Joel Claveau, MD, FRCPC, DABD;1 Vincent Ho, MD, FRCPC, FRCP (Lon);2 Teresa Petrella, MD, FRCPC3
1Centre Hospitalier Universitaire de Québec, Hôtel-Dieu de Québec, Melanoma and Skin Cancer Clinic, Quebec City, QC, Canada
2Department of Dermatologic Oncology, British Columbia Cancer Agency, and Department of Dermatology and Science, University of British Columbia, Vancouver, BC, Canada
3Division of Medical Oncology/Hematology, Odette Cancer Centre, Toronto, ON, Canada
The last couple of years have seen the beginning of a new era in the treatment of metastatic melanoma. This disease is typically characterized by its poor prognosis and limited choice of therapy. Two mechanistically diverse classes of agents – BRAF inhibitors and immune modulators – have demonstrated an overall survival benefit. Along with their significant clinical benefits, there are also unique adverse events (AEs) related to these agents. While most of the AEs are mild and easily managed with supportive treatment, others require more aggressive management strategies. Education of all members of the multidisciplinary care team and awareness of these toxicities are crucial in order to optimize patient outcomes. The landscape of melanoma is continually evolving as ongoing trials are evaluating monotherapy and combination options. While these regimens continue to show promise for the future, understanding and managing toxicities of currently available therapies is required.
antineoplastic agents, BRAF inhibitors, CTLA-4 antigen, immunomodulatory agents, lymphatic metastasis, melanoma, skin neoplasms
The management of metastatic melanoma constitutes an important medical challenge, as it accounts for more than 80% of skin cancer deaths, and its incidence has increased over the past decades worldwide.1 In 2013, an estimated 6,000 new cases of melanoma will be diagnosed in Canada and 1,050 deaths will be attributed to this disease.2 Its ability to disseminate to regional and distal sites results in a poor prognosis.3
While surgical treatment of early stage disease is often curative, metastatic melanoma carries a significantly less promising outlook with a high associated health burden and economic cost. A multidisciplinary approach optimizes the management of metastatic melanoma. Patients, including those with metastatic disease, often view their dermatologist as an integral part of their multidisciplinary team and turn to them for information and guidance in decision making. Further, an increasing number of dermatologists are playing a key role in coordinating the care of their patients with melanoma. For this reason, it is crucial for dermatologists to remain informed about treatment options for metastatic disease in order to provide patients with current information and to participate in the management of dermatologic adverse events (AEs) of various therapies.4
New Therapies for Metastatic Melanoma
Until very recently, approved treatment options for patients with metastatic melanoma were limited to chemotherapy and interleukin-2 (IL-2).5 Chemotherapy, particularly with dacarbazine (DTIC), has failed to show a survival benefit over supportive care,5 and treatment with IL-2, while associated with some durable responses, has significant toxicity.6
As a result, metastatic melanoma has become a focus for the development of novel treatment approaches including targeted and immunoregulatory therapies. Targeted therapy is directed toward c-KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homologue), BRAF (v-raf murine sarcoma viral oncogene homologue B), MEK (mitogen-activated protein kinase kinase), and NRAS (neuroblastoma RAS viral (v-ras) oncogene homologue). Of recent interest is vemurafenib – a highly selective inhibitor of mutated BRAF protein kinase – that has demonstrated improved survival in patients with metastatic melanoma. Immunoregulatory therapy targets include CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), PD1 (programmed cell death-1), and PDL1 (PD-Ligand 1),7 whereby disabling these proteins enhance the immune system’s ability to recognize and attack cancer cells. In particular, ipilimumab is a monoclonal antibody against CTLA-4, an inhibitor of T-cell activation. Ipilimumab potentiates an immune response rather than targets the tumor itself.8
Vemurafenib has demonstrated activity in patients with metastatic melanoma who harbor the V600E BRAF mutation. In the pivotal phase III trial (BRIM-3) of previously untreated patients, an early analysis of the data demonstrated a statistically significant benefit in overall survival (OS) with vemurafenib compared with DTIC (hazard ratio [HR] of 0.37; 95% confidence interval [CI]: 0.26-0.55; p<0.001) while the median OS had not yet been reached at the time of publication.9 Based on these findings, vemurafenib received Health Canada approval in 2012 for the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma.10 In a follow-up analysis of the BRIM-3 data with a data cutoff of February 1, 2012, the median OS for vemurafenib was 13.6 months versus 9.7 months for DTIC with an HR for death of 0.70 (95% CI: 0.57-0.87) in favor of vemurafenib.11*
Ipilimumab, in a pivotal phase III trial, demonstrated OS benefit when compared with a glycoprotein 100 vaccine in pretreated patients with unresectable or metastatic melanoma. The median OS was 10.1 months (95% CI: 8.0-13.8) compared with 6.4 months (95% CI: 5.5-8.7) in patients receiving the vaccine.12 In a second phase III trial of ipilimumab in treatment-naïve patients with unresectable stage III or IV melanoma, the OS benefit was reproduced when ipilimumab was combined with DTIC (median OS 11.2 months)13 resulting in approval by Health Canada in 2012.14
|The data shown here were presented at the American Society of Clinical Oncology annual meeting in 2012. They are the most current data available.|
Adverse Events (AEs)
With the approval of vemurafenib and ipilimumab, and increased research into related compounds, their use will rapidly become more widespread. While use of these agents can result in significant clinical benefits, they also have unique AEs. Most AEs are mild and can be managed with supportive treatment, but some require special management strategies.15 Furthermore, as some of the AEs are cutaneous in nature, dermatologists will increasingly be called upon for their expertise in managing them.16 As a result, the timely coordination and follow-up between members of the multidisciplinary care team will be important.
In the phase III BRIM-3 trial, the most common AEs observed with vemurafenib included grade 2 and 3 arthralgias (18% and 3%), rash (10% and 8%), photosensitivity (12% grade 2 or 3), fatigue (11% and 2%), cutaneous squamous cell carcinoma (SCC) (12%), keratoacanthoma (KA) (2% and 6%), nausea (7% and 1%), alopecia (8% grade 2), and diarrhea (5% and <1%). AEs led to dose interruption or modification in 38% of patients enrolled in the study.9
Broader experience outside of a phase III setting has demonstrated that the cutaneous AEs associated with vemurafenib therapy include a toxic erythema-like eruption, a keratosis pilaris-like eruption (Figure 1), which have been documented in as many as 20% of patients at one institution, and hyperkeratosis of hands/ feet (Figure 2).17 Photosensitivity (Figure 3) and the development of secondary cutaneous SCC/KA (Figure 4) are also relatively common.16 SCC/KA usually develops between weeks 2 and 14.15 It is generally well-differentiated with no metastatic potential and can be treated with surgical excision.18 At baseline, patients should have a thorough skin examination and be monitored regularly throughout treatment. A dermatologist should be consulted when any new skin lesions develop and excisions should be arranged.15 As far as the rash is concerned, daily use of a moisturizing cream could be used as a preventive measure. Mild-to-moderate eruptions are usually managed with moderate strength topical steroids prescribed in a sufficient amount. If the rash becomes severe, a dermatologist should be consulted for treatment recommendations.15 Table 1 summarizes some of the cutaneous AEs associated with BRAF inhibition and suggests management options.
|Adverse Event||Management Considerations|
|Toxic erythemalike eruptions||
|Papillomas (Figure 5)||
|Squamous cell carcinomas of the KA type||
|Alterations of nevi, melanomas||
|Table 1. Management options for cutaneous AEs associated with BRAF inhibition15,19-23
SPF = sun protection factor; UV = ultraviolet
|Figure 1: Keratosis pilaris-like eruption|
|Figure 2: Hyperkeratosis of feet|
|Figure 3: Photosensitivity|
|Figure 4: Secondary cutaneous SCC of the KA-type|
|Figure 5: Papillomas|
With respect to ipilimumab treatment, the AEs are immune response-related (irAEs) and cover a wide range of systems including dermatologic, gastrointestinal, hepatic, and endocrine. Of the irAEs, dermatologic toxicity is the most common and appears in weeks 2-4 of treatment. Dermatologic irAEs include pruritus, rash, and vitiligo and are reported in over 40% of patients for all grades, while grade 3 and 4 events are seen in 1-3% of patients.15
Patients should be monitored for signs and symptoms of dermatitis, such as rash and pruritis. For mild-to-moderate events, topical moisturizers, antipruritics, and oatmeal baths can be used to manage symptoms. If there is no improvement within one week, topical or systemic corticosteroids can be administered (0.5 mg/kg/day of prednisone or equivalent). No dose interruption is necessary for mild events but may be considered for moderateto- severe events. Severe events should be treated with systemic corticosteroids at 1-2 mg/kg/day of prednisone or equivalent. For patients with Stevens-Johnson syndrome, toxic epidermal necrosis, or rash complicated by full thickness dermal ulceration or necrotic, bulbous, or hemorrhagic manifestations, ipilimumab should be permanently discontinued, patients should ideally be taken in charge by specialized units, and systemic corticosteroids administered at the same dosage used to manage severe events. Corticosteroid tapering should occur over 4-6 weeks once symptoms improve to mild severity or resolve.14,15,24
A Paradigm Shift
As a result of the ability to identify specific mutations in a patient’s melanoma, the disease has recently earned the designation as “an unlikely poster child for personalized cancer therapy.”25 The treatment paradigm for metastatic melanoma is changing with the novel agents now available for treating this disease. As these agents transition from the clinical trial context to widespread clinical practice, and as newer therapies and combinations thereof continue to be studied, the multidisciplinary team will face challenges not only in the optimal choice of therapy for their patients, but also in the timely and aggressive management of their AEs. As the development of new anticancer agents accelerates, education and awareness of these AEs across disciplines is essential in order to ensure the safety of patients being treated with these drugs.
Development of resistance to these new agents has been demonstrated. To overcome this, it is important to understand the mechanisms of resistance. Early evidence provides a rationale for the combination of immune modulation with ipilimumab and BRAF inhibition with vemurafenib.15 However, there are a number of overlapping toxicities with these agents, particularly dermatologic AEs. Effective management strategies for these AEs will need to be developed concurrently with clinical investigations of efficacy in order to optimize patient outcomes.
The improvements in accuracy of predicting response to therapy will undoubtedly lead to better disease control, resulting in a renewed sense of hope in a therapeutic area that has historically had poor outcomes.
The authors acknowledge medical writing support from Diana Stempak, MSc, PhD and Cathie Bellingham, PhD of New Evidence; this support was funded by Hoffmann-La Roche.
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- Hamid O, Boasberg PD, Rosenthal K, et al. Systemic treatment of metastatic melanoma: new approaches. J Surg Oncol. 2011 Sep;104(4):425-9.
- Fox MC, Lao CD, Schwartz JL, et al. Management options for metastatic melanoma in the era of novel therapies: a primer for the practicing dermatologist: part I: management of stage III disease. J Am Acad Dermatol. 2013 Jan;68(1):1.e1-9.
- Maio M. Melanoma as a model tumour for immuno-oncology. Ann Oncol. 2012 Sep;23 Suppl 8:viii10-4.
- Petrella T, Quirt I, Verma S, et al. Single-agent interleukin-2 in the treatment of metastatic melanoma: a systematic review. Cancer Treat Rev. 2007 Aug 7;33(5): 484-96.
- Eggermont AM. Advances in systemic treatment of melanoma. Ann Oncol. 2010 Oct;21 Suppl 7:vii339-44.
- Andrews S, Holden R. Characteristics and management of immunerelated adverse effects associated with ipilimumab, a new immunotherapy for metastatic melanoma. Cancer Manag Res. 2012;4:299-307.
- Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun;364(26):2507-16.
- PrZELBORAF™ (vemurafenib) Product Monograph. Date of revision: December19, 2013. Hoffmann-La Roche, Mississauga, ON.
- Chapman PB, Hauschild A, Robert C, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30:8502.
- Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug;363(8):711-23.
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun;364(26):2517-26.
- PrYERVOY™ (ipilimumab) Product Monograph. Date of revision: October 21, 2013. Bristol-Myers Squibb Canada, Montreal, QC. Available at: http://www.bmscanada.ca/static/products/en/pm_pdf/Yervoy_EN_PM.pdf. Accessed January 26, 2014.
- Lemech C, Arkenau HT. Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities. Clin Med Insights Oncol. 2012;6:53-66.
- Fox MC, Lao CD, Schwartz JL, et al. Management options for metastatic melanoma in the era of novel therapies: a primer for the practicing dermatologist: part II: management of stage IV disease. J Am Acad Dermatol. 2013 Jan;68:13. e1-13.
- Huang V, Hepper D, Anadkat M, et al. Cutaneous toxic effects associated with vemurafenib and inhibition of the BRAF pathway. Arch Dermatol. 2012 May;148(5):628-33.
- Zimmer L, Vaubel J, Livingstone E, Schadendorf D. Side effects of systemic oncological therapies in dermatology. J Dtsch Dermatol Ges. 2012;10:475-86.
- Manousaridis I, Mavridou S, Goerdt S, et al. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereol. 2013 Jan;27(1):11-8.
- Haenssle HA, Kraus SL, Brehmer F, et al. Dynamic changes in nevi of a patient with melanoma treated with vermurafenib. Arch Dermatol. 2012 Oct;148(10):1183-5.
- Dalle S, Poulalhon N, Thomas L. Vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Oct;365(15):1448–50.
- Anforth R, Fernandez-Peñas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol. 2013 Jan;14(1):e11-8.
- Claveau J. Side effects of vemurafenib. In: Canadian Melanoma Conference. Banff, Alberta; 2013.
- Trinh VA, Hagen B. Ipilimumab for advanced melanoma: a phamacologic perspective. J Oncol Pharm Pract. 2013 Sep;19(3):195-201.
- Smalley KS, Sondak VK. Melanoma–an unlikely poster child for personalized cancer therapy. N Engl J Med. 2010 Aug;363(9):876-8.