Generic placeholder image

Recent Patents on Anti-Cancer Drug Discovery


ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Review Article

Safety Profiles and Pharmacovigilance Considerations for Recently Patented Anticancer Drugs: Cutaneous Melanoma

Author(s): Debora Basile, Camilla Lisanti, Maria A. Pizzichetta, Paolo Baldo*, Giulia Fornasier, Francesco Lo Re, Giuseppe Corona and Fabio Puglisi

Volume 14, Issue 3, 2019

Page: [203 - 225] Pages: 23

DOI: 10.2174/1574892814666190726130351

Price: $65


Background: Malignant melanoma is a skin cancer responsible for 90% of cutaneous cancer- related deaths. In recent years, breakthroughs in treatment strategy have revolutionized the prognosis in both early and advanced melanoma patients. In particular, treatment with monoclonal antibodies targeting co-inhibitory checkpoints or specific molecular pathways leads to a new era of promising options, by prolonging the survival time of these patients.

Moreover, unlike the chemotherapy that was used until some time ago, these new drugs have a good and more manageable toxicity profile. However, because of the recent introduction in clinical practice of the new agents, there is a learning curve among physicians regarding early recognition and management of the associated side effects.

Objectives: The analysis of the toxicity profiles of the different agents currently studied for the treatment of early and advanced melanoma, and the description of several relevant recent patents in this field, are the aims of this review.

Methods: This is a systematically conducted review based on current clinical guidelines and on international Pharmacovigilance databases (AERS-Eudravigilance - WHO Vigibase).

Results: Our systematic analysis outlines a comprehensive overview of the pharmacology, clinical application and the safety of recent anticancer drugs to treat melanoma, which can be an essential instrument for health professionals and researchers.

Conclusion: The new oncological therapies against melanoma are based on increasingly specific biological and immunological targets. For this reason, the potential toxicities that are expected from patients would be less relevant than the systemic "classical" chemotherapy. However, the new therapies are not free from the risk of causing adverse reactions, some of which must be managed promptly and appropriately; moreover, the multiplicity of the metabolic pathways exposes the new target therapies to relevant potential interactions. This review can help to understand how important it is not to underestimate potential adverse drug reactions related to new targeted therapies.

Keywords: Adjuvant melanoma, advanced melanoma, adverse drug reactions, drug-related toxicity, immunotherapy, pharmacovigilance, side effects, targeted therapy.

Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Bastholt L, et al. Diagnosis and treatment of melanoma. European Consensus-based Interdisciplinary Guideline - Update 2016. Eur J Cancer Oxf Engl 2016; 63: 201-17.
Johnson MM, Leachman SA, Aspinwall LG, Cranmer LD, Curiel-Lewandrowski C, Sondak VK, et al. Skin cancer screening: Recommendations for data-driven screening guidelines and a review of the US Preventive Services Task Force controversy. Melanoma Manag 2017; 4(1): 13-37.
Roach REJ, Plasmeijer EI, van Doorn R, Bergman W, Kukutsch NA. The value of clinical characteristics for the diagnosis of melanoma in patients presenting at a pigmented lesion clinic. Br J Dermatol 2016; 174(6): 1401-3.
Mayer JE, Swetter SM, Fu T, Geller AC. Screening, early detection, education, and trends for melanoma: Current status (2007-2013) and future directions: Part I. Epidemiology, high-risk groups, clinical strategies, and diagnostic technology. J Am Acad Dermatol 2014; 71(4): 599.
Wolff K, Goldsmith L, Katz S, Gilchrest B, Paller AS, Leffell D. Fitzpatrick’s Dermatology in General Medicine. 7th Edition. 2008. Available from:. publications/fitzpatricks-dermatology-in-general-medicine-7th-edition-2
Lin WM, Luo S, Muzikansky A, Lobo AZC, Tanabe KK, Sober AJ, et al. Outcome of patients with de novo versus nevus-associated melanoma. J Am Acad Dermatol 2015; 72(1): 54-8.
Russo T, Piccolo V, Lallas A, Giacomel J, Moscarella E, Alfano R, et al. Dermoscopy of malignant skin tumours: What’s new? Dermatology Basel Switz 2017; 233(1): 64-73.
Pizzichetta MA, Massi D, Mandalà M, Queirolo P, Stanganelli I, De Giorgi V, et al. Clinicopathological predictors of recurrence in nodular and superficial spreading cutaneous melanoma: A multivariate analysis of 214 cases. J Transl Med 2017; 15(1): 227.
Pizzichetta MA, Kittler H, Stanganelli I, Ghigliotti G, Corradin MT, Rubegni P, et al. Dermoscopic diagnosis of amelanotic/hypomelanotic melanoma. Br J Dermatol 2017; 177(2): 538-40.
Shaikh WR, Xiong M, Weinstock MA. The contribution of nodular subtype to melanoma mortality in the United States, 1978 to 2007. Arch Dermatol 2012; 148(1): 30-6.
Kelly JW, Chamberlain AJ, Staples MP, McAvoy B. Nodular melanoma. No longer as simple as ABC. Aust Fam Physician 2003; 32(9): 706-9.
Pizzichetta MA, Kittler H, Stanganelli I, Bono R, Cavicchini S, De Giorgi V, et al. Pigmented nodular melanoma: The predictive value of dermoscopic features using multivariate analysis. Br J Dermatol 2015; 173(1): 106-14.
Scarfì F, Galeone M, Bassi A, Arunachalam M, Massi D, Difonzo EM. Melanoma manifesting as a verrucous lesion in the interdigital toe space. Int J Dermatol 2014; 53(9): 1125-6.
Kirkwood JM, Richards T, Zarour HM, Sosman J, Ernstoff M, Whiteside TL, et al. Immunomodulatory effects of high-dose and low-dose interferon alpha2b in patients with high-risk resected melanoma: The E2690 laboratory corollary of intergroup adjuvant trial E1690. Cancer 2002; 95(5): 1101-12.
Di Trolio R, Simeone E, Di Lorenzo G, Buonerba C, Ascierto PA. The use of interferon in melanoma patients: A systematic review. Cytokine Growth Factor Rev 2015; 26(2): 203-12.
Eggermont AMM, Spatz A, Robert C. Cutaneous melanoma. Lancet Lond Engl 2014; 383(9919): 816-27.
Balch CM, Gershenwald JE, Soong S-J, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol Off J Am Soc Clin Oncol 2009; 27(36): 6199-206.
Balch CM, Gershenwald JE, Soong S-J, Thompson JF, Ding S, Byrd DR, et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: Comparison of nodal micrometastases versus macrometastases. J Clin Oncol Off J Am Soc Clin Oncol 2010; 28(14): 2452-9.
Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: A systematic review and meta-analysis. J Natl Cancer Inst 2010; 102(7): 493-501.
Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: First analysis of intergroup trial1690/S9111/C9190. J Clin Oncol Off J Am Soc Clin Oncol 2000; 18(12): 2444-58.
Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol Off J Am Soc Clin Oncol 1996; 14(1): 7-17.
Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: Results of intergroup trial E1694/S9512/C509801. J Clin OncolOff J Am Soc Clin Oncol 2001; 19(9): 2370-80.
Tannir NM, Cohen L, Wang X, Thall P, Mathew PF, Jonasch E, et al. Improved tolerability and quality of life with maintained efficacy using twice-daily low-dose interferon-alpha-2b: Results of a randomized Phase II trial of low-dose versus intermediate-dose interferon-alpha-2b in patients with metastatic renal cell carcinoma. Cancer 2006; 107(9): 2254-61.
Eggermont AMM, Suciu S, Santinami M, Testori A, Kruit WHJ, Marsden J, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: Final results of EORTC 18991, a randomised Phase III trial. Lancet Lond Engl 2008; 372(9633): 117-26.
Daud A, Soon C, Dummer R, Eggermont AMM, Hwu W-J, Grob JJ, et al. Management of pegylated interferon alpha toxicity in adjuvant therapy of melanoma. Expert Opin Biol Ther 2012; 12(8): 1087-99.
Eggermont AMM, Suciu S, Testori A, Santinami M, Kruit WHJ, Marsden J, et al. Long-term results of the randomized Phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin OncolOff J Am Soc Clin Oncol 2012; 30(31): 3810-8.
Zibelman M, Plimack E, Grahn A, Devane JG, Sherman JW. Combination of immunomodulatory agent with PD-1 or PD-L1 checkpoint inhibitors in the treatment of cancer. US20170021019. (2017).
O’Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: A multicenter single-arm Phase II study. Ann OncolOff J Eur Soc Med Oncol 2010; 21(8): 1712-7.
Calabrò L, Danielli R, Sigalotti L, Maio M. Clinical studies with anti-CTLA-4 antibodies in non-melanoma indications. Semin Oncol 2010; 37(5): 460-7.
Di Giacomo AM, Biagioli M, Maio M. The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications. Semin Oncol 2010; 37(5): 499-507.
Hoos A, Ibrahim R, Korman A, Abdallah K, Berman D, Shahabi V, et al. Development of ipilimumab: Contribution to a new paradigm for cancer immunotherapy. Semin Oncol 2010; 37(5): 533-46.
Ascierto PA, Marincola FM, Ribas A. Anti-CTLA4 monoclonal antibodies: The past and the future in clinical application. J Transl Med 2011; 9: 196.
Lin R, Yellin MJ, Lowy I, Safferman A, Chin K, Ibrahim R. 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 Oncol 2008; 26(Suppl. 15): 9063.
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711-23.
Maio M, Grob J-J, Aamdal S, Bondarenko I, Robert C, Thomas L, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a Phase III trial. J Clin Oncol Off J Am Soc Clin Oncol 2015; 33(10): 1191-6.
Eggermont AMM, Chiarion-Sileni V, Grob J-J, Dummer R, Wolchok JD, Schmidt H, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, Phase 3 trial. Lancet Oncol 2015; 16(5): 522-30.
Hadden J, Berinstein N, Egan J. Uses of Pd-1/Pd-L1 inhibitors and/or CTLA-4 inhibitors with a biologic containing multiple cytokine components to treat cancer. WO2018035395. (2018).
Luke JJ, Ott PA. PD-1 pathway inhibitors: The next generation of immunotherapy for advanced melanoma. Oncotarget 2015; 6(6): 3479-92.
Callahan MK, Wolchok JD. At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J Leukoc Biol 2013; 94(1): 41-53.
Weber JS, Postow M, Lao CD, Schadendorf D. Management of adverse events following treatment with anti-programmed death-1 agents. The Oncologist 2016; 21(10): 1230-40.
Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, et al. safety profile of nivolumab monotherapy: A pooled analysis of patients with advanced melanoma. J Clin Oncol Off J Am Soc Clin Oncol 2017; 35(7): 785-92.
Papadopoulos N, Murphy A, Thurston G, IoffE E, Burova E. Human antibodies to Pd-1. US987500. (2018).
Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372(4): 320-30.
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015; 372(26): 2521-32.
Robert C, Long GV, Schachter J, Arance A, Grob JJ, Mortier L, et al. Long-term outcomes in patients (Pts) with ipilimumab (Ipi)-naive advanced melanoma in the Phase 3 KEYNOTE-006 study who completed pembrolizumab (pembro) treatment. J Clin Oncol 2017; 35(Suppl. 15): 9504.
Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017; 377(19): 1824-35.
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373(1): 23-34.
Robert C, Ghiringhelli F. What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma? The Oncologist 2009; 14(8): 848-61.
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 2002; 99(19): 12293-7.
Yu Z, Si L. Immunotherapy of patients with metastatic melanoma. Chin Clin Oncol 2017; 6(2): 20.
Feng Y, Masson E, Dai D, Parker SM, Berman D, Roy A. Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma. Br J Clin Pharmacol 2014; 78(1): 106-17.
Loo LN, Shi S. Anti-pembrolizumab antibodies. US20170089914. (2017).
VigiAccessTM. Available at:. (Accessed on July 14, 2018)
Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 2007; 26(22): 3291-310.
Zambon A, Niculescu-Duvaz I, Niculescu-Duvaz D, Marais R, Springer CJ. Small molecule inhibitors of BRAF in clinical trials. Bioorg Med Chem Lett 2012; 22(2): 789-92.
Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2006; 2(7): 358-64.
Traxler P, Furet P. Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. Pharmacol Ther 1999; 82(2-3): 195-206.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364(26): 2507-16.
Ascierto PA, Bastholt L, Hersey P, Cinat G, Eggermont AMM, Hauschild A, et al. Side effects and toxicities of targeted therapies in stage IV melanoma. Am J Ther 2015; 22(1): 44-53.
Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012; 366(8): 707-14.
Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma. J Clin Oncol 2012; 30(Suppl. 18).LBA8500
Welsh SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol 2015; 7(2): 122-36.
Garraray LN, Emery C. BRAF mutations conferring resistance to BRAF inhibitors. EP3028699 . (2016).
Kramkimel N, Thomas-Schoemann A, Sakji L, Golmard J, Noe G, Regnier-Rosencher E, et al. Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma. Target Oncol 2016; 11(1): 59-69.
Amin A, Lawson DH, Salama AKS, Koon HB, Guthrie T, Thomas SS, et al. Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma. J Immunother Cancer 2016; 4: 44.
Davies MA, Saiag P, Robert C, Grob J-J, Flaherty KT, Arance A, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): A multicentre, multicohort, open-label, Phase 2 trial. Lancet Oncol 2017; 18(7): 863-73.
Hauschild A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, Phase 3 randomised controlled trial. Lancet 2012; 380(9839): 358-65.
Kefford R, Arkenau H, Brown MP, Millward M, Infante JR, Long GV, et al. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. J Clin Oncol 2010; 28(Suppl. 15): 8503.
Ascierto PA, Minor D, Ribas A, Lebbe C, O’Hagan A, Arya N, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol 2013; 31(26): 3205-11.
Delord J-P, Robert C, Nyakas M, McArthur GA, Kudchakar R, Mahipal A, et al. Phase I dose-escalation and -expansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma. Clin Cancer Res Off J Am Assoc Cancer Res 2017; 23(18): 5339-48.
Dummer R, Ascierto PA, Gogas H, Arance A, Mandala M, Liszkay G, et al. Results of COLUMBUS Part 2: A Phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) versus ENCO in BRAF-mutant melanoma. Ann Oncol 2017; 28(Suppl. 5).
Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367(2): 107-14.
Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: A Phase 1 dose-escalation trial. Lancet Oncol 2012; 13(8): 773-81.
Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, et al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol 2013; 31(4): 482-9.
Morrison S, Eskiocak U. Treatment for melanoma. US9572828 . (2017).
Eskiocak U, Ramesh V, Gill JG, Zhao Z, Yuan SW, Wang M, et al. Synergistic effects of ion transporter and MAP kinase pathway inhibitors in melanoma. Nat Commun 2016; 7: 12336.
López-Lázaro M. Digitoxin as an anticancer agent with selectivity for cancer cells: Possible mechanisms involved. Expert Opin Ther Targets 2007; 11(8): 1043-53.
Frankel AE, Eskiocak U, Gill JG, Yuan S, Ramesh V, Froehlich TW, et al. Digoxin plus trametinib therapy achieves disease control in BRAF wild-type metastatic melanoma patients. Neoplasia 2017; 19(4): 255-60.
Rosen LS, LoRusso P, Ma WW, Goldman JW, Weise A, Colevas AD, et al. A first-in-human Phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Invest New Drugs 2016; 34(5): 604-13.
Lieu CH, Hidalgo M, Berlin JD, Ko AH, Cervantes A, LoRusso P, et al. A Phase Ib dose‐escalation study of the safety, tolerability, and pharmacokinetics of cobimetinib and duligotuzumab in patients with previously treated locally advanced or metastatic cancers with mutant KRAS. The Oncologist 2017; 22(9): 1024. e89
Amaral T, Nouri N, Garbe C. The safety and efficacy of cobimetinib for the treatment of BRAF V600E or V600K melanoma. Expert Rev Anticancer Ther 2016; 16(7): 705-15.
Chapman PB, Robert C, Larkin J, Haanen JB, Ribas A, Hogg D, et al. Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: Final overall survival results of the randomized BRIM-3 study. Ann Oncol Off J Eur Soc Med Oncol 2017; 28(10): 2581-7.
Heinzerling L, Eigentler TK, Fluck M, Hassel JC, Heller-Schenck D, Leipe J, et al. Tolerability of BRAF/MEK inhibitor combinations: Adverse event evaluation and management. ESMO Open 2019; 4(3) e000491
Lugowska I, Koseła-Paterczyk H, Kozak K, Rutkowski P. Trametinib: A MEK inhibitor for management of metastatic melanoma. OncoTargets Ther 2015; 8: 2251-9.
Bendell JC, Javle M, Bekaii-Saab TS, Finn RS, Wainberg ZA, Laheru DA, et al. A Phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Br J Cancer 2017; 116(5): 575-83.
Dummer R, Ascierto PA, Gogas H, Arance A, Mandala M, Liszkay G, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): A multicentre, open-label, randomised Phase 3 trial. Lancet Oncol 2018; 19(5): 603-15.
Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012; 366(3): 207-15.
Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372(1): 30-9.
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, Phase 3 randomised controlled trial. Lancet 2015; 386(9992): 444-51.
Ascierto PA, Streicher HZ, Sznol M. Melanoma: a model for testing new agents in combination therapies. J Transl Med 2010; 8: 38.
Paraiso KHT, Fedorenko IV, Cantini LP, Munko AC, Hall M, Sondak VK, et al. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer 2010; 102(12): 1724-30.
Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: Long-term survival and safety analysis of a Phase 3 study. Ann Oncol 2017; 28(7): 1631-9.
Grob JJ, Flaherty K, Long GV, Nathan PD, Schadendorf D, Ribas A, et al. Pooled analysis of safety over time and link between adverse events and efficacy across combination dabrafenib and trametinib (D+T) registration trials. J Clin Oncol 2016; 34(Suppl. 15): 9534-34.
Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): Updated efficacy results from a randomised, double-blind, Phase 3 trial. Lancet Oncol 2016; 17(9): 1248-60.
Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in Stage III BRAF-mutated melanoma. N Engl J Med 2017; 377(19): 1813-23.
Russo I, Zorzetto L, Chiarion Sileni V, Alaibac M. Cutaneous side effects of targeted therapy and immunotherapy for advanced melanoma. Scientifica (Cairo) 2018; 2018 5036213
Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): Results of a Phase 3, open-label, randomised trial. Lancet Oncol 2015; 16(13): 1389-98.
Daud A, Gill J, Kamra S, Chen L, Ahuja A. Indirect treatment comparison of dabrafenib plus trametinib versus vemurafenib plus cobimetinib in previously untreated metastatic melanoma patients. J Hematol Oncol 2017; 10(1): 3.
Boespflug A, Thomas L. Cobimetinib and vemurafenib for the treatment of melanoma. Expert Opin Pharmacother 2016; 17(7): 1005-11.
Dréno B, Ribas A, Larkin J, Ascierto PA, Hauschild A, Thomas L, et al. Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study. Ann Oncol 2017; 28(5): 1137-44.
Eroglu Z, Ribas A. Combination therapy with BRAF and MEK inhibitors for melanoma: Latest evidence and place in therapy. Ther Adv Med Oncol 2016; 8(1): 48-56.
Morrison S, Piskounova E, Eskiocak U. Combination treatments for melanoma. US9561245 . (2017).
Wang J, Chen J, Miller DD, Li W. Compounds for treatment of cancer. US10022356 . 2018.
FDA Highlights on prescribing informations - Cotellic (Cobimetinib). Available at:. (Accessed on August, 3, 2018.)
Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol Off J Am Soc Clin Oncol 2006; 24(26): 4340-6.
Smalley KSM, Sondak VK, Weber JS. c-KIT signaling as the driving oncogenic event in sub-groups of melanomas. Histol Histopathol 2009; 24(5): 643-50.
Smalley KSM, Nathanson KL, Flaherty KT. Genetic subgrouping of melanoma reveals new opportunities for targeted therapy. Cancer Res 2009; 69(8): 3241-4.
Haq R, Fisher DE, Widlund HR. Combinatorial compositions and methods for treatment of melanoma. US9937161. (2018).
Becker JC, Bröcker EB, Schadendorf D, Ugurel S. Imatinib in melanoma: A selective treatment option based on KIT mutation status? J Clin Oncol 2007; 25(7) e9
Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 2011; 29(21): 2904-9.
Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman R-A, Teitcher J, et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011; 305(22): 2327-34.
Orouji E, Utikal J. Trackling malignant melanoma epigenetically: Histone lysine methylation. Clin Epigenetics 2018; 10(1): 145.
Garmpis N, Damaskos C, Garmpi A, Dimitroulis D, Spartalis E, Margonis GA, et al. Targeting histone deacetylases in malignant melanoma: A future therapeutic agent or just great expectations? Anticancer Res 2017; 37(10): 5355-62.
Boloor A, Kanouni T, Veal JM, Wallace MB. Histone demethylase inhibitors. US10202381. (2018).
Boloor A, Cheng YC, Wallace MB. Histone demethylase inhibitors. US10106534 . (2018).
Bissonette RP, Rolland A, Gillings M. Combination therapies of HDAC inhibitors and PD-1 inhibitors. US10287353 . (2019).

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy