence of advanced/metastatic melanoma in the younger response rate, the OS, and PFS in patients with a given population is increasing, clinical trials in pediatric patients type of cancer [83, 84]. In this regard and based on a appear necessary. Eventually, the rational molecular or recent study announcing the preparation of nanoliposomes- cellular combo therapy is a key strategy, as it shall beneficiate encapsulated bevacizumab with beneficial effects in prolong- alargernumberofpatients. eTh recent resultsreportedin ing the residency of bevacizumab in the vitreous [85], it this paper are quite exciting and, undeniably, constitute a might be interesting to test ipilimumab plus nanoencapsu- newhopefor patients andhealthcareprofessionals. lated bevacizumab in patients with unresectable stage III or stage IV melanoma. Besides, “adoptive T-cell therapy” Abbreviations (ACT), which presents several conceptual similarities with hematopoietic stem-cell transplantations (HSCTs) in terms ACT: Adoptive T-cell therapy of advantages and disadvantages can constitute another ACS: American cancer society therapeutic option to overcome the low response asso- BCP: Bevacizumab/carboplatin/paclitaxel ciated with immunotherapeutic agents (e.g., ipilimumab). CTL-A4: Cytotoxic T-lymphocyte-associated Indeed, successful isolation-expansion-infusion of TIL has antigen 4 shown clinical benefits for the treatment of patients with DITC: Dacarbazine metastatic melanoma [86–91]. For instance, the RR (72%) FDA: Food and drug administration was higher when using nonmyeloablative lymphodepletion HDI: High-dose interferon with cytotoxic chemotherapy and with or without total body HSCT: Hematopoietic stem cell transplantation irradiation (TBI) than when ipilimumab was combined with IL-2: Interleukin-2 IL-2 [86–91]. Interestingly, preclinical work suggested that PD-1: Programmed death-1 V600E selective𝐵 - inhibition enhances T-cell recognition PEG-IFN: Pegylated interferon alpha-2b of melanoma without aeff cting lymphocyte function, provid- MAPK: Mitogen-activated protein kinase ing a rational for the combination of B-RAF inhibitors (e.g., MDR: Median duration response vemurafenib or dabrafenib) with stimulatory immune agents MEK: MAPK/extracellular signal-regulated (e.g., ipilimumab or PD-1/PD-L1) [92]. kinase (ERK) MEKi: MEK inhibitor OS: Overall survival 4. Conclusions PEG: Polyethylene glycol PFS: Progression-free survival The incidence of metastastic melanoma is increasing RAF: Ras-activating factor worldwide. Vemurafenib and ipilimumab, based on their RFS: Relapse/recurrence free survival respective success rates, are bringing hopes to physicians RR: Response rate and patients. Vemurafenib has emerged as a highly selective SCC: Squamous cell carcinoma V600E 𝐵 - mutant melanoma inhibitor and could display TBI: Total body irradiation good response rates in patients with unresectable or TIL: Tumor infiltrating lymphocytes. metastatic melanoma. Nevertheless, its main disadvantage remains the short median duration response as well as its limited use to patients who harbor mutations other than Conflict of Interests V600E V600k 𝐵 - (e.g., 𝐵 - ). Besides, ipilimumab was developed to block the cytotoxic T-lymphocyte-associated The author declares to have no conflict of interests. 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 𝑅𝐴𝐹 Journal of Skin Cancer 7 Acknowledgments alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial,” The Lancet ,vol.372,no. The author would like to thank Dr. Abder Menaa, M. D. for 9633, pp. 117–126, 2008. his pertinent suggestions and critical review of this paper. [14] K. T. Flaherty, I. Puzanov, K. B. 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