INTRODUCTION — Over the last three decades, novel antineoplastic therapy strategies have emerged that exploit molecular abnormalities that exist in certain types of cancer. These drugs are collectively referred to as "molecularly targeted agents." Many of these agents, particularly those interfering with signal transduction (eg, epidermal growth factor receptor [EGFR] inhibitors, multitargeted tyrosine kinase inhibitors [TKIs], BRAF inhibitors), are associated with prominent dermatologic adverse events that may impact quality of life and dosing [1].
This topic will review the dermatologic toxicities seen with several classes of molecularly targeted agents. Cutaneous reaction patterns seen with conventional cytotoxic agents and checkpoint inhibitor immunotherapies used for advanced melanoma and other solid and hematologic tumors are discussed elsewhere. Infusion reactions to monoclonal antibodies used for cancer therapy and conventional chemotherapy agents are also discussed separately.
●(See "Cutaneous adverse effects of conventional chemotherapy agents".)
●(See "Infusion reactions to systemic chemotherapy".)
●(See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".)
EGFR INHIBITORS — The array of drugs that inhibit the epidermal growth factor receptor (EGFR) include:
●Monoclonal antibodies:
●Oral small molecules:
As a group, these drugs are associated with prominent dermatologic adverse events, the most common of which is a papulopustular acneiform eruption (table 1) [2]. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)
Acneiform eruption — The most common cutaneous reaction pattern with EGFR inhibitors is a diffuse, papulopustular acneiform eruption, which is noted in more than two-thirds of patients receiving any of these agents (severe in 10 to 20 percent) [3-6]. The eruption consists of erythematous, follicular papules and pustules, typically without comedones. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)
The acneiform eruption is often dose dependent and typically begins early, within one to two weeks of treatment initiation (picture 1A-C) [7,8]. The lesions typically occur on the face, scalp, chest, and back, sparing the extremities. Scaling of the interfollicular skin may also be present. Significant pruritus accompanies the cutaneous eruption in up to one-third of patients [9].
Studies note a consistent positive correlation between the severity of the acneiform rash and antitumor activity [10-13]. The presence of an acneiform eruption is not a contraindication to continued therapy. In fact, there is evidence that the development of moderate to severe acneiform eruption is associated with an improved survival [14-17]. However, for grade 3 (severe) dermatologic adverse events, dose interruptions and reductions are indicated (table 2). Dose reduction guidelines for most agents are available in their corresponding package inserts. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Benefit of cetuximab and panitumumab' and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Adverse effects'.)
The clinical course, complications, management, and prevention of the acneiform eruption associated with EGFR inhibitors are discussed in detail separately. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)
Other reactions — Although the acneiform rash is the most prominent cutaneous adverse reaction, several other skin reactions are reported with anti-EGFR therapies (table 1), including:
●Paronychia – Cuticular inflammation (often with pyogenic granuloma-like lesions (picture 2)) and secondary bacterial infection (often with Staphylococcus aureus) are frequent adverse events of anti-EGFR agents [18-20]. Onycholysis or onychodystrophy may occur secondary to nail bed inflammation. Treatment options include topical or oral antimicrobials, chemical cauterization, and partial nail avulsion [21]. (See "Paronychia", section on 'Drug-induced paronychia' and "Pyogenic granuloma (lobular capillary hemangioma)".)
●Hair abnormalities – Hair on the scalp and body may become brittle, fine, and/or curly. Hirsutism, trichomegaly (excessive growth of the eyelashes (picture 3)), and an increase in the length of the eyebrows have been described [22,23]. Reversible alopecia has also been reported with EGFR inhibitors. (See "Alopecia related to systemic cancer therapy", section on 'Molecularly targeted agents'.)
●Other – Other reactions include pruritus, xerosis, mucositis, and photosensitivity [2,24,25]. This constellation of symptoms, in addition to the acneiform eruption, has been labeled PRIDE (papulopustules and/or paronychia, regulatory abnormalities of hair growth, itching, and dryness due to epidermal growth factor receptor inhibitors) syndrome [26].
Bullous and exfoliative eruptions, including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), have been rarely reported [27,28]. However, the risk is quite low:
•No increased frequency was observed by the international Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) [29].
•A systematic review of 117 clinical trials including approximately 9000 patients did not find any additional fatal reactions attributed to erlotinib, cetuximab, or panitumumab [30,31].
●Radiation dermatitis – Increased risk of severe radiation dermatitis is reported in patients treated concomitantly with EGFR inhibitors [32,33]. (See "Radiation dermatitis".)
BCR-ABL TYROSINE KINASE INHIBITORS — Inhibitors of the BCR-ABL fusion protein are multitargeted tyrosine kinase inhibitors (TKIs) that inhibit signal transduction through the BCR-ABL fusion protein, which functions as a tyrosine kinase. Examples of this class of drugs include:
●Imatinib – Imatinib is a first-generation multitargeted TKI used for a variety of tumor types, most commonly Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML), which is characterized by the presence of a fusion protein (BCR-ABL, which functions as a tyrosine kinase), and gastrointestinal stromal tumors, which are characterized by KIT mutations.
●Dasatinib, nilotinib, and bosutinib – Dasatinib, nilotinib, and bosutinib are second-generation TKIs that are only used in patients with Ph+ CML.
●Ponatinib – Ponatinib is a third-generation TKI used for the treatment of chronic myeloid leukemia with BCR-ABL1 T315I mutation. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy".)
Skin reactions from inhibitors of the BCR-ABL fusion protein are diverse and include maculopapular rash, alopecia, pigmentation disorders, and keratosis pilaris (table 3). More severe skin reaction can rarely occur.
Maculopapular eruption — The most common cutaneous adverse event of TKIs is an exanthematous, maculopapular eruption. In patients taking imatinib, the frequency of cutaneous eruptions is dose dependent, ranging from 33 percent at doses less than 400 mg daily to 93 percent with daily doses of 600 mg or more [34]. Although mild cases often spontaneously resolve over time despite drug continuation, more severe skin reactions require discontinuation of treatment for up to two weeks followed by reintroduction at a lower daily dose, with or without a temporary course of an oral corticosteroid [35-37].
As with imatinib, cutaneous eruptions have been reported with dasatinib, nilotinib, ponatinib, and bosutinib:
●In a total of 911 patients reported in phase 1 and 2 studies of dasatinib, cutaneous eruptions were reported in 35 percent [38]. Reactions included localized and generalized erythema, papular eruptions, "exfoliative rash," and pruritus. Two cases of dasatinib-induced panniculitis have been described [39].
●In phase 1 and 2 studies, the most frequent nonhematologic side effects of nilotinib were "nonspecific rash" (20 to 28 percent of all patients), pruritus (15 to 24 percent), and dry skin (12 percent) [40,41].
●Ponatinib, which is available only with limited access in the United States because of a high frequency of venous and arterial thromboembolic phenomena, has been associated with rash and dry skin in up to 40 percent of patients [42]. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'VEGFR tyrosine kinase inhibitors'.)
●In clinical trials of bosutinib, adverse skin reactions were reported in 20 to 44 percent of patients and included erythema, maculopapular eruption, pruritic rash, allergic dermatitis, acne, folliculitis, and skin exfoliation [43,44].
Severe cutaneous adverse reactions — Severe reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, have been linked to multitargeted TKIs, in particular to imatinib [45]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
Acute generalized exanthematous pustulosis (AGEP) and Sweet syndrome (acute febrile neutrophilic dermatosis) have both been associated with imatinib therapy [46-49]. (See "Acute generalized exanthematous pustulosis (AGEP)" and "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)
Severe reactions usually prompt permanent drug discontinuation, although in some patients, a causal association may be unclear due to comorbidities and concomitant medications. In such cases, the decision to attempt retreatment with imatinib depends on the severity of the reaction and whether there are other therapeutic alternatives.
Photosensitivity — Photosensitization has been reported in patients treated with imatinib [34,50]. In a prospective study of 54 patients treated with imatinib for chronic myeloid leukemia, four (7 percent) developed photosensitivity [34]. Imatinib has also been associated with pseudoporphyria, a bullous photodermatosis with the clinical and histologic features of porphyria cutanea tarda [51,52]. (See "Pseudoporphyria".)
Photosensitivity has also been reported in patients treated with brigatinib for anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer [53].
Pigmentary changes — A number of patients have noted pigmentary changes of the skin and hair while undergoing treatment with imatinib, including both hypopigmentation (in Black patients [54]) and hyperpigmentation [54-58]. In a systematic review and meta-analysis, the incidence of all-grade pigmentary changes of the skin with imatinib monotherapy was 23 percent [59]. As the KIT receptor is known to play a role in melanogenesis and in melanocyte homeostasis [60], the photosensitivity and pigmentary changes may represent direct physiologic responses by skin melanocytes.
Other — In early clinical trials, up to 60 percent of patients treated with imatinib had edema, typically in a periorbital distribution [61]. Induction of psoriasiform eruptions and exacerbations of psoriasis have occurred in patients treated with imatinib [34,62,63]. In a prospective study of 54 patients treated with imatinib for chronic myeloid leukemia, four developed a psoriasiform eruption; two had a known history of psoriasis [34]. However, improvement of psoriasis has also been reported in one patient receiving imatinib for a gastrointestinal stromal tumor [64].
Other miscellaneous reactions that have been reported in patients receiving imatinib include small vessel vasculitis, erythema nodosum, a graft-versus-host-like skin reaction [65], an exfoliative dermatitis with fever and nonfollicular pustules [34], lichenoid drug eruption [66], and a single report of hand-foot syndrome [67]. Keratosis pilaris and xerosis are also frequent with TKIs that inhibit signal transduction through the BCR-ABL fusion protein, likely related to concomitant platelet-derived growth factor receptor (PDGFR)-alpha inhibition [68].
VEGFR/PDGFR INHIBITORS — Vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitors are a group of small molecule tyrosine kinase inhibitors (TKIs) that target a number of tyrosine receptors and tyrosine kinases involved in tumor growth and angiogenesis, including VEGFR, PDGFR, fibroblast growth factor receptor (FGFR), and rearranged during transfection (RET). These include:
These agents, which are used for the treatment of a variety of tumors (including renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer), are associated with a variety of cutaneous effects, which are summarized in the table (table 3).
Hand-foot skin reaction — Hand-foot skin reaction (HFSR) is the most common cutaneous adverse effect of multitargeted VEGFR TKIs. Its frequency appears to be higher with sorafenib and regorafenib compared with other VEGFR inhibitors [69-74]. Overall, all-grade and high-grade HFSR occurs in approximately 35 and 10 percent of patients, respectively [75,76], and differs in its clinical presentation and histologic appearance from the acral erythema caused by other conventional chemotherapy drugs [77,78]. (See "Cutaneous adverse effects of conventional chemotherapy agents".)
HFSR typically presents with focal, hyperkeratotic, callus-like lesions on an erythematous base in areas of pressure or friction, such as the fingertips, heels and metatarsal areas, and over joints (picture 4A-C). The clinical and histologic appearance of HFSR differs from the classic form of acral erythema that is associated with conventional cytotoxic chemotherapy agents, which is most often characterized by a symmetric edema and erythema of the palms and soles that may progress to blistering and necrosis, with loss of the epidermis and crusting (picture 5 and picture 6) [58,69,70,79,80]. Although HFSR is not included in the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) as its own category, "palmoplantar erythrodysesthesia" can be used to grade HFSR (table 4).
The management and prevention of HFSR are discussed in detail separately and summarized in the algorithm (algorithm 1). (See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors", section on 'Management' and "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors", section on 'Prevention'.)
Hair changes — Diffuse, reversible alopecia has been described in up to 50 percent of patients treated with sorafenib but less frequently in those treated with sunitinib (5 to 21 percent), pazopanib (8 to 10 percent), or axitinib (4 percent) [2,71,81,82]. (See "Alopecia related to systemic cancer therapy", section on 'Molecularly targeted agents'.)
Reversible hair depigmentation can occur during treatment with sunitinib and pazopanib [2]. In a phase 3 trial in which 290 patients with renal cell carcinoma were treated with pazopanib, changes in hair color occurred in 38 percent of treated patients and skin hypopigmentation was noted in 3 percent [83]. In a meta-analysis of 11 trials, the relative risk of all-grade alopecia and hair color changes in cancer patients treated with pazopanib was 1.75 (95% CI 1.33-2.31) and 4.54 (95% CI 3.67-5.62), respectively [84].
It is postulated that pigmentary changes associated with pazopanib may result from alterations in melanocyte proliferation or function secondary to the inhibition of KIT [85].
Squamoproliferative lesions — Sorafenib has been associated with cutaneous squamoproliferative lesions, including keratoacanthomas (KAs) and squamous cell carcinomas (SCCs) [86-91]. In a retrospective study of 131 patients receiving sorafenib for metastatic renal cell carcinoma, seven were diagnosed with SCC and two with KA [87]. Another report described the appearance of 22 squamoproliferative lesions in 13 patients within nine months of initiating sorafenib [86]. One was described as a classic invasive SCC, five as KA-like SCC, and 16 as classic KA. Prospective studies are necessary to clarify the risk and natural history of sorafenib-induced, squamoproliferative lesions.
Squamoproliferative lesions that develop during sorafenib therapy should be treated similarly to lesions that develop in patients not receiving the drug (usually with complete surgical excision). However, spontaneous regression of KAs has been reported after discontinuation of the drug and also in a few patients who continued therapy [86,92]. Definitive guidelines for continuing versus discontinuing sorafenib in patients who develop SCCs or KAs while on therapy have not been established. Close clinical follow-up during treatment is warranted. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)
Other cutaneous effects — A wide range of other cutaneous adverse effects have been described in patients treated with VEGFR inhibitors. Examples include the following:
●Sorafenib and sunitinib – Treatment with sorafenib and sunitinib has been associated with a variety of cutaneous adverse effects, including seborrheic dermatitis-like facial and scalp erythema, scalp dysesthesia, and subungual splinter hemorrhages [71,82]; eruptive, melanocytic lesions [93,94]; Stevens-Johnson syndrome (SJS); mucositis; geographic tongue [95]; erythema multiforme [96] and erythema multiforme-like eruptions [97,98]; periungual erythema [99]; acquired perforating dermatosis [100]; xerosis; and exanthematous rashes [101]. Sunitinib may induce facial edema and pyoderma gangrenosum, a rare, noninfectious neutrophilic dermatosis [102-104]. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis".)
●Vandetanib – Seborrheic dermatitis, acneiform eruption, dry skin, pruritus, photosensitivity, or HFSR have been reported in 28 to 71 percent of patients treated with vandetanib; they were severe (grade 3 or worse) in 3 to 6 percent [105-110]. Paronychia, genital eruptions resembling intertrigo, photodistributed lichenoid drug eruption, and subacute cutaneous lupus erythematosus have also been reported [111]. Severe skin reactions, some leading to death, have been reported with this agent [112,113]. Patients should be counseled to wear sunscreen and protective clothing when exposed to the sun.
●Regorafenib – Regorafenib targets VEGFR-1, VEGFR-2, and VEGFR-3, in addition to RET, KIT, PDGFR-alpha and PDGFR-beta, FGFR1 and FGFR2, and several other membrane-bound and intracellular kinases that are involved in normal cellular function and in pathologic processes. It is approved in the United States for the treatment of refractory metastatic colorectal cancer. In a phase 3 trial (the CORRECT trial), rash/desquamation was reported in 26 percent (versus 4 percent with placebo), and it was severe in 6 versus 0 percent [114]. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Regorafenib'.)
●Cabozantinib – Hair depigmentation, alopecia, dry skin, scrotal erythema/ulceration, and subungual splinter hemorrhages have been reported with cabozantinib, which is approved in the United States for the treatment of advanced medullary thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma [115,116]. (See "Medullary thyroid cancer: Systemic therapy and immunotherapy".)
FGFR INHIBITORS — Selective fibroblast growth factor receptor (FGFR) inhibitors are small molecule tyrosine kinase inhibitors (TKIs) approved for the treatment of cholangiocarcinoma and urothelial carcinoma. These include:
Dermatologic toxicities associated with FGFR inhibitors include hand-foot skin reaction (HFSR) (see 'Hand-foot skin reaction' above), stomatitis and xerostomia, nail changes (eg, paronychia, onychomadesis), and alopecia [117].
BRAF INHIBITORS — The BRAF inhibitors are serine-threonine kinase inhibitors that act as kinase inhibitors in mutant BRAF. They include:
●Encorafenib (second-generation BRAF inhibitor)
All three agents are approved for the treatment of metastatic melanoma with a V600E BRAF mutation. Cutaneous toxicities are common with these agents and include a wide range of manifestations, including nonspecific rash (maculopapular eruption), phototoxicity, and squamoproliferative lesions [118]. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Dabrafenib plus trametinib'.)
Maculopapular rash — A maculopapular eruption is the most common skin reaction associated with BRAF inhibitors. In a meta-analysis of nine randomized trials of vemurafenib, the overall prevalences of all-grade rash and high-grade rash were 45 percent (95% CI 0.34-0.57) and 12 percent (95% CI 0.03-0.38), respectively [119]. A granulomatous dermatitis, presenting as a widespread eruption of grouped, papular lesions coalescing into plaques, has been reported in a few patients months after starting treatment with vemurafenib [120].
Phototoxic reaction — The phototoxic reaction associated with vemurafenib appears to be caused by ultraviolet A (UVA) radiation and may be prevented with the use of broad-spectrum sunscreens (table 5) [121]. A meta-analysis of eight randomized trials (4095 patients) found an overall prevalence of all-grade phototoxic reaction of 30 percent (95% CI 0.23-0.38) among patients treated with vemurafenib.
Squamoproliferative lesions — Patients treated with BRAF inhibitors frequently develop keratinocytic, proliferative lesions, including cutaneous squamous cell carcinoma (cSCC), keratoacanthoma (KA), and verrucous lesions. A meta-analysis of seven randomized trials found a prevalence of cSCC and KA of 18 percent (95% CI 0.12-0.26) and 10 percent (95% CI 0.06-0.15), respectively, among patients taking vemurafenib [119]. In patients taking dabrafenib, verrucous lesions with low to moderate epidermal dysplasia have been reported in up to 66 percent and KAs or well-differentiated cSCCs in 6 to 26 percent [118,122-124].
These squamoproliferative lesions, which are thought to be induced by a paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway, appear in weeks to a few months after initiating treatment, are fast growing, are widely distributed on the body, and may occur in sun-protected sites [125]. In a series of 134 patients with metastatic melanoma treated with dabrafenib or vemurafenib, 32 patients (24 percent) developed one or multiple cSCCs, most of which were in the first three months of treatment [126]. The risk of developing cSCC increased with age, with cSCCs arising in 30 percent or more of patients older than 60 years [126].
Interestingly, skin papilloma and cSCC occur less frequently in patients treated with the combination of encorafenib plus binimetinib compared with encorafenib or vemurafenib as monotherapy. In a randomized, phase 3 trial including 577 patients with BRAF-mutant melanoma, cSCC developed in 4, 8, and 17 percent of patients receiving encorafenib plus binimetinib, encorafenib alone, or vemurafenib alone, respectively [127].
The skin tumors that develop in patients treated with these agents are managed with surgical excision, and patients are usually able to continue treatment without dose adjustment [128].
Hair changes — Alopecia is one of the most common adverse reactions of BRAF inhibitors. It has been reported in over 50 percent of patients receiving encorafenib and nearly 40 percent of patients receiving vemurafenib [129,130]. Changes in hair structure and color have been reported in patients taking dabrafenib [124].
Palmoplantar keratoderma — In clinical trials, palmoplantar keratoderma has been reported in 15 to 25 percent of patients receiving BRAF inhibitors [124,129,131]. Grade 1 to 2 and grade 3 hand-foot skin reaction (HFSR) have been reported in 38 and 14 percent of patients treated with encorafenib, respectively [129].
Other — Other cutaneous adverse events associated with BRAF inhibitors include hyperkeratosis, palmoplantar erythrodysesthesia, acrochordons, keratosis pilaris, actinic keratoses, lichenoid keratoses, papillomas, seborrheic keratoses, and pyogenic granulomas [127,132-136]. Vemurafenib has also been associated with radiation enhancement when radiation therapy was administered concurrently [137,138]. (See "Radiation dermatitis".)
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) has been reported in patients taking vemurafenib [139-141]. Grover's disease (transient acantholytic dermatosis) has been reported in up to 27 percent of patients receiving dabrafenib [124]. (See "Grover's disease (transient and persistent acantholytic dermatosis)".)
BRAF PLUS MEK INHIBITORS — Orally bioavailable inhibitors of mitogen-activated protein kinase (MAPK) enzymes (MEK1 and MEK2) include:
They are approved for the treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation in combination with the BRAF inhibitors vemurafenib, dabrafenib, and encorafenib [142,143]. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Choice of BRAF plus MEK inhibitor therapy' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)
Cutaneous adverse effects of MEK inhibitors are common and include acneiform eruption, pruritus, and xerosis [131,144,145]. Data from studies of combination therapy with dabrafenib plus trametinib for advanced melanoma indicate that the combination therapy is associated with a marked reduction of cutaneous toxicities compared with vemurafenib or dabrafenib alone [123,146,147]:
●In a phase 3 study including 350 patients treated with dabrafenib plus trametinib and 349 patients treated with vemurafenib alone, skin toxicities were less frequent in the combination therapy group than in the vemurafenib group: rash (22 versus 43 percent), photosensitivity reaction (4 versus 22 percent), hand-foot syndrome (4 versus 25 percent), skin papillomas (2 versus 23 percent), cutaneous squamous cell carcinoma (cSCC) and keratoacanthoma (KA; 1 versus 18 percent), and hyperkeratosis (4 versus 25 percent) [146].
●In another phase 3, randomized trial including 211 patients treated with dabrafenib plus trametinib and 212 patients treated with dabrafenib alone, cutaneous adverse events occurred less frequently in the combination therapy group than in the dabrafenib alone group: hyperkeratosis (7 versus 35 percent), alopecia (9 versus 28 percent), skin papilloma (2 versus 22 percent), and cSCC/KA (2 versus 7 percent) [147].
In a phase 2, randomized trial including 192 patients treated with encorafenib plus binimetinib, 194 patients treated with encorafenib alone, and 191 patients treated with vemurafenib alone, cutaneous adverse events occurred less frequently in the combination therapy group than in the encorafenib and vemurafenib groups: rash (22, 41, and 53 percent, respectively), palmoplantar keratoderma (9, 26, and 16 percent, respectively), palmoplantar erythrodysesthesia (7, 52, and 14 percent, respectively), skin papilloma (7, 10, and 19 percent, respectively), and cSCC/KA (3, 8, and 17 percent, respectively) [129].
MET INHIBITORS — Photosensitivity reactions have been reported with capmatinib, a mesenchymal-epithelial transition (MET) kinase inhibitor approved for the treatment of locally advanced non-small cell lung cancer carrying the MET exon 14 skipping mutation that are resistant to first- or second-generation epidermal growth factor receptor (EGFR) inhibitors [148].
PI3K INHIBITORS — Phosphoinositide 3-kinase (PI3K) is a family of highly conserved enzymes involved in the intracellular PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. There are three classes of PI3K kinases (class I [further divided into IA and IB], class II, and class III) and four isoforms (alpha, beta, gamma, delta). Hyperactivation of the PI3K pathway is involved in a variety of human cancers [149]. Class IA PI3K inhibitors include:
Idelalisib and copanlisib are approved in the United States for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and relapsed or refractory follicular lymphoma [150,151]. Duvelisib is approved for the treatment of CLL and SLL [152]. Dacomitinib is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer [153]. Alpelisib is approved for the treatment of breast cancer in combination with aromatase inhibitors [154]:
●Mucocutaneous adverse reactions, including maculopapular rash and oral mucositis, have been reported in approximately 14 and 23 percent of patients, respectively, treated with copanlisib and in 20 to 40 percent and 16 percent of patients, respectively, treated with duvelisib [155-158]. A maculopapular rash has been reported in up to 30 percent of patients treated with alpelisib [159].
●Maculopapular rash and exfoliative skin reactions have been reported in 78 and 7 percent of patients, respectively, treated with dacomitinib [153].
●Serious cutaneous reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN), have been reported in 5 percent of patients treated with duvelisib [152].
CDK 4/6 INHIBITORS — Palbociclib [160,161], abemaciclib [162], and ribociclib [163] are cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced or metastatic breast cancer. They are used in combination with an aromatase inhibitor (palbociclib, abemaciclib, ribociclib), fulvestrant (palbociclib, abemaciclib), or monotherapy (abemaciclib).
Alopecia, maculopapular rash, and pruritus have been reported with CDK 4/6 inhibitors.
JAK INHIBITORS — Ruxolitinib is an orally bioavailable inhibitor of Janus kinase (JAK) 1/2 involved in cytokine signaling and hematopoiesis. Ruxolitinib is approved for the treatment of intermediate or high-risk myelofibrosis; polycythemia vera; and steroid-refractory, acute graft-versus-host disease.
Increased risk of nonmelanoma skin cancer has been reported with ruxolitinib [164].
BTK INHIBITORS — Orally bioavailable, irreversible inhibitors of Bruton's tyrosine kinase (BTK), an integral component of the B cell receptor pathway, include:
●Ibrutinib – Ibrutinib is a first-generation BTK inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of mantle cell lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia (CLL), and chronic graft-versus-host disease [165].
●Acalabrutinib and zanubrutinib – Acalabrutinib and zanubrutinib are second-generation BTK inhibitors approved for relapsed or refractory mantle cell lymphoma [166,167].
Cutaneous adverse effects of BTK inhibitors include petechial to purpuric skin eruptions and nail and hair changes. The overall incidence of dermatologic toxicities is reduced with second-generation BTK inhibitors [168]:
●Petechiae and bruising – Petechiae and bruising are reported to occur in up to 50 to 54 percent of patients treated with ibrutinib, acalabrutinib, and zanubrutinib [169]. One study described mild, petechial eruptions, which did not require skin-directed therapy or ibrutinib dose adjustments, as well as palpable, purpuric eruptions, which improved with topical steroids, oral steroids, and/or temporary interruption of ibrutinib [170]. The BTK inhibitor-associated bleeding diathesis is thought to be due to the inhibition of the platelet BTK, which is involved in collagen-mediated platelet activation [171,172].
●Nail and hair changes – Nail changes, including onychoschizia (lamellar splitting of the nail) and onychorrhexis (longitudinal ridging), have been reported in approximately two-thirds of patients after 6 to 12 months of treatment with ibrutinib [173]. Hair changes include straightening and softening or increased curliness. These effects are postulated to be specific to ibrutinib, acalabrutinib, and zanubrutinib, as they covalently bind to the cysteine residue at the active site of BTK, and disulfide bonds in hair and nail keratins are known to be important for their integrity.
●Skin infections – Opportunistic skin infections with herpes simplex and herpes zoster reactivations and S. aureus superinfection (presenting as folliculitis) are promoted by BTK inhibitor-associated B cell dysfunction, induced neutropenia, and reduction in macrophagic phagocytosis and are greatest during the first year of therapy, with gradual secondary restoration of cellular and humoral immunity [168].
Ibrutinib may also induce panniculitis, presenting as well-defined, erythematous, tender nodules on the legs.
CCR4 INHIBITORS — Mogamulizumab is a C-C chemokine receptor type 4 (CCR4)-directed monoclonal antibody approved by the US Food and Drug Administration (FDA) for the treatment of relapsed or refractory mycosis fungoides or Sézary syndrome [174]. CCR4, expressed on the surface of tumor cells in T cell malignancies, is involved in lymphocyte cell homing to the skin:
Rash is one of the most common adverse events associated with mogamulizumab (mogamulizumab-associated rash), occurring in 25 percent of patients, with 18 percent of these being severe (grade 3). It typically occurs after 15 to 31 weeks of therapy and can present as a lichenoid, psoriasiform, or pustular eruption. Biopsy may be indicated to distinguish drug eruption from disease progression.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in <1 percent of patients. SJS/TEN is thought to occur due to drug-induced depletion of CCR4-expressing FOXP3+ T cells, leading to uncontrolled, cytotoxic CD8+ T cells [175].
Treatment with mogamulizumab should be discontinued for life-threatening grade 4 rash or for any SJS/TEN. If SJS/TEN is suspected, do not resume unless SJS/TEN has been excluded and the cutaneous adverse event has resolved to grade 1 or less [174].
FLT3 INHIBITORS — The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in 30 percent of patients with acute myeloid leukemia (AML), of which nearly a quarter demonstrate internal tandem duplications (ITDs). The FLT3-ITD mutation is associated with an increased risk of relapse and poor prognosis. FLT3 inhibitors induce terminal differentiation of and direct cytotoxicity to FLT3-mutant myeloblasts [176].
FLT3 inhibitors include:
●Sorafenib, lestaurtinib, midostaurin (first-generation multikinase inhibitors).
●Quizartinib, crenolanib, gilteritinib (next-generation inhibitors); they are more potent and have less off-target effects compared with first-generation agents.
The adverse events associated with sorafenib are reviewed above. (See 'VEGFR/PDGFR inhibitors' above.)
Cutaneous adverse events associated with other FLT3 inhibitors include:
●Petechiae, hyperhidrosis, and xerosis – Petechiae, hyperhidrosis, and xerosis have been associated with midostaurin, an orally bioavailable, first-generation multikinase inhibitor approved for the treatment of newly diagnosed AML that is FLT3 mutation positive in combination with standard cytarabine, daunorubicin induction, and cytarabine consolidation; aggressive systemic mastocytosis; systemic mastocytosis with associated hematologic neoplasms; or mast cell leukemia [177].
●Peripheral edema and rash – Peripheral edema and rash have been reported with gilteritinib, an orally bioavailable, next-generation FLT3 inhibitor approved for the treatment of relapsed or refractory AML with FLT3 mutation:
•In the phase 3 ADMIRAL trial, peripheral edema and rash were reported as treatment-emergent adverse events in 24 and 14 percent of patients, respectively [178]. Among 319 patients across three clinical trials, gilteritinib was associated with peripheral edema and rash in 40 and 36 percent of patients, respectively [179].
•A meta-analysis of 2656 patients treated with five different FLT3 inhibitors (sorafenib, lestaurtinib, midostaurin, gilteritinib, and quizartinib) found an overall increased risk of rash, desquamation, petechiae, and pruritus with FLT3 inhibitors compared with controls (relative risk [RR] 1.55, 95% CI 1.28-1.87) [180].
●Neutrophilic dermatoses – Neutrophilic dermatoses, including panniculitis and Sweet syndrome, have also been associated with FLT3 inhibitors. FLT3 inhibition, which leads to terminal differentiation of myeloblasts, may cause differentiation syndrome with associated neutrophilic dermatosis [176,181,182]. Neutrophilic dermatoses may require treatment dose reduction, interruption, or discontinuation. (See "Neutrophilic dermatoses" and "Sweet syndrome (acute febrile neutrophilic dermatosis): Management and prognosis".)
IDH INHIBITORS — Isocitrate dehydrogenase (IDH) 1 and 2 are mutated in 6 to 10 percent and 9 to 13 percent of patients, respectively, with acute myeloid leukemia (AML) [183]. These IDH1/2 mutations block normal cellular differentiation and drive tumorigenesis [184]:
●Ivosidenib – Ivosidenib is an oral, selective, small molecule IDH1 inhibitor indicated for the treatment of newly diagnosed AML in patients ≥75 years or with comorbidities that preclude use of intensive induction chemotherapy or for relapsed or refractory AML with a susceptible IDH1 mutation.
●Enasidenib – Enasidenib is an oral, selective, small molecule inhibitor of IDH2 indicated for the treatment of relapsed or refractory AML with a susceptible IDH2 mutation.
Peripheral edema has been reported in 39 to 43 percent of patients treated with ivosidenib and in 21 percent of patients treated with enasidenib [185,186]. Rash and pruritus were reported in 14 to 26 percent and 14 percent of patients, respectively, treated with ivosidenib [185].
Edema and rash may present as manifestations of differentiation syndrome, resulting from IDH1/2 therapy. Treatment with IDH1/2 inhibitors may remove the differentiation block in the malignant myeloid clone, leading to a rapid increase in differentiated neutrophils associated with a constellation of findings, including constitutional symptoms, culture-negative fevers, pleural/pericardial effusions, edema, weight gain, hypotension, renal dysfunction, and rash at a time of marked leukocytosis, known as differentiation syndrome [184].
BCL2 INHIBITORS — Venetoclax is an orally bioavailable inhibitor of B cell lymphoma 2 (BCL2), an antiapoptotic protein that is constitutively overexpressed in chronic lymphocytic leukemia (CLL) cells [187]. Venetoclax is approved for the treatment of patients with CLL with 17p deletion who have received at least one prior therapy.
Rash has been reported in 14 percent of CLL patients on venetoclax with concurrent rituximab and in 22 percent of patients on venetoclax post-therapy with idelalisib [187].
SUMMARY
●EGFR inhibitors − Epidermal growth factor receptor (EGFR) inhibitors (eg, cetuximab, panitumumab, erlotinib, gefitinib, lapatinib) are associated with prominent dermatologic adverse events, the most common of which is a papulopustular acneiform eruption (table 1). It typically begins early, within one to two weeks of treatment initiation and is often dose dependent (picture 1A-C) [7,8]. The lesions occur on the face, scalp, chest, and back, usually sparing the extremities. Other reactions associated with EGFR inhibitors include paronychia (picture 2), hair abnormalities, xerosis, mucositis, and photosensitivity. (See 'EGFR inhibitors' above and "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)
●BCR-ABL tyrosine kinase inhibitors − The most common cutaneous adverse event associated with inhibitors of the BCR-ABL fusion protein (eg, imatinib, dasatinib, ponatinib) is an exanthematous, maculopapular eruption. Severe skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and Sweet syndrome, have been reported with imatinib. Other reactions include photosensitivity, pigmentary changes of the skin and hair, edema, psoriasiform eruption, keratosis pilaris, and xerosis. (See 'BCR-ABL tyrosine kinase inhibitors' above.)
●VEGFR/PDGFR inhibitors − Vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitors (eg, sorafenib, sunitinib, pazopanib, regorafenib) are most frequently associated with hand-foot skin reaction (HFSR). It typically presents with focal, hyperkeratotic, callus-like lesions on an erythematous base in areas of pressure or friction, such as the fingertips, heels and metatarsal areas, and over joints (picture 4A-C). HFSR is discussed in detail separately (see "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors"). Other adverse events include a diffuse, reversible alopecia and changes in hair color, maculopapular rash, desquamation, and xerosis. Sorafenib has also been associated with cutaneous, squamoproliferative lesions, including keratoacanthomas (KAs) and squamous cell carcinomas (SCCs). (See 'VEGFR/PDGFR inhibitors' above.)
●BRAF inhibitors − BRAF inhibitors (eg, vemurafenib, dabrafenib, encorafenib) are frequently associated with a maculopapular eruption. Vemurafenib may also cause an ultraviolet A (UVA)-induced phototoxic reaction. Patients treated with BRAF inhibitors frequently develop keratinocytic proliferative lesions, including cutaneous squamous cell carcinoma (cSCC), KA, and verrucal keratotic lesions, which appear weeks to months after initiating treatment. Other reactions include alopecia, palmoplantar keratoderma, palmoplantar erythrodysesthesia, acrochordon, actinic keratosis, and pyogenic granuloma. (See 'BRAF inhibitors' above.)
●MEK inhibitors − Cutaneous adverse effects of MEK inhibitors (trametinib, cobimetinib, and binimetinib) include acneiform eruption, pruritus, and xerosis. Of note, the cutaneous toxicity of the BRAF-MEK combination therapy is markedly reduced compared with BRAF therapy alone. (See 'BRAF plus MEK inhibitors' above.)
●MET inhibitors − Photosensitivity reactions have been reported with capmatinib, a mesenchymal-epithelial transition (MET) kinase inhibitor. (See 'MET inhibitors' above.)
●PI3K inhibitors − Phosphoinositide 3-kinase (PI3K) inhibitors (idelalisib, copanlisib, duvelisib, dacomitinib, and alpelisib) are associated with maculopapular rash and oral mucositis. Serious cutaneous reaction, including DRESS and TEN, have been reported in patients treated with duvelisib. (See 'PI3K inhibitors' above.)
●CDK inhibitors − Cyclin-dependent kinase (CDK) 4/6 inhibitors (palbociclib, abemaciclib, ribociclib) are associated with alopecia, maculopapular rash, and pruritus. (See 'CDK 4/6 inhibitors' above.)
●JAK inhibitors − The Janus kinase (JAK) inhibitor ruxolitinib is associated with an increased risk of nonmelanoma skin cancer. (See 'JAK inhibitors' above.)
●BTK inhibitors − The Bruton kinase (BTK) inhibitor ibrutinib is associated with petechiae, bruising, and nail and hair changes. (See 'BTK inhibitors' above.)
●CCR4 inhibitors − Rash is one of the most common adverse events associated with the C-C chemokine receptor type 4 (CCR4) inhibitor mogamulizumab. SJS/TEN, scaly plaques, pustular eruption, folliculitis, and nonspecific or psoriasiform dermatitis have also been reported. (See 'CCR4 inhibitors' above.)
●FLT3 inhibitors – FMS-like tyrosine kinase 3 (FLT3) inhibitors (midostaurin, gilteritinib) are associated with neutrophilic dermatoses. Midostaurin is also associated with petechiae, hyperhidrosis, and xerosis. Gilteritinib may cause peripheral edema, rash, and dermatologic manifestations as part of differentiation syndrome. (See "Differentiation syndrome associated with treatment of acute leukemia" and 'FLT3 inhibitors' above.)
●IDH inhibitors − Isocitrate dehydrogenase (IDH) inhibitors (ivosidenib, enasidenib) are associated with peripheral edema, rash, pruritus, and dermatologic manifestations as part of differentiation syndrome. (See 'IDH inhibitors' above.)
●BCL2 inhibitors − The B cell lymphoma 2 (BCL2) inhibitor venetoclax is associated with rash. (See 'BCL2 inhibitors' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Diane MF Savarese, MD, Aimee S Payne, MD, PhD, and Mario E Lacouture, MD, who contributed to earlier versions of this topic review.
