For prevention, the use of non-comedogenic emollient creams is recommended, along with other skin care measures (Table 3) (5,D).33,35 Some clinical practice guidelines recommend considering oral antibiotics such as doxycycline, with or without low- to moderate-potency topical corticosteroids, on the face and chest for 6 weeks from treatment initiation (2b,B).26,35

Regarding the management of grade 1–2 rash, initiation or increased potency of topical corticosteroids is recommended (2b,B),26 although prolonged use is not recommended in our practice (5,D). On the face, topical antibiotics such as clindamycin or erythromycin may be considered (4,C).32,34,35 Additionally, clinical practice guidelines recommend initiating or continuing oral antibiotics from the tetracycline family (e.g., doxycycline) for at least 6 weeks (2b,B).26 If tetracyclines are contraindicated, cephalexin, cefadroxil, trimethoprim-sulfamethoxazole33,35 or macrolides (azithromycin, clarithromycin)32,33 are recommended. In our experience, grade 1–2 cases may be managed with topical antibiotics, whereas in grades ≥2, low-dose oral isotretinoin (typically 5mg/day, not combined with tetracyclines) is widely used. Doxycycline is effective, but chronic use is not recommended. Therefore, we consider low-dose oral isotretinoin preferable for chronic management (5,D).26,36

Some clinical practice guidelines recommend avoiding topical acne treatments (e.g., benzoyl peroxide, retinoids, azelaic acid, or alpha-hydroxy acids) (5,D).33,35 In our opinion, benzoyl peroxide may be used in combination with topical antibiotics, not as monotherapy, or low-dose isotretinoin (never combined with doxycycline) (5,D). In any case, these treatments may cause xerosis and irritation and should be used with caution (5,D).

In cases of grade 3–4 rash, short regimens of systemic corticosteroids are recommended (e.g., prednisone 0.5–1mg/kg for 7 days followed by gradual tapering over 4–6 weeks), and temporary interruption of MEKi treatment should be considered (2b,B).26,35 Additional options for grade ≥3 eruptions (with limited evidence) include oral retinoids (isotretinoin, acitretin) (4,C) or dapsone (4,C).26,36 Our routine practice is to use oral corticosteroids combined with isotretinoin for a limited period in severe inflammatory cases.

Chronic oral antibiotics (typically doxycycline or azithromycin) may also be maintained along with low-dose isotretinoin when the antibiotic is not a tetracycline. Both oral isotretinoin and MEKi may be associated with elevated serum creatine phosphokinase (CPK) levels, so periodic monitoring is recommended (5,D).

If superinfection is suspected—due to lack of response to antibiotics, painful lesions, pustules on extremities/trunk, or honey-colored crusts—bacterial culture is recommended, and antibiotics should be initiated for at least 14 days according to antibiogram results, covering gram-positive organisms (2b,B).26

Treatment recommendations are summarized in Fig. 1.

In mild cases, drying lotions with zinc may be used; if there is no response, topical corticosteroids plus antibiotics are recommended (5,D). Antibiotic monotherapy is not recommended (5,D). Clindamycin lotion may be applied to affected areas, along with a germicidal skin cleanser such as chlorhexidine for daily bathing. For moderate-to-severe folliculitis, oral antibiotics are recommended (4,C).28 In these cases, isotretinoin is less effective than for facial acneiform reactions.32

Management of these symptoms is similar to that of other patients with eczema. We recommend short daily showers, hydration, and application of low-potency topical corticosteroids initially.32 Topical pimecrolimus has also been recommended (4,C).28 For facial involvement, low-potency topical corticosteroids should be used initially for a short period (5,D).32

For progressive eczematous eruptions, medium- to high-potency topical corticosteroids may be used once or twice daily until resolution (usually within 5–7 days) (4,C).28,34

If scalp involvement occurs, moderate- to high-potency corticosteroids in solution or shampoo form may be considered (4,C).32 An oral antihistamine may be added for pruritus control regardless of severity (4,C)34 (Fig. 3).

The management of xerosis should be adapted to the degree of severity and should always begin with general preventive measures (Table 3) (5,D).33,35

In mild-to-moderate cases (grade 1–2), it is advisable to reinforce skin care by avoiding long, hot showers or baths, saunas, and scented soaps. Hydration should be intensified with emollients containing humectants such as 5–10% urea or lactic acid, or greasy ointments containing petrolatum or cholesterol applied at least twice daily, except on the face/upper trunk. In winter, the use of humidifiers may help prevent dryness. If scaling persists, it is advisable to reinforce the use of humectants and always choose fragrance-free products with gentle ingredients. In the presence of eczema, lichenification, or fissures, it may be necessary to add topical corticosteroids to the affected areas (4,C).33,35

When xerosis is severe (grade 3–4), treatment should be intensified. Some clinical practice guidelines recommend adding medium- to high-potency topical corticosteroids and, in severe cases, considering a short course of oral corticosteroids (5,D).35 In our opinion, hydration is the treatment for xerosis. We do not recommend using topical or oral corticosteroids (5,D).

In the presence of fissures, some guidelines recommend the use of liquid cyanoacrylate to promote healing, provided there are no allergies (4,C).35 However, fissures are a rare finding, and we do not recommend the use of liquid cyanoacrylate, which is an adhesive. If fissured eczema is present, it would be preferable to apply a high-potency topical corticosteroid (5,D) (Fig. 3).

As preventive measures, it is necessary to provide detailed instructions for nail care (Table 3) (5,D).26

Regarding treatment, if lesions remain localized, a conservative approach is recommended: high-potency topical corticosteroids as monotherapy or combined with topical antibiotics (4,C). For grade 1 and 2 paronychia, topical application of 2% povidone-iodine twice daily has shown benefit in retrospective series (4,C).37 In grade 2–4 paronychia, the use of oral antibiotics for 8 weeks is recommended, although evidence of their effectiveness is scarce (4,D).26,32,33,35

The options proposed in some guidelines for periungual pyogenic granuloma include silver nitrate once or twice weekly, topical beta-blocker (timolol 0.5% gel), topical trichloroacetic acid, cryotherapy, scraping or curettage, and electrodessication.33,35

In cases of intolerable grade 2 or grade 3–4 paronychia, or in the presence of persistent pyogenic granulomas, surgical treatment is indicated, including partial avulsion of the nail plate (or excision of a longitudinal segment of the nail together with the matrix) and physical destruction of excessive granulation tissue (4,C).26 This approach seeks to relieve pain, prevent infectious complications, and restore nail function.

As a therapeutic algorithm (Fig. 2), we propose management similar to that proposed by Palmeiro et al. (4,C).38 In mild cases, we recommend corticosteroids±topical antibiotics, and in more severe cases, oral antibiotics such as doxycycline (100mg/12h in adults or 100mg/24h in children>8 years) or azithromycin (25–50mg/kg/day in children≤8 years). In cases of pyogenic granulomas, we recommend topical timolol 0.5%, and in severe and persistent cases, surgery with avulsion and partial matricectomy.32

Patient education and prevention are the cornerstones of the management of photosensitivity (Table 3) (5,D).33,35 In cases where preventive measures fail, symptomatic treatment with topical or systemic corticosteroids may help reduce the impact of photosensitive eruptions on the patient's quality of life and allow continuation of treatment without the need to modify the dose (4,C)39,40 (Fig. 3).

Among hair changes, alopecia, hypertrichosis on the face and genitals, trichomegaly, and changes in hair texture such as curly and brittle hair or loose anagen syndrome in young children have been reported.7 All these hair changes usually appear later than other cutaneous AEs and may be reversible after discontinuation of therapy.7

It is necessary to inform the patient about the possibility of this cosmetic change and reassure them that it does not imply a decrease in the number of melanocytes or permanent damage to the skin or hair. No effective pharmacological measures have been described to prevent or treat this complication.

Pruritus may be prevented with appropriate skin care using creams and lotions containing 5–10% urea (4,C).35,41,42 Exposure to UV radiation should be avoided (Table 3) (4,C).35,41

For mild-to-moderate pruritus, the use of emollients containing humectants is recommended (4,C).35 Topical antipruritic agents such as 0.5% menthol, topical corticosteroids, lidocaine, pramoxine, topical doxepin, capsaicin, or camphor may be considered (4,C).26,33,35 Lotions with urea or polidocanol may also relieve pruritus (4,C),26 although, in our experience, their use is not common in clinical practice.

Although oral antihistamines are used to relieve mild-to-moderate pruritus, evidence in the context of targeted therapies is limited and is based mainly on case series. As first-line therapy, non-sedating second-generation antihistamines (such as loratadine) are recommended during the day, reserving first-generation agents (dexchlorpheniramine or hydroxyzine) for nocturnal pruritus because of their sedative effect (4,C).26

Antiepileptic drugs such as pregabalin or gabapentin have been shown to relieve pruritus in the general population. Pregabalin is believed to reduce pruritus at both the peripheral and central levels. However, data on pruritus associated with targeted oncologic therapies come from small case series, so they are recommended only as second-line agents in patients who do not respond to antihistamines (4,C).26 In our experience, their use is not usually necessary in the pediatric population.

Doxepin is a tricyclic antidepressant that is also a potent histamine antagonist and has been used to relieve generalized pruritus, both in topical and oral formulations (4,C).26,33,35 Aprepitant, a neurokinin-1 receptor antagonist, has been shown to reduce pruritus related to several targeted oncologic therapies (4,C).26,33,35 In cases of intense or generalized pruritus, oral corticosteroids or immunosuppressive therapy may be indicated (4,C)26,33,35 (Fig. 3). In our experience, none of these treatments has been necessary in the pediatric population; symptoms are usually controlled with antihistamines.

Although edema (mainly lymphedema) is a rare AE, it may lead to therapeutic failure and therefore requires a multidisciplinary approach, along with rehabilitation for the use of compression devices and lymphatic drainage (4,C).43

For prevention, it is essential that patients maintain good oral hygiene (Table 3) (5,D).33–35

Regarding treatment, 5% doxepin solution or 1–2% topical lidocaine may reduce pain. In addition, mouth rinses with topical corticosteroids may provide symptomatic relief (5,D).26,33 In mild cases, hyaluronic acid gel may be useful, adding triamcinolone acetonide 0.1%+lidocaine 2% in oral adhesive gel and a short course of oral corticosteroids in moderate or severe cases, respectively (4,C).32 Angular cheilitis may be treated with a topical cream containing corticosteroid+antifungal (4,C).32

Finally, it is essential to assess and treat secondary infections, such as those caused by herpes simplex virus or oral candidiasis. In severe cases, pain control and nutritional support are recommended (5,D)26 (Fig. 3).

Management of DRESS syndrome (Drug reaction with eosinophilia and systemic symptoms) requires immediate discontinuation of the causative or suspected drug as the primary therapeutic measure. Systemic corticosteroids are the first-line therapy, especially in moderate-to-severe cases, while topical corticosteroids may be used in patients with mild cutaneous involvement without mucosal involvement. In refractory cases or those with inadequate response to high-dose corticosteroids, immunosuppressive agents are used.44,45

Multidisciplinary collaboration is essential for the management of MEKi-induced cutaneous toxicity. Coordination among dermatologists, oncologists, specialized nursing staff, and other professionals allows early detection, comprehensive management, and personalization of therapeutic strategies according to the severity and type of toxicity.13 This approach facilitates the implementation of preventive measures, timely treatment adjustments, and continuous patient education, reducing the risk of interruptions and optimizing clinical outcomes,13 especially in a context where prospective evidence is limited and the clinical presentation of AEs is variable.28