Dermatologic Adverse Events Associated with Selective Fibroblast Growth Factor Receptor Inhibitors: Overview, Prevention, And Management Guidelines

ABSTRACT. Fibroblast growth factor receptor (FGFR) tyrosine kinases, which are expressed on the cell membrane, are involved in a wide range of biological functions such as cell proliferation, survival, migration, and differentiation. The identification of FGFR fusions and other alterations in a wide range of solid tumors, including cholangiocarcinoma and bladder cancer, has resulted in the development of sev- eral selective FGFR inhibitors for use in these indications, for example infigratinib, erdafitinib, derazantinib, pemigatinib, and futibatinib. In addition to the typical adverse events associated with tyrosine kinases, the FGFR inhibitors appear to give rise to a number of adverse events affecting the skin. Here we describe these skin events,which include the more common nail adverse events (e.g., onycholysis), palmar–plantar erythrodysesthesia syn- drome, and stomatitis, as well as less common reactions such as calciphylaxis. This review aims to provide oncolo- gists with an understanding of these dermatologic events and proposes guidelines for the management of treatment- emergent dermatologic adverse events. Awareness of possi- ble adverse events associated with specific drugs should allow physicians to educate patients as to what to expect and implement effective management plans at the earliest possible opportunity, thereby preventing premature discon- tinuation while maintaining patient quality of life. The Oncologist 2020;9999: Implications for Practice: Identification of FGFR aberrations in cancers such as cholangiocarcinoma and bladder cancer led to development of selective FGFR inhibitors for these indications, based on clinical benefit and safety profiles.

INTRODUCTION
Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular pro- liferation, survival, migration, and differentiation [1]. Twenty-two mammalian FGFs have been identified to date, many of which depend on interaction with FGF receptors (FGFRs) for their biological effects [2]. The human FGFR family comprises five members: FGFR1, FGFR2, FGFR3, FGFR4, and FGFR5. FGFRs 1–4 are receptor tyrosine kinases consisting of an extracellular ligand binding domain and a tyrosine kinase domain, which are expressed on the cell membrane [3]. FGFR fusions and other alterations have been reported in a wide range of solid tumors, including cholangiocarcinoma [4], bladder cancer [5], lung cancer [6], and glioblastoma [7]. Identification of targetable genomic alterations has resulted in the development of several FGF/FGFR-directed therapies, primarily small-molecule tyro- sine kinase inhibitors (TKIs) or multikinase inhibitors, with differing profiles (Table 1). A number of selective FGFR TKIs– infigratinib, erdafitinib, derazantinib, pemigatinib, and futibatinib (TAS-120) – are in advanced stages of develop- ment in patients with cholangiocarcinoma and urothelial cancer. Ongoing phase II and III trials of these agents are summarized in Table 2.As FGFs act with other signaling molecules to orches- trate processes such as tissue regeneration and healing, inhibition of FGFR signaling has the potential to lead to on- target adverse events such as hyperphosphatemia, which is believed to result from inhibition of FGFR signaling in the proximal renal tubule, as well as others associated with off- target effects, including alopecia, dry mouth/xerostomia, nail changes, and other dermatologic events [8, 9]. Depending on the breadth of their inhibitory targets, adverse events associated with anti-FGFR TKIs can also include those related to vascular endothelial growth factor receptor inhibition (e.g., hypertension, cardiovascular events, and proteinuria), as seen with earlier-generation multikinase inhibitors, and others commonly reported with TKIs, e.g., gastrointestinal disorders, such as vomiting and diarrhea, skin reactions, and ocular effects, such as dry eye and retinal pigment epithelium detachment.The aim of this review is to provide oncologists with an understanding of the dermatologic events associated with FGFR inhibitors currently in clinical development or approved by regulatory agencies for the treatment of cholangiocarcinoma and urothelial cancers.

Cholangiocarcinoma is a heterogeneous grouping of malig- nancies arising from the biliary epithelium between the canals of Hering and the main bile duct. These are uncom- mon cancers, accounting for only 3% of gastrointestinal can- cers [10]; however, the mortality rate is high and only 8–10% of patients are alive at 5 years after diagnosis [11].The incidence of cholangiocarcinoma varies greatly, with the highest rates seen in Asian countries and lower rates in Western countries [12], although rates of intrahepatic cholangiocarcinoma are increasing in Western countries [13]. In their analysis of Surveillance, Epidemiology, and End Results data, Saha and colleagues reported an increase in rates of intrahepatic cholangiocarcinoma, from 0.44/100,000 in 1973 to 1.18/100,000 in 2012 [14]. This cor-responds to an estimated 8,000 new cases of cholangiocarcinoma per year in the US [15].Treatment options are limited for patients with meta- static cholangiocarcinoma and outcomes are poor. The gemcitabine + cisplatin doublet is the standard of care in the first-line setting, resulting in median overall and progression-free survivals of 11.7 and 8.0 months, respec- tively [16]. After first-line therapy, there are no established systemic options [17, 18]. However, the practice-changing ABC-06 study demonstrated that treatment with a modified 5-fluorouracil/folinic acid + oxaliplatin (FOLFOX) regimen and active symptom control was superior to active symp- tom control alone in patients with cholangiocarcinoma whose disease had progressed during or after treatment with gemcitabine + cisplatin [19]. Despite this, there remains a need for targeted agents with the potential to improve survival in selected patient populations.Alterations in genes encoding FGFRs are common in patients with cholangiocarcinoma, the most common being FGFR2 fusions, FGFR19 amplifications, and FGFR2 mutations [20]. FGFR2 fusions are present in 13–25% of patients with cholangiocarcinoma [20, 21] and therefore represent a promising target for therapy in enriched patient populations.

Key small-molecule FGFR TKIs currently under clinical development for the treatment of cholangiocarcinoma include multikinase and tyrosine kinase inhibitors such as infigratinib, erdafitinib, derazantinib, futibatinib, pazopanib, and Debio 1347. Pemigatinib was approved for use in patients with FGFR2 fusion or rearrangement in April 2020, based on the results of the phase 2 FIGHT-202 study [22]. Other agents with a broader spectrum of activity, e.g., the multikinase inhibitors pazopanib and dovitinib, are also in development for this indication but are not included in this review.An estimated 80,000 new cases of bladder cancer will be diagnosed in the USA in 2019, three-quarters of which will be in men [23].Approximately 12% of patients have regional or distant metastases at diagnosis [24]. Five-year survival rates are 36% for regional and 5% for distant metastases [24]. Treat- ment options for locally advanced disease include surgery followed by cisplatin-based chemotherapy if no neo- adjuvant treatment has been given [25]. For those with metastatic disease, preferred options include gemcitabine + cisplatin for cisplatin-eligible patients and gemcitabine + carboplatin for those who are not eligible [25]. Targeted therapies currently available for patients whose disease progressed on cisplatin-based therapies include atezolizumab and pembrolizumab, which are approved by the U.S. Food and Drug Administration (FDA) for use in patients whose tumors express programmed cell death ligand 1 (PD-L1) [26], enfortumab vedotin for patients who have previously received a programmed cell death-1 (PD-1) or PD-L1 inhibitor [27], and erdafitinib for patients with FGFR2- and FGFR3-altered disease, based on the results of the BLC2001 study [28].

Selective small-molecule FGFR TKIs currently in develop- ment for use in patients with urothelial carcinoma include infigratinib, pemigatinib, erdafitinib, and rogaratinib. Dermatologic adverse events, including hair loss/alopecia, hand–foot skin reaction or palmar–plantar erythrodysesthesia syndrome (PPES), stomatitis (oral mucositis), and nail changes, have been reported in phase II studies in patients with cholangiocarcinoma and urothelial carcinoma treated with FGFR inhibitors (Figure 1; Tables 3 and 4). The pathophysiological mechanisms behind these adverse events are not yet fully elucidated. Several possible mechanisms have been proposed, including inhibition of FGFR in keratinocytes, inducing dysregulation of hair-follicle homeostasis and epidermal proliferation and/or differentia- tion with downregulation of tight junction gene expression, as demonstrated in FGFR-deficient mice [29] and by inhibiting hormonal (non-pathological) FGF signaling by FGF-19, -21, and -23 [30]. FGF2 expression has been shown to be upregulated in the nail epithelium after digit amputa- tion in the mouse, suggesting a role for FGF signaling in digit regeneration [31].Nail changes are common in patients undergoing treatment with FGFR TKIs [32]. Patients can develop significant adverse events, the most important of which is onycholysis[33] and dose adjustment may be required as a result of this adverse event. Other less common nail events include paronychia, Beau’s lines/onychomadesis, and brittle nails (onychoschizia). Paronychia was reported in 24% and 17% of patients with cholangiocarcinoma and urothelial carci- noma, respectively, treated with erdafitinib [28, 34]; fur- thermore, onycholysis and nail dystrophy were observed in18% and 16%, respectively, of patients with urothelial carci- noma [28].

Paronychia and onychomadesis were reported in 7% and 18%, respectively, of patients with cholangiocarcinoma who received infigratinib [35].Nail adverse events, which typically develop within 1–2 months of treatment initiation, can be prolonged and debil- itating [32, 36], and in severe cases can cause pain and dis- comfort, which can lead to treatment discontinuation [37].Alopecia is a psychosocially impactful consequence of cyto- toxic chemotherapy and treatment with kinase inhibitors [38]. Alopecia, which includes the textural changes, thin- ning, or patchy hair categorized as grade 1 alopecia, and the complete hair loss categorized as grade 2 alopecia, has been reported in patients with cholangiocarcinoma treated with infigratinib. Specifically, 26% of patients treated with infigratinib [35], 46% of those treated with pemigatinib [22] and 24% of patients treated with derazantinib [39] experi- enced grade 1 or 2 alopecia. In patients with urothelial car- cinoma, grade 1 or 2 alopecia occurred in 31%, 39%, and 29% of patients treated with infigratinib [40], pemigatinib [41], and erdafitinib [34].Other body hair can also be adversely affected in patients undergoing treatment with FGFR inhibitors, e.g., eyelash trichomegaly has been reported with infigratinib [33].Palmar–Plantar Erythrodysesthesia Syndrome (Hand–Foot Skin Reaction; Hand–Foot syndrome) PPES has been reported with chemotherapy and TKI treat- ment. It is characterized by hyperkeratosis and focal cal- luses, which result in diffuse xerosis and erythema combined with fissures, mostly localized to digits.

This skin reaction was reported in 21%, 29%, and 18% of patients with cholangiocarcinoma receiving infigratinib[35], erdafitinib [42], and futibatinib [43], respectively, and in 12% and 23% of patients with urothelial carcinoma receiv- ing infigratinib [40] and erdafitinib [28], respectively. Among patients with cholangiocarcinoma, grade 3/4 PPES was reported in 5% of patients treated with infigratinib [35] and 4% of those treated with pemigatinib [22], whereas 8% of infigratinib-treated [40] and 5% of erdafitinib-treated patients with urothelial cancer [28] reported this event. Of note, this adverse event differs from that seen with traditional chemotherapeutic agents. PPES with cytotoxic agents such as capecitabine and doxorubicin is characterized by diffuse erythema, edema, and pain of the entire surface of the palms and soles [44]. With VEGFR/PDGFR multikinase inhibitors, painful blisters located in areas of friction or pressure in the palms and soles are observed [44, 45]. Con- versely, with FGFR inhibitors, the ventral aspect of the distal digits and lateral aspects of the palms and soles is affected by erythema and pain, accompanied by onycholysis and secondary paronychia, reminiscent of changes observed with microtubule inhibitors (i.e. taxanes). PPES often pre- sents as a mild-to-moderate cutaneous edema, erythema, and hyperkeratosis with FGFR inhibitors; this evolves into painful digits that can impact on patients’ quality of life [46, 47], and can ultimately limit daily functioning and lead to areduction of the duration and intensity of treatment or its discontinuation [48].Stomatitis is one of the most commonly observed adverse events in patients treated with FGFR inhibitors, with lesions appearing rapidly after treatment initiation. In contrast to radiation or cytotoxic therapy induced oral mucositis, sto- matitis is characterized by painful well-defined lesions.

The incidence of stomatitis among patients with cholangiocarcinoma ranged from 7% with derazantinib [39] to 65% with erdafitinib [42]; furthermore, 18% of patients treated with erdafitinib experienced grade ≥3 stomatitis[42]. Among patients with urothelial carcinoma, the inci-dence of stomatitis ranged from 12% with rogaratinib [49] to 58% with erdafitinib [28]. Although usually self-limiting, stomatitis can be very painful and can significantly impact patients’ quality of life.Xerosis is a common side effect of treatment with FGFR inhibitors, reported in 18% of patients in a systematic review of 58 such agents [50]. Xerosis may manifest as pru-reported in one patient treated with infigratinib [53] and another treated with pemigatinib [54]. Of further interest is the risk of non-uremic calciphylaxis, or intimal vascular cal- cifications, resulting in vascular thrombosis and extensive skin necrosis resulting in grade 3 and 4 cutaneous ulcera- tions. These conditions may be related to changes in under- lying serum phosphatase changes known to be associated with these agents [55], or to the role of FGF/FGFR signaling in skeletal development [56]. Expression of FGF-2 and its coreceptor syndecan-4 is increased at sites of calcification in human atherosclerotic plaques, suggesting a role for FGFR inhibition in vascular calcification, a major cause of morbidity and mortality [57].With the exception of calciphylaxis, the dermatologic adverse events described above are predominantly grade1 and 2 in severity, but these adverse events have the potential to disrupt treatment, as reflected by the extent of dose modification shown in Tables 3 and 4. The time to onset of dermatologic adverse events associated with pan- FGFR inhibition is summarized in Figure 2. Awareness and anticipation of these adverse events is critical in order to ensure patient adherence to FGFR-targeted therapies.xerotic dermatitis and can lead to bacterial or viral superin- fection with Staphylococcus aureus, herpes simplex, or other bacterial and viral agents. Although severe or life- threatening complications are uncommon, low-grade xerosis can result in dose delays or discontinuations, poten- tially impacting on the overall efficacy of treatment.

The incidence of dry skin in patients with cholangiocarcinoma treated with the FGFR inhibitors ranged from 10% in derazantinib-treated patients [39] to 35% in erdafitinib-treated patients [42], whereas for those with urothelial cancer, dry skin was reported in 12% of infigratinib-treated patients [40] and 32% of erdafitinib- treated patients [34]. The dry skin associated with FGFR inhibition was generally mild to moderate (grade 1 or 2) in nature.Dry mouth, or xerostomia, is a subjective complaint that can be very severe and represents a significant burden for patients if speech, chewing, swallowing, and general wellbeing are affected [51]. Dry mouth can be associated with dysgeusia, which can occasionally be very severe [36]. FGFs and FGFRs play a central role in salivary gland branching morphogenesis and disruption of these factors or their receptors has been shown to have implications for sal- ivary gland function [52]. Dry mouth, generally grade 1 or 2, was common in patients treated with FGFR inhibitors, occurring in 23–59% of patients with cholangiocarcinoma and 31–46% of patients with urothelial cancers (Tables 3 and 4).Prevention and early treatment of dermatologic adverse events is key to maximizing adherence to therapy and opti- mizing outcomes in patients undergoing treatment with FGFR inhibitors; however, data specific to preventive thera- pies for use with FGFR-targeted therapy are scarce. When preventive measures are unsuccessful and adverse events emerge, effective management strategies can ensure con- tinuation of treatment, particularly if employed at the earli- est appearance of grade 1 symptoms. Management approaches are shown in Figure 3 and summarized below.

Notably, although treatment for skin toxicities will be initi- ated by the oncologic team, referral to a dermatologist for consultation is recommended for patients with grade 3/intolerable grade 2 events, or grade 2 events that havenot responded to ≥4 weeks of therapy.Counseling and education on the potential for nail changes are essential before initiation of treatment with FGFR inhib- itors. Preventive strategies include avoidance of prolonged contact with water, repeated trauma, friction, and pressure on nails and nail beds. The use of protective gloves and lim- iting use of nail polish removers and nail hardeners is also helpful. Patients are also advised to avoid biting nails or cutting nails too short, and to use topical emollients, and loose-fitting socks and footwear. Preventive correction of nail curvature may be considered.Recommended treatments for grade 1 paronychia include topical povidone iodine 2–10% applied twice daily [58] or daily nail soaking in 1:1 vinegar:water for 15 minutes a day. Patients with grade 2 or 3 paronychia should be treated with a 14-day course of oral antibiotics in addition to dailynail soaking in 1:1 vinegar:water; bacterial cultures should be obtained to confirm sensitivity to antimicrobial agents. Dermatology consultation is recommended for grade ≥2 paronychia, given the potential chronicity of this event.Recommended management options for onycholysis consist of trimming the raised distal nails, clipping of the nails, and application of topical povidone iodine 2-10% bid solution[58] around and under the nails. Oral antibiotics should be started if infection is suspected (bacterial cultures and sen- sitivities should be obtained prior to initiating antibiotics) and nail avulsion may be needed if the patient has painful hematoma or subungual abscess.Preventive measures normally considered for patients undergoing traditional chemotherapy regimens, e.g., scalp compression, scalp cooling, and medications, are not appli- cable to patients receiving FGFR inhibitors and the healthcare provider’s attention should be focused on early identification and management of symptoms.Management of alopecia consists of prophylactic or reactive topical minoxidil 5% applied once daily to the scalp to encourage hair regrowth, and a topical high potency top- ical corticosteroid (e.g., fluocinonide 0.05% solution).

In addition, hair camouflaging methods such as TOPPIKTM, which create the appearance of naturally thicker, fuller hair may be considered. Alopecia typically reverses when treat- ment is discontinued.Prevention strategies for PPES include prophylactic removal of hyperkeratotic areas, application of moisturizing cream containing urea ≥10%, pedicures, and cushioning of callused areas using soft or padded shoes [48]. Other preventive tac- tics include avoidance of activities that cause force or rub- bing on the hands and feet during the first 6 weeks of treatment and limiting contact with harsh chemicals and sources of heat, such as sitting in saunas or the sun.Management of PPES consists of keratolytic agents suchPatients should be advised to moisturize skin to minimize the risk of skin adverse events and to avoid excessive expo- sure to detergents and soaps containing fragrances. Urea preparations have been shown to prevent transepidermal water loss, and salicylic acid preparations are helpful for their keratolytic, bacteriostatic, and fungicidal effects [50]. Exfoliation of scaly areas of xerosis is recommended. For more severe grade 3 xerosis, which results in asteatotic der- matitis, treatment can be initiated with low-potency topical steroids such as hydrocortisone 2.5% cream/ointment or triamcinolone 0.1% cream.Patient education is an important component of dry mouth prevention. The importance of good oral hygiene, regular dentist visits, and other strategies for preventing oral dis- ease should be stressed.Treatment may include systemic and topical salivary stimulants, such as cevimeline and pilocarpine, and intraoral topical agents, such as chewing gums and saliva stimulants and substitutes [59].

High fluoride toothpaste is also recommended to prevent cavities.Owing to the potential for ulcerations to develop and expand rapidly, as well as an extremely poor 1-year mortal- ity rate [60], drug discontinuation should be recommended for patients with calcinosis cutis. Treatment with oral or topical calcium channel blockers, intravenous immunoglob- ulin, and compounded or intralesional sodium thiosulfate may be initiated. For calciphylaxis, treatments generally include three times a week dosing at 3–4 week intervals with intravenous sodium thiosulfate or intralesional sodium thiosulfate diluted 1:1 with 1% lidocaine to minimize the pain [60-62]. Patients should be screened for additional hypercoagulation disorders [63]. In addition, monitoring cal- cium and phosphate levels with phosphate binders, consid- eration for anticoagulation, and use of bisphosphonates may be considered. Dermatologic or endocrine consulta- tions are warranted upon occurrence of grade 3 events and for patients who do not respond to therapy.as urea ≥10%, for grade ≥1 PPES, with addition of high- potency topical steroids such as fluocinonide 0.05% for grade ≥2 symptoms.Preventive strategies include undertaking dental work aimed at eliminating existing tooth and gum disease before the start of treatment and education regarding the impor- tance of thorough and frequent cleaning of the oral cavity. Avoidance of salty, spicy, or citrus-based foods, as well asDose modification in the event of dermatologic adverse events should be performed as recommended in the rele- vant package insert.Unless otherwise recommended, treatment should be continued in cases of grade 1 and 2 adverse events and interrupted for grade 3 adverse events (Figure 1). When dermatologic events improve to grade ≤1, a rechallenge at a reduced dose is recommended.hot beverages, may help prevent stomatitis. Upon emergence of grade 1 or 2 stomatitis, dexametha- sone 0.5 mg/5 ml elixir is recommended; an augmented betamethasone dipropionate 0.05% gel applied to gauze and held against the affected surface may also assist in alle- viating symptoms.

CONCLUSION
The FGFR inhibitors have a distinctive adverse-event profile that includes a range of dermatologic adverse events, the incidences of which vary between agents. The events are seldom severe or life threatening but can nonetheless limit the delivery of treatment through dose holds and may lead to premature drug discontinuation. In order to optimize patient outcomes, physicians should be mindful of possible untoward events associated with the drug being used, edu- cate their patients, and be ready to implement effective management plans in a timely fashion. Prescribing informa- tion for erdafitinib should be consulted if appropriate [64]. Intervention and treatment at the earliest possible opportu- nity may prevent premature discontinuation while maintaining patients’ quality of Futibatinib life.