Abstract
The advent of protein kinase inhibitors and immunotherapy has profoundly improved the management of advanced melanoma. However, with these therapeutic advancements also come drug-related toxicities that have the potential to affect various organ systems. We review dermatologic adverse events from targeted (including BRAF and MEK inhibitor-related) and less commonly used melanoma treatments, with a focus on diagnosis and management. As immunotherapy-related toxicities have been extensively reviewed, herein, we discuss injectable talimogene laherparepvec and touch on recent breakthroughs in the immunotherapy space. Dermatologic adverse events may severely impact quality of life and are associated with response and survival. It is therefore essential that clinicians are aware of their diverse presentations and management strategies.
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Systemic melanoma treatments have improved survival in patients but are associated with significant specific dermatologic adverse events. |
Dermatologic adverse events from melanoma treatments are common, and prompt recognition and management can improve patient quality of life and cancer outcomes. |
1 Introduction
Melanoma is the fifth most common cancer in the USA, representing 5.2% of all new cancer diagnoses [1, 2]. An estimated 2.1% of the population is expected to develop melanoma during their lifetime, with the incidence increasing in the USA [2]. While new cases have been on the rise, the death rates have slowly been in decline [1, 2]. Improvements in earlier-stage detection, as well as new treatment options, especially for patients with advanced-stage melanoma, are contributing to this improvement. Systemic therapies for advanced melanoma include inhibitors of V-raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen and extracellular-regulated protein kinase (MEK); talimogene laherparepvec (T-VEC); and immune checkpoint inhibitors (ICIs); with additional novel therapies in clinical trials. However, these therapies are not without side effects, and specific dermatologic adverse events (dAEs) are associated with each drug class. The range of clinical presentations is diverse, and when severe, can result in treatment discontinuation. Interestingly, these dAEs are also often associated with therapeutic response. In this review, we will focus on the diagnosis and management of dermatologic adverse events (dAEs) from melanoma therapies, so that dermatologists and oncologists will be positioned to best identify the culprit agent and mitigate toxicity, improving both melanoma and quality-of-life-threatening outcomes.
2 Targeted Therapies: BRAF and MEK Inhibitors
Among the revolutionary advancements in metastatic melanoma treatment in the last decade are drugs targeting BRAF and MEK. BRAF and MEK are two protein kinases involved in the Ras/Raf/MEK mitogen-activated protein kinase (MAPK) cell signaling pathway for cell replication and growth (Fig. 1). Mutations anywhere along this pathway, especially in BRAF and MEK genes, can result in uncontrolled cell growth and division, leading to tumorigenesis [3, 4]. Fifty percent of patients with metastatic melanoma have BRAF mutations, with 80% of the mutations caused by the substitution of valine by glutamic acid at position 600 (BRAF V600E) [3]. This mutation induces a 500-fold increase in BRAF activity. Patients with BRAF V600E mutations respond to both BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi). Mutations substituting valine for lysine (V600K) comprise around 15% of BRAF mutations and also respond to BRAF and MEK inhibition. BRAFi (dabrafenib, vemurafenib, encorafenib) and MEKi (trametinib, cobimetinib, binimetinib) stop oncogenic signaling. Their implementation has led to improved survival in patients [5,6,7]. Somatic testing is recommended for patients with stage III and IV melanoma to guide treatment. These therapies individually have notable, specific dAEs. However, BRAFi and MEKi are now rarely used as monotherapy in the treatment of melanoma, as combination therapy with these two classes of drugs increases efficacy and decreases adverse events [8]. Nonetheless, the clinical experience of their use in melanoma treatment has been helpful for understanding adverse events when these medications are used as monotherapy in other malignancies. Skin toxicities from BRAF and MEK inhibitors and management strategies are summarized in Table 1 [9].
The RAS/RAF/MEK/ERK pathway is activated when a ligand binds to a growth factor or cytokine receptor, inducing the binding of the protein Grb2 with SOS, a guanine nucleotide exchange factor (not shown). SOS exchanges GDP for GTP on RAS (HRAS, NRAS, and KRAS), a GTPase on the inner plasma membrane. This conformation induces RAS activation, leading to the recruitment and subsequent activation of the protein kinase RAF (ARAF, BRAF, and CRAF), initiating a phosphorylation signaling cascade with sequential phosphorylation of MEK (MEK1 and MEK2), MAPK, and MYC. The latter translocates into the nucleus and upregulates genes involved in cell growth and division. Mutations anywhere along this pathway, especially in BRAF and MEK genes, can result in uncontrolled cell growth and division, leading to tumorigenesis
2.1 BRAFi (Vemurafenib, Dabrafenib, Encorafenib)
dAEs impact up to 95% of patients on BRAFi monotherapy [10]. Other important adverse effects include fever, headache, arthralgia, and fatigue [11]. Here, we focus on the most common dAEs, though awareness of other toxicities can help identify the culprit drug in patients on combination therapy.
2.1.1 Inflammatory Reactions
2.1.1.1 Maculopapular/Morbilliform Eruptions
Transient morbilliform eruptions are the earliest eruptions that arise and are common dAE form BRAF inhibition [10]. The eruption is pruritic and includes both macules and papules, expanding centripetally from the trunk [12]. Patients with morbilliform eruptions should undergo laboratory evaluation to assess for evidence of systemic hypersensitivity, including complete blood count with differential, transaminases, and urinalysis to look for eosinophilia, hepatic involvement, and nephritis, respectively. If symptomatic, topical steroids, oral antihistamines, and emollients may be considered as first-line treatment [10, 12]. For higher-grade reactions, those not responsive to topical steroids and antihistamines, or in cases associated with systemic hypersensitivity, oral steroids may be considered, with dose reduction and treatment discontinuation reserved as last-line intervention [10, 12].
2.1.1.2 Severe Cutaneous Adverse Reactions
While most morbilliform exanthems are overall benign behaving, evaluation for severe cutaneous adverse reactions (SCAR), such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), is warranted [13,14,15]. If an eruption is accompanied by edema or lymphadenopathy and DRESS is suspected, the following labs can be obtained to aid in the diagnosis: a complete blood count (CBC) with differential to evaluate for atypical lymphocytes, eosinophilia, thrombocytopenia, and other hematological disorders; a complete metabolic panel to evaluate liver and kidney involvement; and viral serologies, including human herpesvirus 6 (HHV-6), Epstein–Barr virus (EBV), and cytomegalovirus (CMV) [16]. When SJS/TEN is on the differential, physical examinations should evaluate for skin tenderness, erosions, bullae, and mucosal involvement; importantly, these reactions are exceedingly rare. We also recommend early skin biopsy, such as fresh frozen or STAT formalin-fixed to rapidly assess for full thickness epidermal necrosis when SJS/TEN is suspected. Grade 4 cutaneous side effects, including DRESS requiring hospitalization and SJS/TEN require collaborative management between dermatology, oncology, and additional consultants as needed. Cancer treatment interruption or discontinuation is almost always required.
2.1.1.3 Acneiform/Papulopustular Eruptions
Papulopustular eruptions also present early during therapy and are less common than morbilliform drug eruptions when combination therapy is used [17]. The eruptions are similar to those seen with epidermal growth factor inhibitors (EGFRi), consisting of inflammatory pustules and open and closed comedones, but can present more diffusely, most commonly on the face and trunk (Fig. 2) [17]. Management of acneiform eruptions includes topical steroids (triamcinolone 0.1% for the body, hydrocortisone 2.5% for the face), topical clindamycin lotion, and may include metronidazole cream, mupirocin, and/or tretinoin 0.05% cream in certain circumstances, depending on the pattern of involvement and degree of dryness [18, 19]. Doxycycline or minocycline can be added for more severe cases. If the eruption is refractory to these measures, low-dose oral acitretin (10 mg every other day to daily), isotretinoin (10–20 mg daily), or oral steroids can be considered [12, 20, 21]. For more severe eruptions (grade 3 and above), therapy interruption can be considered while toxicities are addressed [18, 22].
BRAF inhibitor acneiform eruption (Photo courtesy of Nicole LeBoeuf, MD, MPH)
2.1.1.4 Panniculitis
The development of neutrophilic panniculitis, which presents as tender, subcutaneous nodules most commonly on the lower legs (Fig. 3), is a rare side effect of BRAFi that can occur as early as 1 week after treatment initiation and clinically resembles erythema nodosum (EN) [23,24,25,26]. Evaluation of patients with EN-like lesions should include an inquiry of symptoms including concomitant arthralgias, fever, and myalgias; and laboratory workup consisting of CBC, C-reactive protein, creatine kinase, and a complete metabolic panel [23]. A skin biopsy is warranted and should be considered to ensure no subcutaneous metastases of melanoma, or other etiologies such as vasculitis [23]. Conservative management is generally sufficient for first-line management of panniculitis. Nonsteroidal antiinflammatory drugs should be initiated early to decrease the risk of anticancer therapy interruption [26]. Topical and intralesional corticosteroids can also be employed as a treatment strategy [23]. If treatment escalation is needed, oral corticosteroids, such as prednisone (as low as 5 mg daily is often sufficient) until nodule resolution, can be considered [27]. Interruption in therapy or dose reduction in BRAFi may also be needed, with re-escalation once symptoms have sufficiently improved [23].
BRAF inhibitor panniculitis (Photo courtesy of Nicole LeBoeuf, MD, MPH)
2.1.1.5 Sweet’s-Like Dermatosis
Sweet’s syndrome is a neutrophilic disorder and rare side effect of BRAFi [28, 29]. Patients present with abrupt-onset, asymmetric, tender erythematous juicy plaques and nodules most commonly on the upper extremities [30]. Extracutaneous manifestations include pyrexia, arthralgias, headache, fatigue, and conjunctivitis [30]. This condition can be drug induced, as with BRAFi, malignancy associated, especially with hematological cancers, and autoimmune associated. Biopsy is diagnostic and is characterized by papillary dermal edema with neutrophils in the reticular dermis without vasculitis [31]. Systemic corticosteroids are considered first-line treatment, and antineutrophilic agents, such as dapsone or colchicine, can be considered as steroid-sparing agents [30].
2.1.2 Photosensitivity
Of the BRAFi, vemurafenib is associated with the highest incidence of photosensitivity, specifically to ultraviolet A (UVA) light (315–400 nm), with 23–67% of melanoma patients experiencing symptomatic photosensitivity (Fig. 4) [7, 10, 32,33,34]. Photosensitivity reactions include both immediate and delayed reactions, with a median time to onset of 1.7 weeks after starting BRAF therapy [10]. In an extended follow-up of a phase III randomized clinical trial comparing vemurafenib with dacarbazine in patients with previously untreated, metastatic melanoma harboring a BRAF V600E mutation (BRIM-3 trial), 37% and 4% of melanoma patients taking vemurafenib had a grade 1/2 and grade 3 photosensitivity skin reaction, respectively, compared with 5% of patients with a grade 1/2 reaction in the dacarbazine group [7, 35]. Immediate reactions to UV light include erythema, edema, burning, and blistering. Delayed reactions include cheilitis and facial erythematous eruptions. The metric used to determine photosensitivity is the minimal erythema dose (MED), which is the UV threshold dose needed for a person to get a sunburn (perceptible erythema). In patients taking BRAFi, the MED for UVA light remains depressed until approximately 2 weeks after discontinuation [32, 36]. Reactions due to increased photosensitivity include blistering sunburns and solar urticaria [36]. However, not all BRAFi cause the same degree of photosensitivity as vemurafenib. Patients on dabrafenib, for example, have a higher MED than patients on vemurafenib (20 J/cm2 and 12 J/cm2, respectively) [6, 37, 38]. In a multicenter, open-label, phase 3 randomized control trial comparing dabrafenib with dacarbazine, only 3 out of 187 patients (3%) receiving dabrafenib experienced what the authors described as phototoxic reactions [6]. Management of photosensitivity relies primarily on patient education on sun protection and avoidance. Patients should avoid peak sun exposure, wear sun-protective clothing and broad-brimmed hats, and should liberally apply a broad-spectrum sunscreen (preferably a physical blocker) with a sun protection factor (SPF) of 30 or above every 2 h. Importantly, UVA can penetrate through most window glass and thus, daily application is warranted.
BRAF inhibitor photosensitivity, with watch removed for photograph (Photo courtesy of Nicole LeBoeuf, MD, MPH)
2.1.3 Keratinocyte and Melanocytic Neoplasms
BRAFi can paradoxically induce keratinocyte proliferation, leading to disordered keratinization and secondary skin neoplasia. Hand–foot skin reaction (HFSR), though inflammatory, is at least in part a disorder of keratinocyte proliferation. Neoplasia, such as verrucous lesions, cutaneous squamous cell carcinoma (SCC), keratoacanthoma (KA), and melanocytic lesions, are induced by BRAFi [10]. Secondary skin neoplasms can arise within 2 months of initiation of therapy [10]. The mechanism through which BRAFi promote secondary skin tumors is paradoxical activation of the MAPK pathway in cells with a preexisting rat sarcoma (RAS) mutation and wild-type BRAF [39,40,41,42,43].
Other BRAFi-induced dAEs of epidermal proliferation to be aware of are cystic and milia-like lesions, seborrheic keratoses, actinic keratoses, benign verrucous neoplasms and keratosis pilaris [40].
2.1.3.1 Squamous Cell Carcinoma and Keratoacanthomas
In the phase III trial comparing dabrafenib with dacarbazine in patients with previously untreated stage IV or unresectable stage III BRAFV600E mutation-positive melanoma, 6% of patients receiving dabrafenib developed SCCs or KAs (Fig. 5), compared with 0% for the control group [6]. Vemurafenib is associated with an even higher incidence of SCC: in the BRIM-3 trial, 12% of patients on vemurafenib developed cutaneous SCC, compared with < 1% of the dacarbazine group [5]. Additionally, 8% of patients in the treatment group developed KA compared with 0% in the control [5]. In an extended follow-up analysis, the percentages of patients receiving vemurafenib who developed SCC and KA were 19% and 10%, respectively, compared with < 1% for each dAE in the control [7]. Oral retinoids (acitretin dosed 10 mg every other day up to 25 mg daily) may be used to treat and prevent these squamous neoplasms. In most cases, reactive squamous atypia should be treated nonsurgically. Actinic keratoses and benign squamous neoplasms can be treated with cryotherapy or standard topicals, such as 5-fluorouracil (5-FU), imiquimod, or combination 5-FU with calcipotriene [33]. For squamous atypia and well-differentiated lesions, topical and intralesional steroids, intralesional 5-fluorouracil, photodynamic therapy, and electrodesiccation and curettage can be considered [44,45,46]. For refractory, quickly growing, or invasive neoplasms in anatomically important areas, surgery can be considered, employing excision or Mohs based on standard criteria. Dose reduction or discontinuation is rarely required.
BRAF inhibitor keratoacanthoma (Photo courtesy of Nicole LeBoeuf, MD, MPH)
2.1.3.2 Melanocytic Nevi
BRAFi have been associated with the development of melanocytic nevi (termed eruptive nevi) and the growth and pigmentation of existing nevi within a year of starting treatment [8, 33, 42]. For patients on vemurafenib, eruptive nevi occur in 10% of patients [34]. There is also an increased incidence of second primary cutaneous melanomas due to BRAFi [34]. It is important to closely monitor new and changing nevi and maintain a low threshold to biopsy suspicious lesions.
2.1.3.3 Hand–Foot Skin Reaction
Hand–foot skin reaction (HFSR) is a condition characterized by painful, white–yellow hyperkeratotic plaques at pressure points with surrounding and underlying erythema on the palms and soles (Fig. 6) [47]. It is seen in patients receiving all three approved BRAFi therapies, but is most common in patients treated with vemurafenib, with an incidence of up to 60% [34]. To prevent HFSR, patients should be advised to avoid heat and friction, wear well-fitting shoes or orthopedic shoe inserts designed to avoid pressure and friction, and moisturize their hands and feet with urea-based creams; thick ointment-based emollients should be liberally applied prior to strenuous or repetitive activity [10, 22, 34, 48]. Urea-based creams and high-potency topical steroids can be used to prevent and treat HFSR, with BRAFi dose reduction or treatment postponement in severe cases [10, 34, 49].
BRAF inhibitor hand–foot skin reaction (Photo courtesy of Nicole LeBoeuf, MD, MPH)
2.1.4 Hair Changes
BRAFi can induce alopecia and hair texture changes (Fig. 7). In a prospective study (n = 11), nonscarring, diffuse alopecia was observed in 100% of patients on vemurafenib [5, 50]. The actual incidence of clinically relevant thinning may be closer to 25% as described in cohort studies and meta-analyses [51, 52]. Furthermore, patients on BRAFi can develop changes in hair thickness, texture, and color [53]. Patients with traditionally straight hair may notice that they develop gray hair and curls after starting BRAFi therapy [8, 53]. Textural abnormalities can also be observed, with a transition to coarser and more brittle hair [8]. Scalp seborrheic dermatitis and pityriasis amiantacea, characterized by thick adherent scale on the scalp, have also been reported in patients receiving BRAFi [53].
BRAF inhibitor alopecia and hair texture changes (Photo courtesy of Nicole LeBoeuf, MD, MPH)
2.2 MEKi (Selumetinib, Trametinib, Binimetinib, and Cobimetinib)
The first MEKi, trametinib, was approved for the treatment of metastatic melanoma in 2013 [54]. The side effect profile of MEKi is generally similar to that of EGFRi, with some nuances [19]. As with BRAFi, MEKi are rarely used as monotherapy in the treatment of melanoma, since combination therapy with BRAFi has shown increased efficacy and decreased dAEs. They are used as monotherapy for some histiocytic disorders, are under investigation in combination with checkpoint blockade in some solid tumors, and are used in a subset of patients with metastatic mucosal and uveal melanoma, although results are mixed [55,56,57,58]. The most common adverse events from MEKi therapy include fever and edema, which can complicate the cutaneous examination when considering the most common dAEs. dAEs include exanthematous morbilliform eruptions, acneiform eruptions, photosensitivity, xerosis with pruritus, hair and nail disorders, and panniculitis, as well as the uncommon dAE of MEKi-induced dusky erythema. Unlike BRAFi, MEKi are not associated with secondary skin malignancies.
2.2.1 Papulopustular/Acneiform Eruptions
The most common dAEs of MEKi are papulopustular acneiform eruptions on the chest, upper back, and in a seborrheic dermatitis-like distribution on the central face and scalp [11, 20]. Unlike acne, these drug-induced eruptions lack comedones. These affect 40–93% of patients taking MEKi and are similar to the acneiform rashes induced by EGFRi [11, 59]. Like EGFRi-induced acneiform eruptions, these rashes may result in part from drug-induced production of chemokines by epidermal keratinocytes; this results in inflammation and local immunosuppression [11]. Patients may experience pruritus and burning, and develop colonization or secondary infections from bacteria such as Staphylococcus aureus [11]. For acneiform eruptions with secondary infection not responsive to initial treatment approaches, culture should be obtained and antibiotics added based on susceptibilities. As with BRAFi, photosensitivity may occur with MEKi therapy, and can cause flares of the acneiform inflammatory process. Management is similar to the aforementioned treatment for BRAFi-induced acneiform eruptions.
2.2.2 Morbilliform Eruptions
As with BRAFi, MEKi can also cause morbilliform exanthems (Fig. 8). This is dose dependent, occurs early in treatment, and is generally mild and transient [60, 61]. Management involves topical steroids, emollients, antihistamines, and, if refractory, oral steroids [60, 61]. As with all morbilliform eruptions, when extensive, laboratory evaluation and full skin and mucosal examination should be performed to evaluate for a SCAR.
MEK inhibitor morbilliform eruption (Photo courtesy of Nicole LeBoeuf, MD, MPH)
2.2.3 Xerosis with Pruritus
Xerosis is a common side effect for patients on MEKi and can lead to pruritus or eczematous dermatitis. In patients receiving trametinib, for example, 22% experience xerosis [62]. First-line treatments include bland emollients, with ointments and creams preferred over lotions [19]. For patients with skin fissures, medium- to high-potency topical steroids and skin glues can be used [22]. Patients should also be counseled to take short showers (less than 15 minutes) with tepid water, avoiding the use of harsh soaps and using soap only in the axilla and groin.
2.2.4 Hair Disorders
In addition to cutaneous adverse effects, hair disorders can also be precipitated by MEKi in up to 17% of patients. Eyelash trichomegaly, grade 1 alopecia, and hair depigmentation have been observed [63]. Topical minoxidil 2–5% for scalp alopecia and bimatoprost 0.03% ophthalmic solution for the eyelashes may be used to help with hair regrowth [63, 64].
2.2.4.1 Nail Disorders
Paronychia is an often painful inflammation of the nail folds that can impact the quality of life of patients on MEKi (Fig. 9). Avoidance of trauma and pressure on the nails is key for minimizing the impact of these symptoms [11]. Patients can be advised to wear gloves and well-fitting shoes for water work and significant activity [11]. Nails should be trimmed. While patients may use nail lacquers, polish hardeners should be avoided [11]. Patients presenting with paronychia can be treated with high-potency topical steroids, antimicrobial soaks and topicals, culture-guided oral antibiotics (tetracycline antibiotics can be considered empirically given antiinflammatory properties), partial nail avulsion and, when granulation tissue is present, topical silver nitrate, cautery, and/or timolol can be helpful [19, 53, 65, 66].
MEK inhibitor paronychia (Photo courtesy of Nicole LeBoeuf, MD, MPH)
2.2.5 MEKi-Induced Dusky Erythema
A rare dAE associated with MEKi treatment was first described in 2012 by Patel et al. MEKi-induced dusky erythema presents with red to violaceous urticarial or targetoid-like plaques, papules, and macules on the extremities and trunk, with central duskiness and erythematous halos, resembling erythema multiforme (Fig. 10) [59, 67, 68]. This eruption can occur anywhere from a few weeks to a few months after starting a MEKi and is most commonly seen in patients receiving combination therapy with BRAFi [67]. For patients with MEKi-induced dusky erythema, MEKi therapy should be temporarily suspended. First-line treatment is topical or oral steroids [67]. Once improved, MEKi rechallenge is possible with close monitoring of skin and mucosa, given the resemblance of this eruption to erythema multiforme [67].
MEK inhibitor-induced dusky erythema (Photo courtesy of Nicole LeBoeuf, MD, MPH)
2.3 BRAFi/MEKi Combination Therapy
Resistance to BRAFi monotherapy by activating mutations in MEK prompted combination therapy of BRAFi with MEKi. Combination therapy (dabrafenib plus trametinib, vemurafenib plus cobimetinib, encorafenib plus binimetinib) has improved overall survival (OS) and progression-free survival (PFS) when compared with either therapy alone [69,70,71]. When BRAFi and MEKi are used together, patients experience fewer grade 3 or grade 4 toxicities and require fewer dose interruptions or changes [70, 72]. dAEs—such as rash, acneiform dermatitis, hyperkeratosis, primary melanomas, alopecia, hand–foot syndrome, and toxicities of epidermal proliferation—are decreased with combination therapy when compared with BRAFi or MEKi alone.[8, 69, 70, 72,73,74] Combination therapy does not appear to reduce the risk of BRAFi-induced panniculitis or keratosis pilaris [26].
The impact of combination therapy on photosensitivity varies by trial. In the COLUMBUS trial, photosensitivity was seen in 24% of patients on vemurafenib, 4% on encorafenib, and 5% on combination therapy [70]. In the coBRIM trial, however, photosensitivity was more common in patients receiving combination therapy (34% in the cobimetinib and vemurafenib versus 20% in the vemurafenib and placebo groups) [35]. Therefore, it is crucial to counsel patients taking combination therapy on the importance of sun protection and avoidance.
Rates of dAEs in BRAFi and MEKi combination therapy and monotherapy are summarized in Table 2. Lastly, extra-cutaneous side effects to be mindful of in these patients include cardiovascular (hypertension, decreased ejection fraction), ocular (retinopathy), and gastrointestinal toxicities (diarrhea, nausea, vomiting), as they tend to be higher in patients on combination therapy compared with those on vemurafenib monotherapy [70]. Patients on combination therapy also more commonly experience pyrexia, and it is usually more severe [69].
2.4 ERKi
Resistance to BRAFi and MEKi has prompted research into downstream targets of the RAS/RAF/MAPK pathway [75]. While there are currently no US Food and Drug Administration (FDA)-approved therapies to target and inhibit ERK for the treatment of melanoma, preclinical and phase I trials are underway [75]. Since these drugs are not used in clinical practice, their dermatologic toxicities are only briefly reviewed. As an example, in a phase I trial of a novel ERKi, ulixertinib, dAEs were common with a median onset of 3 weeks, and they were similar to the dAEs of BRAFi and MEKi. These included acneiform rash (33%), maculopapular exanthem (27%), pruritus (25%), unspecified rash (23%), xerosis (11%), alopecia (10%), photosensitivity (3%), and erythema multiforme (0.7%) [76]. Nineteen percent of all patients had grade 3 dAEs, 29% had grade 2 dAEs, and 32% had grade 1 dAEs [76]. No patient experienced grade 4 or 5 dAEs [76]. Treatment options for these toxicities should reflect the management of similar morphologies as outlined above for BRAFi and MEKi [76].
3 Intralesional Therapy
In 2015, the FDA approved T-VEC for injectable but unresectable cutaneous, subcutaneous, and nodal lesions for patients with melanoma recurrence after an initial surgery [77, 78]. To date, it remains the only approved oncolytic virus for any purpose in the USA, although there are three other oncolytic viruses approved in other countries [79]. T-VEC is a live, replicating herpes simplex virus (HSV)-1 genetically modified for increased safety, preferential replication in tumor cells, induction of host immunity with expression of granulocyte–macrophage colony stimulating factor (GM-CSF) and deletion of multiple viral genes [80]. There have been no known reports of household contact transmissions [77], although rarely both patients receiving or hospital staff preparing the injection have reported herpetic lesions [81,82,83]. T-VEC patients or providers with concern of possible herpetic lesions should contact Amgen at 1-855-IMLYGIC (1-855-465-9442) for additional testing, as they are currently recruiting for an ongoing, post-marketing study to better characterize the risk of herpetic infection (NCT02910557). The T-VEC mechanism of action is summarized in Fig. 11.
Lysis of the cancer cells allows new viral particles to be released for continued infection of other tumor cells. Additionally, T-VEC promotes release of tumor-derived antigens in an immunogenic fashion that is strengthened by expression of GM-CSF. There is accumulation and maturation of dendritic cells, and it is thought that through both the tumor antigen release and viral progeny producing GM-CSF there is improved cross-priming of CD8+ T cell response by the dendritic cells
The use of T-VEC has been somewhat limited due to logistical concerns surrounding injection therapy and concerns of those who do not yet have experience with the oncolytic virus, as it has a favorable toxicity profile with a low rate of grade 3 or 4 adverse events [77, 84]. Fatigue, chills, pyrexia, nausea, and influenza-like illness are the most common adverse events [77]. The following dAEs are well established: injection-site reactions, vitiligo-like depigmentation, and “cellulitis.”
3.1 Injection-Site Reaction
Nearly one-third (28.4%) of patients receiving T-VEC experience injection-site pain [85]. Acetaminophen or indomethacin can be utilized for either prevention or treatment of the pain (in addition to treating fever or chills) [77, 86]. Prophylactic use of acetaminophen the evening of the injection may prevent constitutional side effects and injection-site symptoms that tend to occur 24–48 h after injection. Patient education and counseling should occur before the intralesional injection, so patients can be prepared for possible injection-site pain.
3.2 Vitiligo-Like Depigmentation
Vitiligo-like depigmentation (VLD) is the most frequent dAE secondary to T-VEC, with a rate of 6.2% in the Oncovex GM-CSF Pivotal Trial in Melanoma (OPTiM), a randomized, open-label phase III trial in patients with unresectable stage IIIB–IVM1c melanoma comparing T-VEC and subcutaneous GM-CSF as a control [84]. The depigmentation onset occurred after a median time of 22 weeks (interquartile range, 9–36 weeks). VLD is known to present in melanoma patients, even before the introduction of T-VEC, due to immunity against shared antigens of melanoma and melanocytes [87]. Autoimmunity against shared antigens is likely augmented secondary to T-VEC-induced release of tumor-derived antigens as well as the accumulation of tumor antigen-presenting dendritic cells promoted by GM-CSF. In two case reports of T-VEC-induced VLD, the patients were in complete remission at the time of publication (16 and 20 months) [88]. The two patients had VLD at both the injection site and more distant locations, which suggested a systemic effect. Similar to ICI induced VLD [89], T-VEC induced VLD may be an indication of response to therapy and associated with positive long-term results [88]. All patients with VLD should be counseled on sun protective practices including the use of broad-spectrum sunscreen and protective clothing to prevent burns of depigmented skin [90]. Currently, the only FDA-approved treatment for vitiligo is the Janus kinase inhibitor cream ruxolitinib, approved in 2022 [91]. Patients with grade 1 VLD may start topical corticosteroids twice daily [92]. Following general guidelines for vitiligo, ultrapotent and potent corticosteroids may be used on the body, but the face, neck, and intertriginous areas should be treated with mid-potency topical corticosteroids [93]. For grade 2 VLD, both topical corticosteroids twice daily and phototherapy in a controlled setting may be recommended [92]. Collaborative management between dermatology and oncology is warranted, and continuation of T-VEC treatment encouraged [92].
3.3 Cellulitis
The only grade 3 or 4 adverse event occurring in ≥ 2% patients receiving T-VEC in OPTiM was “cellulitis,” which affected 2.1% of patients [84]. Cellulitis of any grade affected 5.8% of patients. Cellulitis is a clinical diagnosis characterized by erythema and pain, and in the setting of T-VEC, is regarded as an inflammatory response to the injected organism. Herpes cellulitis from T-VEC clears within 24–48 h and is self-limiting [86]. This is in contrast to bacterial cellulitis, which may complicate the injection site, is persistent, and may be associated with persistent fever and leukocytosis. If bacterial cellulitis is suspected, cultures should be performed, and antibiotic therapy initiated. Patients who are immunosuppressed or those experiencing symptomatic or progressive erythema should be started on empiric treatment with antibiotics [94].
Real-world data suggest dAEs may be more diverse than was seen in trials. Granulomatous dermatitis at the injection site, panniculitis, and Sweet’s-like neutrophilic dermatosis have been reported [95,96,97].
Although T-VEC and ICI combination therapy is still undergoing investigation, adverse events appear to be similar to their known safety profiles without new toxicities [85]. In practice, T-VEC is often added in close proximity to other ICIs (when the effect of the ICI is likely still present) or in combination with ICIs in patients who have developed resistant cutaneous, subcutaneous or nodal metastases. The rate of dAEs is 33.2% and 38.7% for ICI therapy alone and combination T-VEC and ICI therapy, respectively [98]. When controlling for sex, race/ethnicity, age at ICI initiation, ICI type, Charlson Comorbidity Index, and cancer type, however, there is a two-fold (hazard ratio, 1.96; p = 0.009) increase in the risk of dAEs in the patients receiving the combination therapy.[98]
4 Systemically Administered Immunotherapy
The immune system is tasked with differentiating self and non-self and harnessing this system has led to profound success in advancing the treatment of melanoma. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) immune checkpoint pathways negatively regulate T cell activity and are frequently exploited by tumor cells [99]. Inhibiting PD-1 and CTLA-4, the two most clinically important checkpoints, increases activation of the immune system. A recent population-level analysis found the overall incidence of ICI-induced clinically relevant dAEs to be 25.1%, and the median time to onset was 113 days [100]. Female sex has been associated with higher rates of dAEs [101]. Immune-related side effects are associated with ICI therapy response and patient survival [102, 103]. As checkpoint-induced toxicities and their management have been extensively reviewed [11, 104,105,106], here we discuss novel agents minimally discussed in the literature.
A new, first-in-class, fixed-dose combination of nivolumab and relatlimab (Opdualag™) for unresectable or metastatic melanoma was approved by the FDA in March 2022 [107]. Relatlimab is a monoclonal antibody targeting lymphocyte activation gene-3 (LAG-3), which is an activation-induced, CD4-related cell surface molecule [108]. Activated CD4+ T helper cells, cytotoxic CD8+ T cells, and a subset of other immune cells express LAG-3 [109], and IL-2, IL-7, and IL-12 all promote upregulation of LAG-3 expression [110]. LAG-3 mediates T cell homeostasis and negatively regulates T cell expansion and pool size [109, 111]. Melanoma cells exploit this pathway, with MHC II on melanoma cells engaging with LAG-3 on tumor-infiltrating leukocytes to protect against Fas-mediated apoptosis [112]. The survival benefit of dual checkpoint inhibition of LAG-3 and PD-1 was recently shown in a randomized, double-blinded, phase II/III trial in patients with metastatic or unresectable melanoma comparing fixed dose combination therapy with relatlimab–nivolumab to nivolumab alone [113]. In patients receiving relatlimab–nivolumab, the median PFS was 10.1 months (95% CI, 6.4 to 15.7 months), which was more than double the median PFS of 4.6 months (95% CI, 3.4 to 5.6 months) in nivolumab alone. Notably the relatlimab–nivolumab group had a longer PFS than nivolumab alone regardless of BRAF mutation status, American Joint Committee on Cancer metastasis stage of the tumor, lactate dehydrogenase level, or tumor burden.
In terms of safety, 18.9% of patients receiving relatlimab–nivolumab experienced grade 3 or 4 treatment-related adverse events, compared with 9.7% of the patients receiving nivolumab alone [113]. Increased lipase, alanine aminotransferase, aspartate aminotransferase, and fatigue were the most frequent grade 3 or 4 treatment-related adverse events in the relatlimab–nivolumab group. Of note, 14.6% of patients in the relatlimab–nivolumab group had treatment-related adverse events (any grade) that led to discontinuation, in comparison with 6.7% of the nivolumab only group. However, quality-of-life assessments were high and comparable between both groups in the study. Overall, no new safety signals emerged with the relatlimab–nivolumab combination, and the adverse events were favorable in comparison with nivolumab plus ipilimumab combination therapy [114].
The most observed dAEs of combination relatlimab-nivolumab therapy were “rash” and vitiligo-like depigmentation. Importantly, the use of clinical trial data remains limited in understanding specific toxicities from ICIs, as eruptions are often bluntly described as “rash” with little additional diagnostic specificity.
4.1 Rash
Of patients receiving relatlimab-nivolumab, 9% developed an immune-mediated rash of any grade, with 3.4% experiencing grade 2 and 0.6% experiencing grade 3 adverse reactions [113, 115]. Immune-mediated rash resulted in 1.4% of patients having treatment interruptions, although there were no patients who had to permanently discontinue the treatment [115]. Systemic corticosteroids were used in 88% of the patients with immune-mediated rash, which effectively resolved the rash in 70% of these patients. One-quarter of patients who required treatment interruption with relatlimab–nivolumab experienced a recurrence of the rash after reinitiating therapy. As use of relatlimab–nivolumab combination therapy expands, providers should anticipate a diversity of specific dAEs, such as those seen with other ICIs: lichenoid reactions, psoriasis, Grover’s disease, bullous pemphigoid, dermatomyositis, vasculitis, Sjogren’s syndrome, sarcoidosis, and Sweet’s syndrome, among others [104, 116]. Ideally, these toxicities should be described and reported as specifically as possible.
4.2 Vitiligo-Like Depigmentation
VLD occurred in 10.4% of patients receiving relatlimab–nivolumab (Fig. 12) [113]. While studies on LAG-3 inhibition monotherapy are limited, this rate is lower than the 16.5% seen with nivolumab monotherapy in the 3 year follow-up of the phase III trial of patients with advanced melanoma [117]. Interestingly, in one study investigating VLD in patients on ICIs, responders to the therapy were found to have downregulation of LAG-3 [118]. Some authors have argued that VLD in anti-PD-1 therapies is clinically and biologically distinct from vitiligo: anti-PD-1 induced VLD has been described as flecked depigmented macules that coalesce into patches that do not exhibit Koebnerization and occur on skin commonly exposed to the sun [106, 119]. More recently, other authors have concluded that this may represent active vitiligo with similar disease mechanisms [120]. As mentioned above, all patients with VLD should be counseled on sun protective practices including broad-spectrum sunscreen and sun protective clothing [90]. There is no definitive treatment for VLD, and it does not require treatment unless it begins to negatively impact quality of life. Other treatment is similar to T-VEC-induced vitiligo (above).
Immunotherapy-induced vitiligo-like depigmentation on Wood’s lamp examination (Photo courtesy of Nicole LeBoeuf, MD, MPH)
5 Therapies Used in the Refractory Setting
5.1 Topical Imiquimod
Though not a systemic therapy, topical imiquimod can induce systemic and cutaneous adverse events and has been used off-label for various stages of melanoma. In practice, imiquimod may be used across the melanoma spectrum, from in situ to metastatic disease. It is used as an adjunct in patients who decline surgery, for those whom resection is not practical or when previous resections have not been successful, for cutaneous metastasis not otherwise responsive to systemic or intralesional therapy, and in patients who are not candidates for these or other surgical approaches [121]. Imiquimod is an immunomodulatory agent with antiviral and antitumor properties that is FDA approved for the treatment of genital and perianal warts, superficial truncal and extremity basal cell carcinoma, and actinic keratoses [122, 123]. Its mechanism of action is via toll-like receptor-7 mediated release of inflammatory cytokines, such as interferon-α, IL-6 ,and TNF-α [122, 124]. For in situ lesions, imiquimod has shown clearance rates up to 100% when used both as first-line treatment and after incomplete excision, though recurrence rates remain an area of investigation [125,126,127,128,129]. Topical imiquimod is used in the treatment of advanced melanoma with in-transit or distant metastatic cutaneous lesions, with most evidence derived from case reports [130, 131]. dAEs of topical imiquimod include pruritus, burning, erythema, and scaling in addition to crusting, vesicles, erosions, and weeping. These dAEs resolve with cessation of the drug. For open, weeping erosions, topical antimicrobials may be used [132, 133]. Additionally, imiquimod-induced localized vitiligo-like depigmentation confirmed with histopathology has been reported in patients being treated for genital warts, basal cell carcinoma, and extramammary Paget disease [134,135,136,137]. Though not fully understood, the pathogenesis may be due in part to the stimulation of toll-like receptors on melanocytes and the subsequent inhibition of melanogenesis with increased apoptosis of melanocytes [138, 139]. When imiquimod is applied to cosmetically sensitive areas and on patients with darker skin phototypes, the potential consequences of depigmentation and hypopigmentation can be significant. Though there has been no data on the use of ruxolitinib in imiquimod-induced vitiligo, this, along with cessation of imiquimod, may be considered. Lastly, imiquimod has been reported to induce and exacerbate psoriasis at both local and distant sites from application [140, 141]. The mechanism is thought to be due in part to imiquimod’s involvement in the IL-17 and IL-23 axis [142]. Treatment follows standard psoriasis guidelines, which include myriad options such as topical corticosteroids, topical vitamin D analogs, topical calcineurin inhibitors, and phototherapy for mild psoriasis; in the setting of active malignancy, the general approach to systemic agents includes apremilast and IL17/12/23 inhibitors considering comorbidities and malignancy status [143]. TNF inhibitors are generally avoided, though research on their impact on malignancy response is ongoing.
5.2 Imatinib Mesylate
The protooncogene KIT may be mutated in melanoma. It is a receptor tyrosine kinase that is involved in cell growth, division, and survival, especially in melanocytes. Mutations in KIT are most commonly seen in mucosal and acral melanoma [144, 145]. Imatinib is a receptor kinase inhibitor of Abl, KIT, and platelet-derived growth factor receptor. It is most commonly used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumor, and has been used as a second-line treatment for metastatic or unresectable melanomas with KIT mutations, although durable responses and best overall response rates are low with limited clinical efficacy in metastatic melanoma [121, 146,147,148,149]. Imatinib is generally well tolerated, but dAEs are common [150]. These include morbilliform exanthems, psoriasiform eruptions, periorbital edema, hyperpigmentation, and hypopigmentation [150, 151]. Less common conditions reported with imatinib treatment include SJS and neutrophilic dermatoses, and diverse dAEs reported as individual cases [151]. Treatments for these conditions are as previously discussed.
5.3 Larotrectinib and Entrectinib
Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are found in approximately 28% of spitzoid melanomas, 2.5% of acral melanomas, and less than 1% of cutaneous or mucosal melanomas [152]. For melanoma patients with NTRK gene fusions who have progression of their metastatic or unresectable disease despite immunotherapy and/or BRAF therapy, the National Comprehensive Cancer Network (NCCN) guidelines recommend the use of tropomyosin kinase (Trk) inhibitors larotrectinib and entrectinib as second-line therapy [121, 153, 154]. dAEs appear to be rare and are not well documented; only toxicities with incidences of 15% were reported in the pivotal trial [153, 155]. dAEs with entrectinib are better reported; in an integrated analysis of three phase I/II trials of 54 adults with metastatic or locally advanced solid tumors positive for NTRK fusions who received entrectinib, dAEs included rash (6%), skin pain (4%), hyperesthesia (3%), and pruritus (2%) [155, 156]. Notably, no melanoma patients were included in this study.
6 Additional Ongoing Clinical Trials
Striving toward better patient outcomes and improved quality of life while undergoing anticancer therapy relies on novel research. There are currently over 1000 clinical trials investigating melanoma therapies that are either soon to be recruiting, recruiting, enrolling by invitation, or active [157]. Of note, therapies under investigation include those classically used to treat hematologic malignancy, such as navitoclax (ClinicalTrials.gov Identifier: NCT01989585) or histone deacetylase inhibitors (ClinicalTrials.gov Identifier: NCT04674683). Importantly, these therapies are not associated with significant rates of specific skin toxicities. For the purpose of this review article, we have summarized the current phase III clinical trials of melanoma therapies (systemic and not systemic) with novel mechanisms that may introduce new dAEs in Table 3.
7 Conclusions
There has been remarkable progress in therapeutic strategies for patients with advanced melanoma over the recent decades. As we utilize new additions in our therapeutic armamentarium, we also see a diversity of drug-related toxicities. In this review, we focus on diagnosis and management of dAEs of targeted therapies as well as less commonly used melanoma treatments. Specific recognition of the presentations and knowledge of mitigation strategies for dAEs is critical for decreasing patient morbidity and mortality. Dermatologists and oncologists must be prepared to diagnose and manage these adverse events promptly, while minimizing disruptions to the anticancer therapy regimen. Ultimately, the ability to diagnose a specific toxicity and attribute it to the correct drug allows patients to maximize cancer treatment, only removing an agent or therapeutic class when absolutely necessary.
As novel therapies and combinations are trialed, there will undoubtedly be an increase in the number of patients suffering from dAEs. We hope that dermatologists and oncologists will persistently continue to educate themselves on emerging specific toxicities to maximize patient quality of life as well as cancer outcomes.
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Fay, C.J., Jakuboski, S., Mclellan, B. et al. Diagnosis and Management of Dermatologic Adverse Events from Systemic Melanoma Therapies. Am J Clin Dermatol 24, 765–785 (2023). https://doi.org/10.1007/s40257-023-00790-8
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DOI: https://doi.org/10.1007/s40257-023-00790-8