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Cutaneous adverse effects of antimelanoma therapies

Author: Dr Peru Urigoitia-Ugalde, Onco-Dermatology Fellow; Prof Fernandez-Penas, Dermatologist, Westmead Hospital, NSW, Australia. DermNet NZ Editor in Chief: Adjunct A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. January 2020.


Introduction

The introduction of targeted cancer therapies and immunotherapy has revolutionised the management and prognosis of metastatic melanoma, significantly improving drug response rates and disease-free survival.

These drugs are associated with a range of adverse effects, and cutaneous toxicities are the most frequently observed.

Melanoma metastases

What are targeted therapies?

Targeted therapies (BRAF inhibitors and MEK inhibitors) are drugs to treat BRAF-mutant metastatic melanoma. Activating mutations in the BRAF gene are present in 50–70% of melanomas. The most common mutation occurs at position 600, where valine (V) is substituted by glutamic acid (E) (V600E) [1].

What is immunotherapy?

Immunotherapy includes anti-cytotoxic T lymphocyte antigen 4 (CTLA4) antibodies and programmed cell death protein 1 (PD1) antibodies. These drugs are used to treat metastatic melanoma, renal cell carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma, and others.

How do these drugs work?

Targeted therapies

Mutations in the BRAF gene lead to overactivation of the mitogen-activated protein kinase (MAPK) pathway, which plays a key role as a regulator of cell growth, differentiation, and survival. Inhibition of the BRAF kinase and the mitogen-activated extracellular signal-regulated kinase (MEK) leads to inhibition of cellular proliferation.

The mechanism behind most of the cutaneous toxicities associated with BRAF inhibitors is thought to be a paradoxical activation of the mitogen activated kinase (MAPK) in cells without the BRAF mutation, which leads to cellular hyperproliferation [2].

Immunotherapy

CTLA4 and PD1 are immune-checkpoint receptors that down-regulate T-cell immune function and promote self-tolerance.

  • The inhibition of these targets induces activation of the immune system and anti-tumour activity of cytotoxic T cells.
  • The induction of a tolerance break against the tumor may be responsible for the development of immune related adverse events [3].

What are the cutaneous adverse effects of targeted therapies?

BRAF inhibitors

BRAF inhibitors include vemurafenib and dabrafenib. Cutaneous adverse effects are common.

Hyperkeratotic keratinocytic lesions

Cutaneous squamous cell carcinoma (SCC) frequently occurs in patients treated with a BRAF inhibitor as single agent. The incidence decreases with the addition of a MEK inhibitor. The majority of the SCC develop during the first 3 months of therapy, in sun-damaged and non-sun-damaged locations. Most SCC are well-differentiated or are a keratoacanthoma type. Excision is the standard treatment with a high rate of cure. Oral acitretin can be used as a preventive agent, since it reduces epidermal proliferation and does not interfere with the action of the targeted therapy.

Verrucal keratosis presents as a hyperkeratotic papule resembling a viral wart or small keratoacanthoma. They are considered premalignant and therefore precursors to cutaneous SCC and should be monitored. Treatment options include cryotherapy or surgery. Acitretin can be used as a preventive therapy.

Transient acantholytic dermatosis

Transient acantholytic dermatosis (Grover disease) is a common cutaneous eruption associated with BRAF inhibitors. It presents on the trunk as rapid-onset, itchy papules with a crusted top. Treatment includes topical corticosteroids, keratolytic agents (such as urea and salicylic acid) and acitretin for long-term control.

Palmoplantar keratoderma

Palmoplantar keratoderma presents as hyperkeratotic plaques or calluses over areas of pressure or friction (mainly on the feet). Blisters are uncommon. The keratoderma can be very painful and limit the patient’s daily activities. Treatment with keratolytic agents (such as urea or salicylic acid) and potent topical corticosteroids are indicated (eg, clobetasol propionate ointment). Patients should be educated to avoid friction and to wear wide, comfortable shoes.

Adverse effects of targeted therapy

Melanocytic lesions

Changes in melanocytic lesions have been reported in patients on BRAF inhibitors, including the development of new naevi and regression or hyperpigmentation of existing naevi. An increased frequency of new primary melanoma has also been reported. These new melanomas have been shown to be wild type for the BRAF mutation, suggesting that paradoxical activation of the MAPK pathway may play a role [4].

Pruritus

Drug-induced pruritus is commonly reported in patients taking BRAF inhibitors. Pruritus can be secondary to drug-induced dry skin or transient acantholytic dermatosis. General measures such as the use of soap-free cleansers and emollients are recommended. Topical corticosteroids can be used if dermatitis arises.

Photosensitivity

Drug-induced photosensitivity is more commonly seen with vemurafenib than dabrafenib and is induced by exposure to ultraviolet (UV) A radiation. Sun protection, including the use of broad-spectrum high protection factor sunscreen, is recommended.

Other

Adverse effects of targeted therapy
 

MEK inhibitors

MEK inhibitors include trametinib and cobimetinib. These drugs are usually administered in combination with BRAF inhibitors.

Acneiform eruptions

Acneiform drug eruptions are the most common cutaneous adverse events associated with MEK inhibitor monotherapy, appearing in a seborrhoeic distribution (face, scalp, upper chest and back). Papules and pustules are present, but comedones are absent, unlike acne vulgaris. Oral tetracyclines (doxycycline, minocycline) and isotretinoin are used to prevent and treat acneiform eruptions.

Others

Drug-induced pruritus; topical corticosteroids may be used for symptomatic treatment.

Combination therapy

As melanoma started to develop resistance to single-agent BRAF inhibitors, MEK inhibitors were introduced as a combination therapy (dabrafenib + trametinib, vemurafenib + cobimetinib). The addition of a MEK inhibitor to a BRAF inhibitor improves the blockade of the mitogen-activated protein kinase (MAPK) pathway.

The combination increases response rates and shows an improved toxicity profile in comparison to monotherapy. There is a noticeable reduction in squamoproliferative lesions (cutaneous SCC, verrucal keratosis, acantholytic dermatosis, palmoplantar keratoderma), hair follicle changes, and acneiform eruptions [4,5].

Folliculitis

Folliculitis is the most common adverse effect of BRAF inhibitor and MEK inhibitor combination therapy and is usually mild. An antiseptic wash is usually sufficient to treat it [4].

What are the cutaneous adverse effects of immunotherapy?

Anti-CTLA4 antibody

The anti-CTLA4 antibody is ipilimumab.

Maculopapular exanthem

Ipilimumab commonly causes a maculopapular exanthem or morbilliform drug eruption. It is usually mild to moderate in severity, appearing on the trunk and extremities. Mild cases can be managed without discontinuation or dose reduction of ipilimumab. Topical corticosteroids or topical calcineurin inhibitors can be used. In more severe cases, ipilimumab should be discontinued and oral prednisone may be indicated.

Vitiligo-like depigmentation

Vitiligo-like depigmentation has been reported with ipilimumab. Patients should be educated about sun protection. An association between the development of vitiligo and better disease prognosis has been reported in multiple studies [5].

Others

Other cutaneous adverse effects of immunotherapy can include:

Anti-PD1 antibodies

Anti-PD1 antibodies include nivolumab and pembrolizumab.

They are better tolerated than anti-CTLA4 antibodies. However, anti-PD1 antibodies show similar immune-related adverse reactions [4,6]. The types of reactions can include:

See also Cutaneous adverse effects of checkpoint inhibitors.

Adverse reactions to immunotherapy

Combination therapy

The combination of anti-CTLA4 and anti-PD1 antibodies shows superior efficacy compared to monotherapy, but it is also associated with an increase in adverse events [7]. The most common is drug-induced pruritus. Others include morbilliform eruption and lichenoid drug eruption. Severe cutaneous adverse reactions such as acute generalised exanthematous pustulosis (AGEP) have been reported.

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Related information

 

References

  1. Eggermont AM, Spatz A, Robert C. Cutaneous melanoma. Lancet 2014; 383(9919): 816–27. PubMed
  2. Carlos G, Anforth R, Clements A, Menzies AM, Carlino MS, Chou S, Fernandez-Peñas P. Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma. JAMA Dermatol 2015; 151: 1103–9. PubMed
  3. Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med 2015; 13: 211. PubMed
  4. Hwang SJ, Anforth R, Carlos G, Fernandez-Peñas P. Cutaneous Adverse Events of New Anti-melanoma Therapies: Classification and Management. Actas Dermosifiliogr 2017; 108: 6–16. PubMed
  5. Liu RC, Consuegra G, Fernandez-Peñas P. Management of the cutaneous adverse effects of antimelanoma therapy. Melanoma Manag 2017; 4: 187–202. PubMed Central
  6. Hwang SJ, Carlos G, Wakade D, Byth K, Kong BY, Chou S, Carlino MS, Kefford R, Fernandez-Peñas P. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: A single-institution cohort. J Am Acad Dermatol 2016; 74: 455–61.e1. PubMed
  7. Hassel JC, Heinzerling L, Aberle J, Bähr O, Eigentler TK, Grimm MO, Grünwald V, Leipe J, Reinmuth N, Tietze JK, Trojan J, Zimmer L, Gutzmer R. Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. Cancer Treat Rev 2017; 57: 36–49. PubMed

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