Today, melanoma is considered as a spectrum of melanocytic malignancies that can be characterized by clinical and molecular features, including targetable mutations in several kinases. The successful development of therapies, targeting mutated BRaF (v-raf murine sarcoma viral oncogene homolog B1) or c-KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog), has resulted in new treatment options including vemurafenib, imatinib and mitogen-activated protein kinase inhibitors. These molecules are selected if the respective mutation is present. after this first progress in the treatment of advanced melanoma, there is expectation that combinations of kinase inhibitor will additionally improve the overall survival rates and progression-free survival in advanced melanom

Dummer, R.

Eggmann, N.

Goldinger, S. M.

Rinderknecht, J.

Rozati, S.

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From chemotherapy to targeted treatmentR. Dummer*, S. Rozati, N. Eggmann, J. Rinderknecht & S. M. GoldingerDepartment of Dermatology, University Hospital Zurich, Zurich, SwitzerlandToday, melanoma is considered as a spectrum of melanocytic malignancies that can be characterized by clinical andmolecular features, including targetable mutations in several kinases. The successful development of therapies,targeting mutated BRAF (v-raf murine sarcoma viral oncogene homolog B1) or c-KIT (v-kit Hardy-Zuckerman 4 felinesarcoma viral oncogene homolog), has resulted in new treatment options including vemurafenib, imatinib and mitogen-activated protein kinase inhibitors. These molecules are selected if the respective mutation is present. After this ﬁrstprogress in the treatment of advanced melanoma, there is expectation that combinations of kinase inhibitor willadditionally improve the overall survival rates and progression-free survival in advanced melanoma.Key words: biochemotherapy, chemotherapy, kinase inhibitor, melanoma, metastatic melanoma, targeted therapyintroductionMelanoma is the most common lethal cutaneous malignancy.It is derived from melanocytes originating from the neuralcrest. The genetic events and their relationship to thecomplex interaction with the microenvironment transformingnormal melanocytes into melanoma are under intensiveinvestigation.retrospective view of chemotherapyFor decades chemotherapy was the backbone of systemictreatment in cases of distant metastasis. Dacarbacine (DTIC) isstill the most used cytotoxic agent in metastatic melanoma andremains the standard ﬁrst-line treatment in wild-typemelanomas [1]. Temozolomide is a chemically related oraldrug and therefore convenient for outpatient therapy. Itdemonstrated efﬁcacy equal to that of DTIC in two phase 3trials [2] although the difference in overall survival,progression-free survival or overall response rate was not seenbetween the two arms, despite dose intensiﬁcation in theEORTC trial [2]. Temozolomide penetrates into the centralnervous system (CNS) and may induce regression of CNSmetastases. Polychemotherapy containing cisplatin, vindesineand DTIC or the combination of carboplatin and paclitaxel [3]may produce responses in 20–40% of the patients. However, animpact on disease-free or overall survival was never shown inrandomized trials, considering that these therapies havesubstantial persisting toxic effects.Biochemotherapy, a combination of interleukin-2 (IL-2)and/or interferon-α (IFN-α) with chemotherapeutic agentssuch as DTIC, cisplatin and vinblastine, has demonstrated ahigh response rate although it was not translated into improvedsurvival and was associated with an increase in toxicity [4, 5].molecular dissection of melanomaIn the last decade, melanoma was dissected into severalmolecular subgroups based on genomic alterations includingmutations, deletions and ampliﬁcations in addition to clinicalfeatures. Up to 50% of melanomas derived from skin withoutchronic sun damage (intermittently exposed to UV) containmutations in the gene encoding the serine–threonine proteinkinase v-raf murine sarcoma viral oncogene homolog B1(BRAF). BRAF together with ARAF and CRAF activate asecond protein known as mitogen-activated protein kinasekinase (MEK), which in turn activates extracellular signal-regulated kinase (ERK). Additionally, 20% of melanomaspresent RAS (rat sarcoma) mutations. Finally, a minorpercentages have activating mutations in the KIT gene, whichare most common in mucosal melanomas derived from thegenital regions [6, 7], or mutations in GNA11/ or GNAQgenes in uveal melanomas [8, 9]. Some of the targetablemutations in KIT gene are also found in acral and othermucosal melanomas but with lower frequency. The KITreceptor protein tyrosine kinase is a transmembrane proteinconsisting of extracellular and intracellular domains. Most KITmutations are localized to exon 11, which codes for thejuxtamembrane domain and exon 13, which codes for a kinasedomain.breakthrough with kinase inhibitortherapy in melanoma subgroupsThe best-validated targeted therapies in melanoma are theselective BRAF inhibitors, vemurafenib (PLX4032, Zelboraf™)and dabrafenib (GSK2118436). Both are relatively selective for*Correspondence to: Dr R. Dummer, Department of Dermatology, University HospitalZurich, Zurich, Switzerland; E-mail: reinhard.dummer@usz.chsymposiumarticlesymposium article Annals of Oncology 23 (Supplement 10): x101–x103, 2012doi:10.1093/annonc/mds308© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: journals.permissions@oup.com.their intended target, V600E BRAF, with little cross-reactivityfor wild-type BRAF and CRAF [10, 11]. Few other kinases areinhibited with 10- to 100-folds of the concentration needed toinhibit V600E BRAF. These agents inhibit selectively thegrowth of cells that harbor a V600E BRAF mutation. In severalclinical trials, vemurafenib and dabrafenib have bothdemonstrated impressive clinical efﬁcacy with the response ratein the range of 50% in V600E-mutated advanced melanomas[11–13].Unfortunately, the response duration is highly variable asshown by phase 2 and phase 3 trials. In a phase 2 trial,vemurafenib produced objective responses in 53% of 132patients with metastatic melanoma harbouring a V600E orV600K mutation [14]. The median duration of response was6.7 months. In a phase 3 trial, with dacarbazine monotherapyas the control arm, overall survival was signiﬁcantly improvedamong the 337 patients with V600E mutant metastaticmelanoma compared with the 338 patients who receiveddacarbazine (hazard ratio 0.37; 95% CI, 0.26 to 0.55; P < 0.001)[15], as was the progression-free survival. In addition, theresponse rate was much better in the vemurafenib arm (48%objective response rate versus 5%; P < 0.001). These data led tothe approval of vemurafenib in the United States, Europeancommunity and Switzerland.The appearance of acanthopapillomas, keratoacanthomasand cutaneous squamous cell carcinomas early in the course oftreatment with these kinase inhibitors needs special attention[16, 17]. Furthermore, there are well-documented cases of newprimary melanomas that do not present a BRAf V600mutation [14, 18]. Other more common toxic effects observedwith vemurafenib include arthralgia, photosensitivity [14], rashand fatigue. Generally, these toxic effects are mild to moderatein severity and, when severe, can be managed with doseinterruption and/or reduction. The most common toxic effectsobserved with dabrafenib are comparable, except there is nophotosensitivity [11].Multiple in vitro studies have demonstrated that mutatedBRAF signaling is mediated via MEK and ERK [19]. Thus,selective MEK inhibitors have shown efﬁcacy in patients withBRAF mutant metastatic melanoma. Selumetinib was the ﬁrstallosteric, selective MEK inhibitor to be evaluated in a phase 2clinical trial in patients with metastatic melanoma [20]. Thisagent produced an objective response rate in patients withBRAF mutant tumors but not in wild-type tumors and thusreinforcing the importance of selecting a speciﬁc patientpopulations. In the phase 1 dose escalation clinical trial,GSK1120212 demonstrated an objective response rate of 44%with a median progression-free survival of 7.4 months inpatients with BRAF mutant melanoma [21]. This agent isbeing evaluated in additional phase 2 and phase 3 trials inBRAF mutant melanoma. Other MEK inhibitors are currentlyinvestigated in NRAS-mutated melanomas with somepromising results. The combination of kinase inhibitors suchas concomitant BRAF and MEK inhibitor therapy is deﬁnitelya key to the future of development strategies.The kinase inhibitor imatinib has proven efﬁcacy in patientswith advanced melanoma harboring KIT mutations [22]. KITmutations are found in low frequency (10% or less) inmelanomas arising from a mucosal or acral lentiginoussurfaces [23]. As the vast majority of patients with metastaticmelanoma suffer from primary tumors on glabrous skin(trunk, extremities and head/neck), the number of patients inthe metastatic setting with mutated KIT is small. Durableresponses were observed in 16% of a 51 patient cohort witheither mutations in KIT or ampliﬁcation [24]. In a phase 2 trialin which 43 patients with KIT mutations or ampliﬁcation wereenrolled, 23% of patients had objective responses [25]. In bothstudies, certain mutations in exons 11 and 13 of v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog(particularly the L576P mutation in exon 11) were associatedwith the highest response rate. Thus, it appears that sensitivityto KIT inhibition exists in metastatic melanoma [20] but it isconﬁned to a subset of this already small subpopulation ofpatients.After decades of standstill, progress in understanding thebiology of melanomas has resulted in powerful targetedtherapies with impact on progression-free and overall survival.Ongoing research is focussed on resistance mechanisms andstrategies to overcome them [26]. In order to further improvethe outcome in this still poor prognosis population, patientsshould be encouraged to participate in well-designed clinicaltrials.disclosureRD receives research funding from Astra Zeneca, Novartis,Cephalon, Merck Sharp & Dhome, Transgene, Bristol-MyersSquibb, Roche, GlaxoSmithKline, Bayer and has a consultantor advisory board relationship with Astra Zeneca, Novartis,Cephalon, Merck Sharp & Dhome, Transgene, Genta, Bayer,Roche, Bristol-Myers Squibb, GlaxoSmithKline, Spirig.references1. Eigentler TK, Caroli UM, Radny P et al. Palliative therapy of disseminatedmalignant melanoma: a systematic review of 41 randomised clinical trials. LancetOncol 2003; 4(12): 748–759.2. Patel PM, Suciu S, Mortier L et al. Extended schedule, escalated dosetemozolomide versus dacarbazine in stage IV melanoma: ﬁnal results of arandomised phase III study (EORTC 18032). Eur J Cancer 2011; 47(10):1476–1483.3. Hauschild A, Agarwala SS, Trefzer U et al. Results of a phase III, randomized,placebo-controlled study of sorafenib in combination with carboplatin andpaclitaxel as second-line treatment in patients with unresectable stage III orstage IV melanoma. J Clin Oncol 2009; 27(17): 2823–2830.4. Hamm C, Verma S, Petrella T et al. Biochemotherapy for the treatment ofmetastatic malignant melanoma: a systematic review. Cancer Treat Rev 2008;34(2): 145–156.5. Ives NJ, Stowe RL, Lorigan P et al. Chemotherapy compared withbiochemotherapy for the treatment of metastatic melanoma: a meta-analysis of18 trials involving 2,621 patients. J Clin Oncol 2007; 25(34): 5426–5434.6. Omholt K, Grafstrom E, Kanter-Lewensohn L et al. KIT pathway alterations inmucosal melanomas of the vulva and other sites. Clin Cancer Res 2011; 17(12):3933–3942.7. Schoenewolf NL, Bull C, Belloni B et al. Sinonasal, genital and acrolentiginousmelanomas show distinct characteristics of KIT expression and mutations. Eur JCancer 2012; 48(12): 1842–1852.8. Van Raamsdonk CD, Bezrookove V, Geen G et al. Frequent somatic mutations ofGNAQ in uveal melanoma and blue naevi. Nature 2009; 457(7229): 599–602.symposium article Annals of Oncologyx | Dummer et al. Volume 23 | Supplement 10 | September 20129. Van Raamsdonk CD, Griewank KG, Crosby MB et al. Mutations in GNA11 inuveal melanoma. N Engl J Med 2010; 363(23): 2191–2199.10. Bollag G, Hirth P, Tsai J et al. Clinical efﬁcacy of a RAF inhibitor needs broadtarget blockade in BRAF-mutant melanoma. Nature 2010; 467(7315): 596–599.11. Kefford RA, Arkenaua H, Brown MP et al. Phase I/II study of GSK2118436, aselective inhibitor of oncogenic mutant BRAF kinase, in patients with metastaticmelanoma and other solid tumors. J Clin Oncol 2010; 28(Suppl): Abstract 8503.12. Long GV, Kefford RF, Carr PJ et al. Phase 1/2 study of GSK2118436, a selectiveinhibitor of V600 mutant (mut) BRAF kinase: evidence of activity in melanomabrain metastases (mets). Ann Oncol 2010; 21(Suppl 8): viii12.13. Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF inmetastatic melanoma. N Engl J Med 2010; 363(9): 809–819.14. Dummer R, Rinderknecht J, Goldinger SM. Ultraviolet A and photosensitivityduring vemurafenib therapy. N Engl J Med 2012; 366(5): 480–481.15. Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib inmelanoma with BRAF V600E mutation. N Engl J Med 2011; 364(26): 2507–2516.16. Oberholzer PA, Kee D, Dziunycz P et al. RAS mutations are associated with thedevelopment of cutaneous squamous cell tumors in patients treated with RAFinhibitors. J Clin Oncol 2012; 30(3): 316–321.17. Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomasin patients treated with BRAF inhibitors. N Engl J Med 2012; 366(3): 207–215.18. Zimmer L, Hillen U, Livingstone E et al. Atypical melanocytic proliferations andnew primary melanomas in advanced melanoma patients undergoing selectiveBRAF inhibition. J Clin Oncol 2012; 30(19): 2375–2383.19. Pratilas CA, Taylor BS, Ye Q et al. (V600E)BRAF is associated with disabledfeedback inhibition of RAF-MEK signaling and elevated transcriptionaloutput of the pathway. Proc Natl Acad Sci USA 2009; 106(11):4519–4524.20. Kirkwood JM, Bastholt L, Robert C et al. Phase II, open-label, randomizedtrial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomidein patients with advanced melanoma. Clin Cancer Res 2012; 18(2):555–567.21. Infante JR, Fecher LA, Nallapareddy S et al. Safety and efﬁcacy results from theﬁrst-in-human study of the oral MEK 1/2 inhibitor GSK1120212. J Clin Oncol2010; 28(Suppl): Abstract 2503.22. Hodi FS, Friedlander P, Corless CL et al. Major response to imatinib mesylate inKIT-mutated melanoma. J Clin Oncol 2008; 26(12): 2046–2051.23. Curtin JA, Busam K, Pinkel D et al. Somatic activation of KIT in distinct subtypesof melanoma. J Clin Oncol 2006; 24(26): 4340–4346.24. Carvajal RD, Antonescu CR, Wolchok JD et al. KIT as a therapeutic target inmetastatic melanoma. JAMA 2011; 305(22): 2327–2334.25. Guo J, Si L, Kong Y et al. Phase II, open-label, single-arm trial of imatinibmesylate in patients with metastatic melanoma harboring c-Kit mutation orampliﬁcation. J Clin Oncol 2011; 29(21): 2904–2909.26. Dummer R, Flaherty KT. Resistance patterns with tyrosine kinase inhibitors inmelanoma: new insights. Curr Opin Oncol 2012; 24(2): 150–154.Annals of Oncology symposium articleVolume 23 | Supplement 10 | September 2012 doi:10.1093/annonc/mds308 | x

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