Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities

Charlotte Lemech, Hendrik-Tobias Arkenau, Charlotte Lemech, Hendrik-Tobias Arkenau

Abstract

The last 12 months have seen the beginning of a new era in the treatment options available for patients with metastatic cutaneous melanoma, a disease previously characterised by its poor prognosis and limited treatment options. Two mechanistically diverse agents have now demonstrated an overall survival benefit in different patient subgroups and further clinical trials are ongoing with emerging single agents and novel combinations. The first agent to demonstrate an overall survival benefit was the CTLA-4 antibody, ipilimumab, illustrating the importance of the immune system and immunomodulation in melanoma tumorigenesis. The second group of agents to show a survival benefit were the selective BRAF inhibitors, vemurafenib and GSK2118436, in patients who are BRAF V600 mutation positive. In addition, in the same BRAF mutant patient population, MEK inhibitors also show promising results and are currently under investigation in later stage trials. Although ipilimumab, BRAF and MEK inhibitors are just passing through the clinical trials arena, their use will rapidly become more widespread. Along with their significant clinical benefits, there are also unique adverse events related to these agents. Although the majority are mild and can be managed with supportive treatment, some toxicities require special management strategies. We outline up-to-date clinical development and management guidelines for ipilimumab, as well as the BRAF and MEK inhibitors.

Keywords: BRAF-inhibitor; MEK-inhibitor; cutaneous melanoma; diarrhea; fever; immune related adverse events; ipilimumab; ocular toxicity; skin rash; squamous cell carcinoma.

References

    1. Cancer Research UK. Skin cancer – UK incidence statistics. [Accessed Aug 2011]. 2010. Available at:
    1. National Cancer Institute—Surveillance Epidemiology and End Results. SEER Stat Fact Sheets: Melanoma of the Skin. [Accessed Jul 2010]. 2010. Available at: .
    1. Chapman PB, Einhorh LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999;17(9):2745–51.
    1. 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;18:158–66.
    1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved Survival with Ipilimumab in patients with Metastatic Melanoma. New Engl J Med. 2010;363(8):711–23.
    1. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma. New Engl J Med. 2011;364:2517–26.
    1. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New Engl J Med. 2011;364(26):2507–16.
    1. Kefford R, Arkenau H, Brown MP, et al. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumours. J Clin Oncol. 2010;28(15s):abstr 8503.
    1. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182:459–65.
    1. Weber J. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother. 2009;58:823–30.
    1. Yang YF, Zou JP, Mu J, et al. Enhanced induction of antitumor T-cell responses by cytotoxic T lymphocyte-associated molecule-4 blocakade: the effect is manifested only at the restricted tumor-bearing stages. Cancer Res. 1997;57(18):4036–41.
    1. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734–6.
    1. Medscape Reference: Drugs, Diseases and Procedures. Ipilimumab – Yervoy – Pharmacology. [Accessed Oct 2011]. .
    1. Hamid O, Chin K, Li J, et al. Dose effect of ipilimumab in patients with advanced melanoma: results from a phase II, randomized, dose-randing study. J clin Oncol. 2008;(Suppl 26):abstr 9025.
    1. Weber JS. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Imm Imm. 2009;58:823–30.
    1. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:6043–53.
    1. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nature Med. 1998;4:321–7.
    1. . Accessed Oct 2011. [Accessed November 29, 2011]. .
    1. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.
    1. Platz A, Egyhazi S, Ringborg U, Hansson J. Human cutaneous melanoma: a review of NRAS and BRAF mutation frequencies in relation to histogenic subclass and body site. Mol Oncol. 2008;1:395–405.
    1. Houben R, Becker JC, Kappel A, et al. Constitutive activation of the Ras-Raf signalling pathway in metastatic melanoma is associated with poor prognosis. J of Carcinogenesis. 2004;3(1):6.
    1. Jakob JA, Bassett RL, Ng CS, et al. Clinical characteristics and outcomes associated with BRAF and NRAS mutations in metastatic melanoma. J Clin Oncol. 2011;29(Suppl):abstr 8500.
    1. Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239–46.
    1. Karasarides M, Chiloeches A, Hayward R, et al. B-RAF is a therapeutic target in melanoma. Oncogene. 2004;23:6292–8.
    1. Cheng S, Chu P, Hinshaw M, et al. Frequency of mutations associated with targeted therapy in malignant melanoma patients. J Clin Oncol. 2011;29(Suppl):abstr 8597.
    1. Catalogue of Somatic Mutations in Cancer (Cosmic) website. Wellcome Trust Sanger Institute; [Accessed Oct 2011].
    1. Dhomen N, Marais R. BRAF signalling and targeted therapies in melanoma. Hematol Oncol Clin of North Am. 2009;23(3):529–45.
    1. Rubinstein JC, Sznol M, Pavlick AC, et al. Incidence of the V600 K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med. 2010;6:67.
    1. Thomas NE, Edmiston SN, Alexander A, et al. Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant melanoma. Cancer Epidemiol Biomarkers Prev. 2007;16:991–7.
    1. Flaherty KT. Is it Good or Bad to find a BRAF mutation? J Clin Oncol. 2011;29(10):1229–30.
    1. Long GV, Wilmott JS, Howle JR, et al. Morphologic and immunohistochemical (IHC) changes in metastatic melanoma (MM) tissue and associations with clinical outcome in patients on BRAF inhibitors (BRAFi) J Clin Oncol. 2011;29(Suppl):abstr 8542.
    1. Hoeflich KP, Gray DC, Eby MT, et al. Oncogenic BRAF is required for tumor growth and maintenance in melanoma models. Cancer Res. 2006;66:999–1006.
    1. Calipel A, Lefevre G, Pouponnot C, et al. Mutation in B-raf in human choroidal melanoma cell lines mediates cell proliferation and transformation through the MEK/ERK pathway. J Biol Chem. 2003;278:42409–18.
    1. Eisen T, Ahmad T, Flaherty KT, et al. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J of Cancer. 2006;95:581–6.
    1. McDermott DF, Sosman JA, Gonzalez R, et al. Double-Blind Randomized Phase II Study of the combination of Sorafenib and Dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group. J Clin Oncol. 2008;26(13):2178–85.
    1. 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 IV melanoma. J Clin Oncol. 2009;27(17):2823–30.
    1. Medscape Reference: Drugs, Diseases and Procedures. Vemurafenib-Zelboraf. [Accessed Oct 2011]. .
    1. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. New Engl J of Med. 2010;363:809–19.
    1. Ribas A, Kim KB, Schuchter LM, et al. BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAFV600E mutation-positive melanoma. J Clin Oncol. 2011;29(Suppl):8509–9.
    1. Long GV, Kefford RF, Carr PJA, et al. Phase 1/2 study of GSK2118436, a selective inhibitor of V600 mutant (mut) BRAF Kinase: Evidence of Activity in Melanoma Brain Metastases (mets) Ann Oncol. 2010;21(Suppl 8):abstr LBA27.
    1. Zhang XD, Borrow JM, Zhang XY, Nguyen T, Hersey P. Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene. 2003;22:2869–81.
    1. Messersmith WA, Hidalgo M, Carducci M, Eckhardt SG. Novel Targets in Solid Tumors: MEK inhibitors. Clin Adv Hem and Onc. 2006;4(11):831–6.
    1. Lorusso PM, Krishnamurthy S, Rinehart J, et al. A phase 1–2 clinical study of a second generation oral MEK inhibitor, PD 0325901, in patients with advanced cancer. J Clin Oncol. 2005;23(16S):3011.
    1. Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetic and pharmacodynamic sutdy of the oral, small-molecule mitogen-activated protein kinase kinase1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Onc. 2008;26:2139–46.
    1. Dummer R, Robert C, Chapman PB, et al. AZD6244 (ARRY-142886) vs. temozolomide (TMZ) in patients with advanced melanoma: an open-label, randomized, multicenter, phase II study. J Clin Oncol. 2008;26(Suppl):abstr 9033.
    1. Falchook G, Infante JR, Fecher LA, et al. The Oral MEK 1/2 Inhibitor GSK1120212 Demonstrates Early Efficacy Signals. Ann Oncol. 2010;21(Suppl 8):abstr 4950.
    1. Infante J, Falchook G, Lawrence D, et al. Phase I/II study of the Oral MEK1/2 Inhibitor GSK1120212 Dosed in Combination with the Oral BRAF Inhibitor GSK2118436. J Clin Oncol. 2011;29(Suppl):abstr CRA8503.
    1. Corcoran RB, Settleman J, Engelman JA. Potential Therapeutic Strategies to overcome Acquired Resistance to BRAF or MEK inhibitors in BRAF mutant cancers. Oncotarget. 2011;2(4):336–46.
    1. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to BRAF (V600E) inhibition by RTK or NRAS upregulation. Nature. 2010;468:973–7.
    1. Emery CM, Vijayendram KG, Zipser MC, et al. MEK1 mutations confer resistance to MEK and BRAF inhibition. Proc Natl Acad Sci U S A. 2009;106(48):20411–6.
    1. Wagle N, Emery C, Berger MF, et al. Dissecting Therapeutic Resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol. 2011;29(22):3085–96.
    1. Kahler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. JDDG. 2010;8:1–9.
    1. Yervoy (ipilimumab): Immune-mediated adverse reaction management guide. [Accessed Oct 2011]. .
    1. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind multicentre, phase 2, dose-ranging study. Lancet Onc. 2010;11(2):155–64.
    1. Robert C, Wolchok JD. Correspondence: Ipilimumab plus Dacarbazine in Melanoma. New Engl J Med. 2011;365:1256–8.
    1. Weber J. Review: Anti-CTLA-4 Antibody Ipilimumab: case studies of clinical response and immune-related adverse events. The Oncologist. 2007;12:864–72.
    1. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-Lymphocyte-Associated Antigen 4. J Clin Onc. 2006;24(15):2283–9.
    1. Minor CR, Chin K, Kashani-Sabet M, et al. Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm. 2009;24(3):321–5.
    1. Phan GQ, Weber JS, Sondak VK. CTLA-4 Blockade with monoclonal antibodies in patients with metastatic cancer: surgical issues. Ann of Surg Onc. 2008;15(11):3014–21.
    1. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy fo ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15(17):5591–8.
    1. Lin R, Yellin MJ, Lowy A, et al. An analysis of the effectiveness of specific guidelines for the management of ipilimumab-mediated diarrhoea/colitis: prevention of gastrointestinal perforation and/or colectomy. J Clin Onc. 2008;26(15s):abstr 9063.
    1. Thumar JR, Kluger HM. Ipilimumab: A promising immunotherapy for melanoma. Oncology. 2011;24:1–13.
    1. Chmiel K, Suan D, Liddle C, Nankivell B, et al. Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy. J Clin Oncol. 2011;29:e237–40.
    1. Blansfield JA, Beck KA, Tran K, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28:593–8.
    1. Fadel F, El Karoui K, Knebelmann B, et al. Anti-CTLA4 antibody-induced lupus nephritis. N Engl J Med. 2009;361:211–12.
    1. Kefford R. Meeting Report from the 7th International Melanoma Congress, Sydney, Nov 2010. Pigment Cell Mel Res. 2010;24:e1–15.
    1. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF. Cell. 2010;140:209–21.
    1. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimmers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427–30.
    1. Infante J, Falchook G, Lawrence D, et al. Phase I/II study of the Oral MEK1/2 Inhibitor GSK1120212 Dosed in Combination with the Oral BRAF Inhibitor GSK2118436. J Clin Oncol. 2011;29(Suppl):abstr CRA8503. change to 47.
    1. LoRusso PM, Krishnamurthi SS, Rinehard JJ, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral MAPK/ERK inhibitor PD-0325901 in patients with Advanced Cancer. Clin Cancer Res. 2010;16(6):1924–37.
    1. Haura EB, Ricart AD, Larson TG, et al. A Phase II Study of PD-0325901, an Oral MEK Inhibitor, in Previously Treated Patients with Advanced Non- Small cell Lung Cancer. Clin Cancer Res. 2010;16:2450–7.
    1. Sebolt-Leopold JS. Advances in the development of cancer therapeutics directed against the RAS-Mitogen-Activated protein kinase pathway. Clin Cancer Res. 2008;14:3651–6.
    1. . [Accessed November 29, 2011]. Identifier NCT01245062.
    1. Long GV, Wilmott JS, Howle JR, et al. Morphologic and immunohistochemical (IHC) changes in metastatic melanoma (MM) tissue and associations with clinical outcome in patients on BRAF inhibitors (BRAFi) J Clin Oncol. 2011;29(Suppl):abstr 8542.
    1. Boni A, Cogdill AP, Dang P, et al. Selective BRAF V600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70(13):5213–9.
    1. Mulcahy N. Ipilimumab is for community-based oncologists too, says expert. Medscape Oncology. 2011 Apr;

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa