Management of Cutaneous and Extracutaneous Side Effects of Smoothened Inhibitor Therapy for Advanced Basal Cell Carcinoma Shalini V

Published OnlineFirst March 19, 2015; DOI: 10.1158/1078-0432.CCR-14-3180

Review Clinical Cancer Research Management of Cutaneous and Extracutaneous Side Effects of Smoothened Inhibitor Therapy for Advanced Basal Cell Carcinoma Shalini V. Mohan and Anne Lynn S. Chang

Abstract

Smoothened inhibitors represent the ﬁrst class of targeted mechanism of smoothened inhibitors and the most commonly drugs approved for use in advanced and metastatic basal cell observed cutaneous and extracutaneous side effects. We also carcinoma. For many patients with limited treatment options, highlight possible mechanisms for these adverse events and this drug class has led to signiﬁcant clinical improvements, but current management strategies. Clin Cancer Res; 21(12); 1–7. 2015 is not without side effects. In this review, we outline the basic AACR.

Introduction humans lend insight into how SIs may exert their toxicities (8, 20– 31). While data are still being collected on side effects specificto Smoothened inhibitors (SI) are a class of drugs newly approved individual SIs, several side effects, such as hair loss, muscle by the FDA for use in advanced basal cell carcinomas (BCC). spasms, and gastrointestinal (GI) and taste disturbances, are Because BCCs are the most common human malignancy world- common to several SIs and are likely class effects. Adverse effects wide, with an age-adjusted incidence of 1,000 to 1,500 per (AE) may be significant enough to lead to drug discontinuation 100,000 adults in the United States (1), the ability to suppress (15, 16, 32), and therefore the ability to adequately manage these their growth in a targeted fashion is a highly significant step AEs is crucial to treatment adherence and patient quality of life. forward in cutaneous oncology. The significance of these side effects and lack of effective treatment Smoothened (SMO) is a 7-transmembrane protein in the options for these drug toxicities are illustrated in the pivotal phase hedgehog (Hh) signaling pathway that when aberrantly activated II study of vismodegib, in which 12% of advanced BCC patients can function as an oncogene by promoting unregulated activation discontinued treatment due to an AE (16), and more recently in an of the Hh pathway (2–4). The Hh signaling pathway is respon- international study with a 30-month follow-up in which 22.1% of sible for midline embryonic development and is generally advanced BCC patients discontinued treatment due to an AE (32). silenced in adults except for activity in hair follicles and taste To date, there is no evidence that SI-induced cutaneous or extra- buds (5–11). Aberrant activation of this pathway results in cutaneous side effects correlate with drug response, unlike other tumorigenesis and is associated with BCCs and medulloblastoma targeted therapies such as EGFR inhibitors, for which an acne-like (2–4, 6, 7). SIs block Hh signaling, leading to suppression of rash is associated with tumor response (33). tumor growth and tumor regression (12–17). Although there are Although not discussed in this review, SIs are potent teratogens many potential targets within this pathway, most compounds in that lead to severe midline defects in the developing fetus and are clinical development that block Hh signaling target SMO, includ- not to be used in females of childbearing potential or male ing vismodegib (GDC-0449), which is already commercially partners of females of childbearing potential who do not agree available (18). Other SIs currently being studied in clinical trials to use two forms of reliable contraception (34). include sonidegib (LDE225), saridegib (IPI-926), and BMS- Because of dose effects of drug toxicities, this review considers 833923 (XL139; refs. 12–15, 17). the rates of side effects based on phase II and/or FDA-approved A number of cutaneous and extracutaneous side effects of SIs dose whenever possible. Long-term data on AEs are still being have been reported (12, 14–17, 19), although few studies have collected as more patients are exposed to SIs, but high-quality data been conducted on the mechanisms of the clinical side effects in are available for some of these drugs through phase I and II clinical humans. Nevertheless, data on the function of the Hh pathway trials (12–17, 19, 35). The side effects discussed here were selected from preclinical animal models and the limited clinical trials in on the basis of literature reports and incidence and are not meant to be comprehensive.

Department of Dermatology, Stanford University School of Medicine, Redwood City, California. Cutaneous Adverse Effects of Smoothened Corresponding Author: Anne Lynn S. Chang, Department of Dermatology, Inhibitors Stanford University School of Medicine, 450 Broadway Street, MC 5334, Pavilion Hair loss C, 2nd Floor, Redwood City, CA 94063. Phone: 650-721-7151; Fax: 650-721-3464; Approximately 15% to 60% of patients treated with SIs expe- E-mail: [email protected] rienced alopecia within 2 to 4 months of initiating SI therapy; doi: 10.1158/1078-0432.CCR-14-3180 exact rates depend on the speciﬁc SI (Table 1; refs. 12– 2015 American Association for Cancer Research. 17, 21, 30, 35–43). Alopecia is reported more frequently with

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vismodegib than other SIs, with up to 58% and 63% of patients answer this question. Because of the possibility of new-onset affected in phase I and II trials, respectively (16, 19, 35, 43). A SCCs after initiation of SIs, total-body skin examinations with phase II study of sonidegib revealed an alopecia incidence rate of a low threshold to biopsy new suspicious lesions appears prudent. 43% at the 200-mg daily dosage (12, 13). SI-related alopecia is reported to affect eyebrows, eyelashes, and body hair, although Extracutaneous Adverse Effects of our clinical observations have shown that some patients with hair Smoothened Inhibitors loss in one anatomic location may be spared hair loss in other locations. In humans, the Hh pathway is reported to maintain Gastrointestinal toxicity (nausea, vomiting, diarrhea, and bulge cell phenotype and is likely needed for normal hair follicle constipation) regeneration (30). SI-related alopecia is reversible following dis- Nausea and vomiting were the most common GI toxicities, continuation of the drug, with patients seeing evidence of affecting up to one-third of patients receiving vismodegib, soni- – regrowth after 4 to 6 weeks (42). degib, or saridegib (Table 2; refs. 12 16, 35). On the basis of data from 198 patients enrolled in phase I and II trials of vismodegib, 95% of patients experienced grade 1 or 2 GI disturbances, includ- Hypersensitivity reaction ing nausea, vomiting, diarrhea, constipation, and pain (45). Two cases of patients experiencing drug hypersensitivity reac- Grade 3 or 4 GI irritation was reported in 10% of patients tions following treatment with vismodegib were recently reported (45). In a phase II trial of sonidegib, 33% of patients treated (Table 1; refs. 41, 42). One report describes a 77-year-old woman with the 200-mg daily dosage experienced nausea (12, 13). Only 3 being treated with vismodegib for numerous and recurrent BCCs of 28 patients exposed to varying doses of BMS-833923 in a phase who developed on-target side effects in addition to sudden onset I study reported nausea (17). No formal studies to date have of fevers, chills, myalgia, and fatigue 3 weeks after drug initiation examined the efficacy of currently available antiemetics for (41). Treatment was discontinued, and laboratory testing revealed SI-induced nausea or vomiting. Anecdotally, medications such elevated liver function and hypereosinophilia. These laboratory as ondansetron or metoclopramide have been used and can values normalized 10 days after discontinuation of vismodegib. provide significant relief. SI-related diarrhea and constipation fi Kwong and colleagues reported a case of a man in his fties who can be reduced or resolved with loperamide or stool softeners, developed erythematous dermal plaques on his arms and chest respectively, although no formal studies have been conducted to after 8 months of treatment with vismodegib (42). The patient identify the agents that are most effective in reducing or elimi- was not exposed to any other medications or drugs during nating these side effects. fi fi treatment with vismodegib. A skin biopsy con rmed super cial The Hh pathway is highly expressed in the GI epithelium and and deep perivascular dermatitis with eosinophils, consistent plays an important role in function and repair (5). In animal with a cutaneous drug eruption. The patient was treated with models, paracrine Hh signaling has been demonstrated from the topical steroids and did not need to discontinue vismodegib. The stomach to the colon and has been found to be important in exact incidence of dermal hypersensitivity reaction in patients modulating villus core smooth muscle (23). Disruption of this being treated with vismodegib is unclear and likely to be <20% as pathway through SIs may explain the GI side effects of nausea, rash was not one of the common side effects in the phase II study vomiting, diarrhea, and constipation (27). that led to FDA approval (16). Amenorrhea Squamous cell carcinoma and keratoacanthoma Amenorrhea or menstrual irregularity has been reported in One potential concern with the use of targeted therapies is the women of childbearing potential taking vismodegib (Table 2; possibility that abrogation of one pathway may lead to activation refs. 35, 46). For instance, in an expanded access study of vismo- of another. A recently published case report describes patients degib, 4 of 8 women of childbearing age experienced irregular without a history of squamous cell carcinoma (SCC) who devel- menses or amenorrhea while on vismodegib (35). In this small oped keratoacanthoma (a low-grade variant of SCC originating number of patients, there were no clear differences in weight loss from hair follicles) immediately after initiation of vismodegib for or hormonal birth control use between those who did or did not locally advanced BCC (laBCC; Table 1; ref. 36). Other reports have experience menstrual irregularity. Strasswimmer and colleagues described patients who developed cutaneous SCC following reported a case of a 34-year-old patient who developed amenor- vismodegib treatment, both as new tumors and as lesions within rhea one month after starting vismodegib and resumed menses 5 the existing laBCC tumor bed (37–40). In a recent international weeks after discontinuation (46). After hormonal evaluation, this study of 104 patients receiving vismodegib for advanced BCC, patient's amenorrhea was attributed to blockade of follicle-stim- 11% developed SCC (32). ulating hormone-receptor–dependent signal transduction at the The etiology of this connection may be multifactorial and can level of the ovaries. While the exact mechanism of amenorrhea be thought of on both a cellular and clinical level. On a cellular remains to be further clarified, an alternative hypothesis might level, SMO inhibition may select for tumor cells that are not involve SI effects on the uterus—the exogenous hormone-induced driven by the Hh pathway, including SCCs (18, 40). On a clinical menses of a patient treated in our practice with a prior bilateral level, UV light exposure is a common risk factor for both BCC and oophorectomy ceased after initiation of SI therapy. To date, we are SCC (44); therefore, individuals exposed to high levels of UV may not aware of any cases in which menstrual cycles did not resume develop both types of skin cancer. In addition, patients receiving after vismodegib cessation. SIs may have more frequent or more complete skin examinations, which may lead to a detection bias. Although no data from Dysgeusia randomized trials currently exist to support this hypothesis, Taste disturbance or dysgeusia was reported within the first 1 to long-term outcomes studies are under way that may help to 2 months following SI initiation in 16.7% to 70.6% of patients,

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Table 1. Cutaneous side effects of SIs organized by reported time to clinical onset Average time Reported Reported or Management Observed side to onset of severity hypothesized options (level IV effect Incidence symptoms (grade) mechanism evidence)a Selected references Hair loss Vismodegib: 58%–63%b 2–4mof 1/2b,c,d,e Inhibition of hair No known effective Vismodegib: Sonidegib: 16.7%–43%c 3/4b follicle regeneration: treatment to date, Sekulic et al., 2012 (16) Saridegib: 22%d Rittie et al., 2009 (30) reversible after Dirix et al., 2012 (43) BMS-833923: 15%e Chiang et al., 1999 (21) discontinuation Chang et al., 2014 (35) Sonidegib: Migden et al., 2014 (12), Dummer et al., 2014 (13), Rodon et al., 2014 (15) Saridegib: Jimeno et al., 2013 (14) BMS-833923: Siu et al., 2010 (17) Hypersensitivity Unknown 3 wks–8 mo 1/2 Not well characterized Antihistamines, Vismodegib: reaction topical steroids Lam et al., 2014 (41) Kwong et al., 2014 (42) SCC Vismodegib: 11% 1 mo–8 y 3 Unclear if advanced Excision, regular full- Vismodegib: BCC patients have body skin Iarrobino et al., 2013 (37) increased risk of examination for Orouji et al., 2014 (38) SCC versus surveillance Saintes et al., 2014 (39) detection bias from Zhu et al., 2014 (40) increased monitoring Sekulic et al., 2014 (32) while receiving SIs versus Mouse model of SCC SI drug effect formation via Ptch1 In a mouse model, a particular mutation: Wakabayashi Ptch1 mutation can lead to et al., 2007 (58) Ras activation with SCC formation, independent of Hedgehog signaling but it is currently unknown whether SIs could mimic this effect Keratoacanthoma Not well 2–7 wks 3 Promotion of squamous Surgical excision and Vismodegib: characterized differentiation regular full-body skin Aasi et al., 2013 (36) checks NOTE: The side effect profile is pooled from published literature in human trials for SIs, including vismodegib (GDC0449), sonidegib (LDE225), saridegib (IPI-926), and BMS-833923 (XL139). Shaded rows indicate a side effect observed with more than 1 SI. aLevels of evidence: level II: prospective comparative studies, systematic review of level II studies or level I studies with inconsistent results; level III: case–control studies, retrospective comparative studies, systematic review of level III studies; level IV: case series with no comparison group, retrospective case series. bVismodegib at 150-mg daily dose. cSonidegib at 200-mg daily dose. dSaridegib at 160-mg daily dose. eBMS-833923 based on phase I study of 28 patients at 30 to 540 mg daily, as AE rates at individual doses not provided. fBased on a phase II study of vismodegib (35). depending on the particular SI used (Table 2; refs. 12– taste (20, 22, 24, 26). Inhibition of Shh signaling through SIs likely 17, 20, 25, 29, 31, 35, 46–49). While not formally studied, leads to disruption of these structures, thus accounting for the dysgeusia's contribution to lack of appetite has been suggested dysgeusia observed in patients treated with SIs. by clinical observation. Grade 2 dysgeusia includes altered taste with change in diet (per Common Terminology Criteria for Myopathy (including symptoms of muscle spasms and muscle Adverse Events version 4; ref. 50), potentially leading to weight pain; myalgia) loss, an adverse event also associated with SIs (12, 13, 16, 35). Myopathy is one of the most common AEs of SIs (12– Sonidegib and saridegib had the lowest reported dysgeusia inci- 14, 16,35,44), with up to 71% of patients treated with vismodegib, dence rates with 16.7 to 38% and 27.8%, respectively (12–15). In 50% of patients treated with sonidegib, 33% of patients treated our clinical experience and as reported in the Basal Cell Nevus with saridegib, and 44% of patients treated with BMS-833923 Network patient support group newsletter, patients experience a having reported muscle spasms (Table 2; refs. 12–14, 16, metallic or bland taste associated with most food and beverages 17, 35, 44). Clinically, myopathy is often one of the first AEs to (51). Patient-reported suggestions for coping with SI-related be reported (35). Many of our patients on vismodegib indicated dysgeusia include consumption of spicy, sweet, cold, or acidic myopathy can significantly affect their quality of life and may foods and use of baking soda as a mouth rinse before eating (51). even lead patients to discontinue treatment with SIs. There is little Data from preclinical animal models provide evidence to sug- evidence to suggest that a correlation exists between the symptoms gest that dysgeusia is an on-target effect of Hh pathway inhibition of myopathy and elevated creatine kinase (CK) levels. Oral muscle (20, 22, 24, 26). Sonic Hh (Shh)-responsive cells maintain the taste relaxants (e.g., cyclobenzaprine) may transiently decrease the buds and filiform and fungiform papillae, all of which play a role in severity or number of muscle spasms; however, future studies are

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Table 2. Extracutaneous side effects of SIs organized by reported time to clinical onset Observed Average time Reported Management side to onset of severity Reported options (level IV Selected effect Incidence symptoms (grade) mechanism evidence)a references Nausea Vismodegib: 1wk–4mof 1/2b,c,d,e Impaired Antiemetic (e.g., ondansetron), Vismodegib: 19.3%–29%b 3/4b,c GI motility appetite stimulant (e.g., megestrol, Sekulic et al., 2012 (16) Sonidegib: 16.7%–33%c dronabinol), H2 antagonists Chang et al., 2014 (35) Saridegib: 33%d Sonidegib: BMS-833923: 11%e Migden et al., 2014 (12) Dummer et al., 2014 (13) Rodon et al., 2014 (15) Saridegib: Jimeno et al., 2013 (14) BMS-833923: Siu et al., 2010 (17) Amenorrhea or Vismodegib: 1 mo 1 Mechanism unclear, May resolve upon discontinuation of Vismodegib: irregular menses up to 50%b could be target vismodegib Chang et al., 2014 (35) effects on uterus Strasswimmer et al., 2014 (46) Dysgeusia Vismodegib: 1–2mof 1/2b,c,d,e Inhibition of lingual Supportive care (e.g., strongly Vismodegib: 51%–70.6%b papillae development ﬂavored food, baking soda mouth Sekulic et al., 2012 (16) Sonidegib: 16.7%–38%c 3/4d in animal model: rinse, etc.)f Chang et al., 2014 (35) Saridegib: 27.8%d Liu et al., 2004 (49) Sonidegib: BMS-833923: 44%e Castillo et al., 2014 (20) Migden et al., 2014 (12) Dummer et al., 2014 (13) Rodon et al., 2014 (15) Saridegib: Jimeno et al., 2013 (14) BMS-833923 Siu et al., 2010 (17) Muscle spasm Vismodegib: 1–2mof 1/2b,c,d,e Inhibition of muscle Muscle relaxant (e.g., Vismodegib: 68%–70.6%b 3/4b,c repair in animal model: cyclobenzaprine), levocarnitineg Sekulic et al., 2012 (16) Sonidegib: 33.3%–50%c Li et al., 2004 (25) Chang et al., 2014 (35) Saridegib: 33%d Straface et al., 2009 (31) Sonidegib: BMS-833923: 44%e Piccioni et al., 2014 (29) Migden et al., 2014 (12) Dummer et al., 2014 (13) Rodon et al., 2014 (15) Saridegib: Jimeno et al., 2013 (14) BMS-833923: Siu et al., 2010 (17) Elevated CKh Sonidegib: 6–8 wks 2–4 Inhibition of Hh-regulated Monitor for rhabdomyolysis, avoid Sonidegib: c 16.7%–29% skeletal muscle repair overexertion and concomitant Migden et al., 2014 (12) medications that may exacerbate Dummer et al., 2014 (13) Rodon et al., 2014 (15)

Hepatotoxicity Vismodegib: 1–3mo 2–4 Drug–drug interaction, Consider removing Vismodegib: 1%–26.5%b direct hepatocellular any interacting concomitant Ventarola and Silverstein, 2014 (47) Saridegib: up damage, impaired medications Ash and Jolly, 2014 (48) to 88.9%d hepatocyte regeneration Saridegib: Jimeno et al., 2013 (14) Weight loss Vismodegib: 4–10 moi 1/2b,c Likely multifactorial, Appetite stimulant, Vismodegib: b 16%–46% including decreased calorie-dense dietary supplements Sekulic et al., 2012 (16) Sonidegib: 3/4b,c dietary intake due to GI Chang et al., 2014 (35) 16.7%–27%c side effects Sonidegib: Migden et al., 2014 (12) Dummer et al., 2014 (13) Rodon et al., 2014 (15) NOTE: The side effect proﬁle is pooled from published literature in human trials for SIs, including vismodegib (GDC0449), sonidegib (LDE225), saridegib (IPI-926), and BMS- 833923 (XL139). Shaded rows indicate a side effect observed with more than 1 SI. aLevels of evidence: level II: prospective comparative studies, systematic review of level II studies or level I studies with inconsistent results; level III: case–control studies, retrospective comparative studies, systematic review of level III studies; level IV: case series with no comparison group, retrospective case series. bVismodegib at 150-mg daily dose. cSonidegib at 200-mg daily dose. dSaridegib at 160-mg daily dose. eBMS-833923 based on phase I study of 28 patients at 30 to 540 mg daily, as AE rates at individual doses not provided. fBased on McNabb, 2013 (51). gL-carnitine beneﬁt is currently being evaluated in a clinical trial (NCT01893892). hElevated CK is a laboratory parameter not assessed in vismodegib clinical trials; therefore, the incidence rate is unknown because physicians and patients cannot spontaneously report CK levels. iBased on a phase II study of vismodegib (35).

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needed to identify the best method of treating this common side aminophen (56, 57). Although additional data are needed to effect. Levocarnitine, an amino acid derivative that is commercially provide guidance on laboratory monitoring for patients on SI available as a supplement, is currently being tested in a random- therapy, periodic laboratory monitoring may be considered in ized, double-blind, placebo-controlled trial in patients with vis- those taking potentially hepatotoxic medications. modegib-associated muscle spasms (NCT01893892) based on The Hh pathway is important in the hepatic repair response anecdotal patient reports of decreased muscle spasm frequency following chronic liver injury in human liver cells (28); therefore, and severity while taking this agent. inhibition of Hh signaling may prevent repair of adult liver The mechanism of myopathy in humans taking SIs has not injuries. However, the specific mechanism of SI-associated hep- been established. In animal models, activation of the Shh path- atotoxicity has not been reported. way promotes regeneration of myofibers (25, 29, 31); therefore, inhibition of the pathway with SIs may impede muscle repair. Weight loss Weight loss associated with SI treatment may be multifactorial Elevated creatine kinase in origin, including decreased oral intake from dysgeusia, GI Currently, the incidence of CK elevations appears to vary with toxicity, and/or advanced BCC. Compared with other toxicities, the different SIs. Assessment of CK levels was not included in weight loss has a later onset with vismodegib, with a reported vismodegib clinical trial protocols; therefore, the incidence of median time to onset of 175 days after initiation (35). Because of elevated CK in these studies is unclear. Vismodegib does not the late onset and the relatively short follow-up times in many require monitoring of CK levels based on the package insert (3); clinical trials, the true incidence of weight loss may be under- however, patients with risk factors for CK elevation may be reported. For instance, in an expanded access study of vismodegib considered for monitoring, as elevated CK has been reported with a median exposure time of 5 months, approximately 20% of with vismodegib treatment (52, 53). For instance, our clinical patients experienced grade 1 or 2 weight loss, whereas in a phase II experience in patients taking multiple medications suggests that study with median exposure time of 10 months, approximately CK elevation may occur in rare instances and is reversible upon 46% of patients experienced grade 1 to 4 weight loss (Table 2; discontinuation of vismodegib. In contrast, studies of sonidegib refs. 16, 35). Similarly, a phase II study of sonidegib showed that included CK monitoring, which has been shown to result in grade 27% of patients receiving the 200-mg once-daily dosage experi- 2 to 4 CK elevation in up to 29% of patients (Table 2), with or enced weight loss (Table 2; refs. 12, 13). without clinical symptoms, in a dose-dependent fashion (12, 13). Management of weight loss depends on the severity of the side The incidence of CK elevation in patients exposed to saridegib or effect. For moderate to severe weight loss, high calorie nutritional BMS-833923 in phase I studies was not reported (14). CK mon- supplements and consultation with an oncologic nutritionist may itoring may be considered in individuals with risk factors for be of benefit. In our patients, oral megestrol acetate or dronabinol rhabdomyolysis, such as alcohol abuse, concomitant medications has helped to stimulate appetite but formal studies are needed to (including HMG-CoA reductase inhibitors, itraconazole, cyclo- determine the optimal strategies to combat or reduce the weight sporine, colchicine, and erythromycin), overexertion, or muscular loss side effect. dystrophy (54, 55), although evidence-based guidelines currently do not exist for this practice. Although there is no clear association between muscle spasm or Discussion myalgia symptoms and CK elevations, it could be hypothesized Because the SI drug class is new, long-term data on AEs and their that CK elevation may result from impaired repair of cellular management are forthcoming. Studies directed at managing side muscle damage, as discussed in the section on myopathy (29, 31). effects are underway and more are needed. Multidisciplinary care Hepatotoxicity to manage toxicities, including regular skin cancer surveillance Hepatotoxicity in the form of transaminitis or cholestasis has by a dermatologist, is crucial. Given the potential long-term been reported in patients being treated with SIs (Table 2; refs. 12– nature of SI treatment, with responsive metastatic BCC patients fi 17, 20, 25, 29, 31, 35, 46–49). For vismodegib, the rate of dosed inde nitely until tumor progression, the ability to success- occurrence did not exceed 30% (47, 48). Similar effects were seen fully manage side effects is critical for patient adherence and with saridegib in patients with solid tumors, in whom the major quality of life. dose-limiting toxicity was transient and reversible grade 3 alanine aminotransferase and/or aspartate aminotransferase elevation at Disclosure of Potential Conflicts of Interest the phase II dose of 160 mg/day (1 of 18 patients; 6%; ref. 14). A.L.S. Chang reports receiving commercial research grants from Eli Lilly, Some of the reported cases of hepatotoxicity occurring in patients Genentech/Roche, and Novartis Pharmaceuticals Corporation, and is a con- being treated with SIs may be due to concomitant use of medica- sultant/advisory board member for Genentech/Roche and Novartis Pharma- ceuticals Corporation. No potential conflicts of interest were disclosed by the tions that may also contribute and thus enhance this side effect. other author. For instance, elevated liver enzymes and cholestasis were reported in an individual on vismodegib therapy after starting a nonste- roidal anti-inflammatory drug for muscle spasms (48). Postmar- Acknowledgments keting data for vismodegib based on a summary from the FDA The authors thank Christopher Reina, PhD, and Jillian Brechbiel, PhD, of Articulate Science, LLC, for medical editorial assistance with this article. Adverse Events Reporting System spanning January 2012 to Financial support for editorial assistance was provided by Novartis Pharma- January 2013 revealed 15 cases of hepatotoxicity, including ceuticals Corporation. elevated liver enzymes or bilirubin, hepatitis, and hepatocellular damage (47). These cases included patients taking vismodegib Received December 8, 2014; revised February 19, 2015; accepted March 3, with other known hepatotoxic drugs, such as erlotinib and acet- 2015; published OnlineFirst March 19, 2015.

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www.aacrjournals.org Clin Cancer Res; 21(12) June 15, 2015 OF7

Management of Cutaneous and Extracutaneous Side Effects of Smoothened Inhibitor Therapy for Advanced Basal Cell Carcinoma

Shalini V. Mohan and Anne Lynn S. Chang

Clin Cancer Res Published OnlineFirst March 19, 2015.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-14-3180

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