Epidermal grown factor receptor (EGFR) inhibitors

Epidermal growth factor receptor (EGFR) has been recognized as a significant regulator of cancer cell proliferation, apoptosis, angiogenesis, and metastasis. Ligand binding to the receptor causes receptor dimerization, which activates the intracellular tyrosine kinase domain.⁵ EGFR also plays a significant role in normal skin homeostasis.⁶ Activation of EGFR in epidermal keratinocytes promotes cell cycle progression, differentiation, and migration, which are all critical for normal skin function and wound healing.⁷ The most common cutaneous side effects for EGFR inhibitors are an acneiform eruption, paronychia, xerosis, eczema, mucositis, and geographic tongue. Acne folliculitis appears on the face and upper trunk 8–10 days after treatment initiation. In phase 1 trials, erlotinib at the maximally tolerated dose induced a pustular acneiform eruption in 50% of cases during the second week of therapy.⁸ The eruption can be extremely prurituc and EGFR inhibitors have cutaneous side effects that lead to dose alteration in >75% of patients.⁹ The presence and severity of acne folliculitis has been correlated with tumor response and survival.¹⁰ This reaction has been reported with cetuximab, panitumumab, nimotuzumab, erlotinib, and gefitinib.^11–13 Oral tetracyclines combined with topical steroids are the gold standard treatment. Retinoids and topical antibiotics have not been proven useful in these patients as the etiology is not follicular plugging and rupture, but epithelial dysregulation.¹¹ Staphylococcus colonization can worsen the eruption and cultures and antibiotics are recommended if lesions are pustular or crusted (Figure 1).

The human epidermal growth factor receptor (HER)1/2 blockers have the same side effects as EGFR inhibitors, but are milder. Trastuzumab, lapatinib, dacomitinib, and afatinib all have had reported acneiform eruptions.^14–17 Similarly, the vascular endothelial growth factor (VEGF) inhibitors have overlap between the EGFR inhibitors, with mucositis and geographic tongue, and the multikinase inhibitors, with hand–foot skin reaction (HFSR), which is discussed below.¹⁸

BCR-ABL tyrosine kinase inhibitors

Imatinib mesylate targets the BCR–ABL gene and has been used in the treatment of chronic myeloid leukemia and acute lymphoblastic leukemia. It has been shown to frequently cause dose-dependent cutaneous reactions, including facial edema, morbilliform eruption, urticaria, eczematous dermatitis, and AGEP.^{19, 20} One patient developed an eczematous rash with histologic features of mycosis fungoides.²¹

Second- and third-generation Bcr–Abl-specific TKIs, dasatinib, nilotinib, and ponatinib have been associated with follicular lichenoid eruptions of the scalp, face, and body that can be pruritic and lead to scarring alopecia.²² This alopecia is irreversible, even upon dose cessation.

Multikinase inhibitors

Sunitinib and sorafenib are the multikinase inhibitors targeting VEGF receptor, platelet-derived growth factor receptor (PDGFR), c-Kit, and FLT-3. Sorafenib also inhibits RAF kinase. They were developed for advanced renal cell carcinoma but have also been used for hepatocellular carcinoma, gastrointestinal stromal tumors, and thyroid cancer. They are most associated with the HFSR as well as mucositis, alopecia, xerosis, and xerostomia. However, because they overlap with multiple groups of targeted therapies, the cutaneous squamous cell carcinoma (SCC) of BRAF inhibitors and the acneiform eruption of VEGF inhibitors can be seen as well.²³

HFSR appears within 2–4 weeks of starting the therapy and is present in one-fifth to one-third of patients, with sorafenib having a slightly higher incidence. Patients develop a focal keratoderma at points of friction and pressure, which can vesiculate, leading to painful blisters (Figure 2). The risk of developing HSFR depends on which drug the patient is on and which cancer type is being treated. The original proposed mechanism was that the VEGFR blocking capabilities of these drugs caused the patients to have a poor response to damage caused by pressure and trauma.^{24, 25} Most recently, the Fas/Fas ligand response was implicated, proven by blocking the reaction by administering anti-Fas ligand antibody. These are the same mediators of Stevens Johnsons and TEN.²⁶

Although more common in multikinase inhibitors such as sorafenib and sunitinib, these lesions have been reported with BRAF inhibitors.²⁷ These are distinct from the more common hand–foot syndrome/acral erythema (AE)/toxic erythema of chemotherapy seen with cytotoxic chemotherapies. HFSR does not have the diffuse erythema and edema of hand–foot syndrome and also has a longer latency period before appearing (2–4 weeks). HFSR usually self-resolves with continued treatment with the multikinase inhibitors.²⁸

mTOR inhibitors

Overlapping with the EGFR signaling pathway is the PI3K/AKT pathway, which activates mammalian target of rapamycin (mTOR). This molecule is associated with cell growth and angiogenesis and sirolimus or rapamycin was the original drug in this category, followed by everolimus and temsirolimus. All are associated with the papulopustular rash of EGFR inhibitors, which has an incidence of 45.8% in the most recently developed drug, temsirolimus. They all also can induce the more classic morbilliform drug eruption and oral mucositis. As opposed to cytotoxic chemotherapies, individual deeper oral ulcerations more similar to aphthous stomatitis are present as well. Finally, everolimus and temsirolimus also had a population with eczematous dermatitides.²⁹

BRAF inhibitors

BRAF inhibitors, first introduced in metastatic melanoma patients, have significant cutaneous side effects that include inflammatory, follicular, and neoplastic eruptions. These side effects lead to dose cessation or reduction in <10% of patients.³⁰ Of the inflammatory cutaneous toxicities, neutrophilic dermatoses, including acute febrile neutrophilic dermatosis (Sweet’s syndrome) and neutrophilic panniculitis, have been attributed to the use of BRAF inhibitors.^30–36

Two patients with the erythematous pseudovesicular papules and plaques of Sweet’s syndrome of the trunk and extremities presenting with systemic symptoms of fever and arthralgias have been reported.^{36, 37} The patients with neutrophilic panniculitis presented with tender, erythematous nodules of the legs and occasionally arms, and had histology consistent with a neutrophilic lobular panniculitis.^31–34 Vitiligo,³⁸ cutaneous sarcoidosis,³⁹ Grover’s disease,⁴⁰ and hidradenitis suppurativa⁴¹ have been reported less commonly.

Patients on BRAF inhibitors also have increased radiation sensitivity to UV (ultraviolet) light and radiation therapy with quicker and more severe sunburns and acute radiation dermatitis, respectively.^{42, 43} Further, cases of radiation recall dermatitis have been reported as well.^{44, 45}

Epidermal and follicular dysregulation contribute significantly to BRAF inhibitor cutaneous side effects. Palmoplantar hyperkeratosis or keratoderma is a thickening of the epidermis without inflammation presenting as thick yellow plaques of the palms and soles similar to a large callus. Most commonly, the keratoderma is seen on the feet in pressure points, without vesiculation.⁴⁶ A superficial keratotic plugging of the follicle results in a keratosis pilaris-like eruption. This is seen frequently on the trunk and extremities and is more often asymptomatic than pruritic. It was noted in 5–9% of patients in phase 2 and 3 trials,^{47, 48} although this may be underreported.^{27, 49, 50}

Neoplastic lesions cause the highest morbidity in these patients. Actinic keratoses (AKs) represent precancerous epithelial lesions typically associated with chronic sun damage. The incidence of AKs is 6–16% in vemurafenib patients^47–49 and 5–10% in dabrafenib patients.^{46, 51–53} Wart-like keratoses are papillated, hyperkeratotic, well-demarcated papules that are often inflamed and appear in an eruptive nature during BRAF inhibitor therapy. They appear about 3–4 months after therapy.⁵³ These lesions are not true verruca as human papilloma virus testing has been negative in multiple reports.^{54, 55} Prompt treatment of both types of lesions with cryotherapy, photodynamic therapy, curettage, and topical 5-fluorouracil (5-FU) helps prevent SCC formation (Figure 3).

Patients with SCC usually present with dome-shaped, well-demarcated, hyperkeratotic, erythematous papules, and nodules. They are quickly growing and more prevalent in older patients with chronic sun damage.⁴⁶

The incidence of SCC is 4–31% in vemurafenib patients^{47, 48, 56} and 6–11% in debrafenib patients.^{51, 52, 57, 58} Sosman et al. showed that they are predominantly well-differentiated or keratoacanthoma-type SCC, which are less aggressive than the normal array of sun-induced SCC. The median time to occurrence is 8 weeks. HRAS upregulation has been implicated in a portion of BRAF-induced SCC causing a paradoxical upregulation of the MAP kinase pathway.⁴⁷

Patients have been reported to have involution of nevi as well as new and darkening nevi. The new nevi have shown wild-type BRAF, lack the V600E mutation, and appear in 8–14 weeks.⁵⁹ These lesions have been biopsied as common nevi, dysplastic nevi, and new primary cutaneous melanomas. Five of 464 patients in the phase 2 and 3 clinical trials with vemurafenib had a new melanoma.⁶⁰

MEK inhibitors

Selumetinib and trametinib, two new MEK inhibitors, just downstream of BRAF have similar side effects to the EGFR inhibitors.⁶¹ Interestingly, the addition of a MEK inhibitor to a BRAF inhibitor decreases the squamous proliferations seen with the BRAF inhibitor alone, possibly addressing the HRAS mutation as well.

Immune check point inhibitors

Immunomodulatory drugs used for melanoma include ipilimumab and nivolumab or pembrolizumab. Ipilimumab is a monoclonal antibody targeting CTLA4, which inhibits binding of the costimulatory molecule, CD28. Blocking CTLA4 allows unopposed activation of cytotoxic T cells and stimulates the immune response to metastatic melanoma. The main side effects are morbilliform or eczematous eruptions.⁶² Similarly, pembrolizumab blocks PD-1, which, when bound to its ligand, decreases the cytotoxic effects of T cells. This molecule is upregulated in tumor cells and is thought to be a more specific target than CTLA4. The cutaneous side effects are similar to ipilimumab, but also include vitiligo.⁶³

Cytokines

Roles have already been established for interleukin 2 (IL-2) as alternative treatment for advanced metastatic melanoma and renal cell cancer and for interferon-α (IFN-α) as standard treatment for chronic myelogenous leukemia, hairy-cell leukemia, cutaneous T-cell lymphoma, melanoma, and Kaposi sarcoma (KS). In addition to significant toxicities (Table 4) such as capillary leak syndrome, there is a 72% incidence of cutaneous reactions reported with IL-2.⁶⁴ Commonly, a pruritic diffuse erythroderma occurs 1–3 days after administration and resolves with desquamation 2 days after cessation of therapy (Figure 4).⁶⁴ This reaction is clinically similar to toxic shock syndrome and has been associated with staphylococcal sepsis in some patients. Intra-arterial IL-2 also causes hypersensitivity to iodine-containing contrast dyes in up to 30% of patients.⁶⁵ Of potential importance, one study of IL-2 for metastatic melanoma has reported a possible correlation between the development of vitiligo and good prognosis.⁶⁶ Although IFN-α is relatively less toxic than IL-2, several cutaneous reactions have been reported in the literature. Perhaps one-third of patients will develop a local injection-site reaction. In a study of 1000 patients receiving IFN-α, alopecia and herpes labialis exacerbation were common with 10% and 5% incidence, respectively.^{65, 67} Similar to nonmodified recombinant IFN-α, pegylated IFN-α has been shown to cause local cutaneous ulcerations at sites of subcutaneous injection.⁶⁸ Both IFN-α and IL-2 also induce and/or exacerbate seborrheic dermatitis and psoriasis.⁶⁵