Australasian Journal of Dermatology (2015) 56 (Suppl. 1), 1–7
Current landscape for treatment of advanced basal cell carcinoma Peter Foley Skin & Cancer Foundation Inc, Carlton; The University of Melbourne, Parkville; St. Vincent’s Hospital Melbourne, Fitzroy, Victoria, Australia
ABSTRACT Basal cell carcinomas (BCCs) account for around 80% of non-melanoma skin cancer. Australia has the highest incidence of BCC globally and the rates continue to increase in both Australia and New Zealand. BCC causes significant morbidity, placing an enormous burden on the healthcare system. Treatment of patients with advanced BCC can be particularly challenging. A panel of UK experts recently defined advanced disease as BCC that in which current treatment modalities are considered potentially contraindicated by clinical or patient-driven factors. Research has found that mutations in the hedgehog signalling pathway underpin the pathogenesis of the vast majority of sporadic BCC, as well as Gorlin syndrome. The first-in-class oral small molecule hedgehog pathway inhibitor – vismodegib–is now approved in a number of countries for use in locally-advanced and metastatic BCC and has resulted in improved outcomes in the majority of patients treated. With a number of similar agents in the pipeline, research is now focusing on identifying mechanisms that may contribute to resistance to this agent in some lesions. Key words: advanced, basal cell carcinoma, hedgehog, vismodegib.
(BCC) and squamous cell carcinoma (SCC) – BCCs are more common with some estimates suggesting that these lesions account for 80% of NSMC.2 Australia has by far the highest incidence of BCC in the world.1 2006 data suggest that the age-standardised rate per 100 000 is 884.3 However, more recent projections indicate this figure is now considerably higher. The ratio of BCC to SCC is approximately 5:2.1,3 The rate of BCC in patients over the age of 60 years continues to rise, whereas it has appeared to stabilise in those younger than 60.3 Between 1997 and 2010, NMSC treatments increased by 86% and it is anticipated that the number and total cost without inflation of these treatments will rise a further 22% by 2015. NMSC remains the most costly cancer in Australia, placing an ever increasing burden on the healthcare system.4 In New Zealand, latest figures suggest the agestandardised incidence of BCC and SCC per 100 000 is 299 and 118, respectively. Between 1999 and 2010, the annual incidence of BCC increased by 4%, with the greatest increases in people aged over the age of 50 years.5 Despite rarely metastasising and an estimated cure rate of more than 95% when diagnosed and treated early, BCC causes significant morbidity. If patients present late in the course of disease, treatment can be particularly challenging.6 This paper reviews the current definition of advanced BCC and traditional treatment options. The mechanism of action, clinical efficacy, and safety of vismodegib – the firstin-class, small molecule hedgehog signalling pathway inhibitor to be approved for use in advanced BCC – will be examined and future directions in therapy discussed.
A recent large systematic review found that, relative to other malignancies, the incidence worldwide of nonmelanoma skin cancer (NMSC) is high and it is growing.1 Of the two most frequently seen types – basal cell carcinoma
Although usually amenable to treatment by surgical methods, BCCs can progress to a point locally where surgery, radiation therapy, or other lesion-directed modalities are no longer an option or, less often, metastasise to distant sites.2 The aggressiveness of growth patterns of BCCs is dependent on their histology. The three main histological types are described and depicted in Fig. 1. Non-aggressive growth patterns include nodular, superficial, and adnexal variants. Aggressive growth patterns
Correspondence: Associate Professor Peter Foley, Skin & Cancer Foundation Inc, 80 Drummond Street, Carlton, Vic. 3053, Australia. Email: [email protected]
Submitted 22 January 2015; accepted 27 January 2015. © 2015 The Australasian College of Dermatologists
P Foley et al. Table 1
Factors driving a diagnosis if advanced BCC9
Tumour size Tumour location (eg, H-zone) Number of tumours Tumour subtype (eg, morphoeic) Likelihood of successful treatment
Age Performance status
Nodular BCC exhibiting a pearly rolled border, at times with central crusting and ulceration
QoL impact of treatments Patient preference regarding treatment Presence of genetic disorders (eg, Gorlin’s syndrome) Presence of comorbidities (eg, organ transplant)
Adapted from Lear JT et al. British Journal of Cancer (2014) 111, 1476–1481 with permission.
Superficial BCC with scaly erythematous patch or plaque-like appearance
Sclerosing, infiltrative, or morphoeic variant presenting as a scar-like, centrally atrophic, whitish, indurated tumour with indistinct margins Figure 1
Three main clinical patterns of BCCs.
include metatypical/basosquamous, morphoeic, infiltrating, sclerosing and micronodular variants.7 Patients may have BCCs with both growth patterns, with the vast majority of these mixed category lesions originating on the head and neck. The incidence of mixed category BCCs ranges from 11% to 43%. It is estimated that the aggressive growth pattern is not suspected in more than 85% of these lesions, potentially leading to inadequate initial therapy, BCC recurrence, and additional morbidity.8 In locally advanced BCC, tumours generally have become greatly enlarged, resulting in significant tissue invasion and morbidity.9 In some cases, this is because patients neglect to have the BCC assessed, either because of fear of the diagnosis or the treatment, the slow-growing nature of the tumour, older age and accompanying cognitive decline, or lower social milieu.10 BCC metastases are extremely rare and occur only years after development of the initial lesion. Sporadic BCC is, on the whole, slow-growing and despite factors such as large © 2015 The Australasian College of Dermatologists
diameter (ie, >2 cm), frequently incomplete excision, and perivascular involvement, the proportion of patients who experience metastases is estimated to be only 0.0028 to 0.5%.11 The hereditary disorder, Gorlin syndrome or basal cell naevus syndrome (BCNS), predisposes patients to exhibit a marked propensity to develop numerous BCCs during adolescence and occasionally in childhood, particularly after radiation given for treatment of progressive BCC or other cancers. With an estimated incidence of only 1 in 150 000 in the general population, it is characterised by a range of developmental abnormalities, including odentogenic jaw cysts, pits on the palms and soles, splayed ribs, pectus deformity, and a predisposition to develop other cancers such as meningioma and medulloblastoma.12 Clinicians have found it difficult to provide a robust, objective definition of advanced BCC, in part because of the heterogeneity of the disease and variations in clinical practice. Advanced disease has tended to be described as that which can no longer be adequately managed by standard treatment modalities. However, patient opinion can also drive the diagnosis of advanced BCC. A patient may not be prepared to undergo technically appropriate and feasible treatment because of concerns about disfigurement and negative effects on quality-of-life (QoL).9 Recently, a panel of UK experts developed the following definition of advanced BBC: ‘Basal cell carcinoma of American Joint Committee on Cancer (AJCC) stage II or above, in which current treatment modalities are considered potentially contraindicated by clinical or patient-driven factors.’9 Stage II according to AJCC is a tumour larger than 2 cm with no metastases.13 Table 1 shows clinical- and patient-driven factors as described by the panel.9
Standard management There are several effective treatment options for BCC, surgical or nonsurgical, and intended to be curative or at least offering local control. Factors taken into consideration when recommending a therapy include tumour size, location, histological subtype, patient’s health status, age and wishes, possible complications, and aesthetic results.12
Treatment of advanced BCC Surgical therapy with 3-dimensional histology is the gold standard. Surgical techniques include Mohs micrographic surgery and conventional surgery with tumour-adapted margins, curettage, electrodesiccation, and cryosurgery.12 Non-surgical options include photodynamic therapy and topical applications such as imiquimod and 5-fluorouracil. The disadvantage of these modalities is treatment success cannot be histologically validated and recurrence rates may therefore be higher. Nevertheless, they may be more suitable for elderly patients with multiple comorbidities and inoperable tumours.12 Radiotherapy is often confined to postoperative recurrence or if complete resection appears difficult.12 Other indications for radiotherapy include older age, situations where surgery would result in major loss of function, patients unfit for surgery or anaesthesia, or in those with anticoagulation problems.14 Treatment can be particularly challenging for locally advanced, recurrent, and metastatic tumours. In locally advanced BCC, any surgical treatment may be extensive, resulting in cosmetic deformity and negatively impacting patients’ lives.9 Multiple operations may be required for recurrent BCC. In patients with genetic disorders, such as Gorlin syndrome, repeated surgery may eventually become untenable, while radiation therapy may be contraindicated as it carries the risk of leading to more BCCs.9 The therapeutic pathway for metastatic BCC is less welldefined. Beyond surgery and radiation, a range of systemic chemotherapies such as doxorubicin, paclitaxel, and cisplatin/carboplatin have been used.12
VISMODEGIB – A FIRST-IN-CLASS ORAL SMALL MOLECULE Better understanding of the molecular basis for, and aberrant pathways, involved in the pathogenesis of BCC, has resulted in a new targeted approach to therapy. Inhibitors of the hedgehog signalling pathway have shown great promise in the treatment of advanced BCC. The first of these to be approved, vismodegib (Erivedge®, Roche), is available in the US and several European and Asian countries. In Australia and New Zealand, it is indicated for treatment of adult patients with metastatic BCC, or with locally advanced basal cell carcinoma where surgery and/or radiation therapy are not appropriate.
Mode of action The pathogenesis of cancer is underpinned by aberrations in various signalling pathways for tumour growth and metastasis.15 One of these pathways is the hedgehog pathway, somatic mutations of which are present in the vast majority of sporadic BCCs as well as in Gorlin syndrome.9 The hedgehog signalling pathway gets its name from a polypeptide ligand called hedgehog (Hh) found in some fruit flies. This molecule was so called because mutations led to fruit fly larvae that had a spiky, hairy pattern of denticles, similar to that of hedgehogs.15
One of the major regulators of cell growth and differentiation during embryogenesis and early development, the Hh pathway is inactivated in adult tissues by Patched1 receptor (PTCH-1) inhibition. PTCH-1 is a 12transmembrane protein receptor. However, when the Hh ligand binds to PTCH-1, the Hh pathway is reactivated. This allows the 7-transmembrane protein, Smoothened homolog (SMO), to transfer signals downstream via various proteins. Translocation of signalling components between the cytoplasm, plasma membrane, nucleus, and primary cilium further regulate Hh signaling. The primary cilium acts as a sensor to monitor the extracellular environment. Initially, PTCH-1 and SMO are located in the primary cilium and within cytopolasmic vesicles, respectively. After ligand binding to PTCH-1, SMO migrates to the primary cilium. Here it interacts with glioma-associated (Gli) transcriptional factors. This complex eventually results in the nuclear translocation of Gli transcriptional regulators.16 Studies in Gorlin syndrome originally suggested a role of dysregulated Hh pathway signalling in the development of the cancers associated with this condition.16 In most BCCs, genetic mutations inactivate PTCH-1 leading to loss of function. Less commonly, genetic mutations activate SMO (gain of function). The activated Hh pathway then mediates unrestrained basal cell proliferation.15,17,18 Given that inactivation of PTCH-1 or activation of SMO is a common feature of most BCCs, increasing the inhibitory action of the former and suppressing the activation of the latter, became attractive targets for the treatment of BCC and other tumours with hyperactivated Hh pathway.19 The development of vismodegib for use in advanced BCC began with a cell-based high-throughput screen (HTS) to identify small-molecule Hh pathway inhibitors. Modifying the lead candidate from the HTS helped to create a molecule that offered the desired potency, metabolic stability, and pharmacokinetic properties.20 Vismodegib selectively inhibits the Hh signalling pathway, binding to and inhibiting SMO which is a critical signal transducing component of the pathway.20
Clinical Program Efficacy Phase I In the first-in-man Phase I study, vismodegib was administered orally to 68 patients with solid tumours, 33 of whom had advanced BCC documented on pathological analysis and considered by the investigator to be refractory to treatment. A total of 42 patients received 150 mg/day, 23 received 270 mg/day, and 4 received 540 mg/day. Although drug plasma levels differed between the 150 mg and 270 mg doses after a single dose, no dose dependency was demonstrated at steady state above 150 mg. The recommended Phase II dose was established at 150 mg/day as higher doses did not result in increased steady-state plasma concentrations and there were no dose-limiting toxic effects.21 Of the 68 patients enrolled, 62 were available for at least one follow-up tumour assessment and evaluation of © 2015 The Australasian College of Dermatologists
P Foley et al.
response. Responses were only observed in patients with BCC and medulloblastoma. In advanced BCC, the overall response rate (complete and partial) was 19 of 33 (58%). At the time of study closure, 12 of the patients with advanced BCC had treatment durations of 8.5 to 26.5 months and were enrolled in an extension study. As of January 2010, the median duration of response was 12.8 months and ongoing.21
Phase II ERIVANCE study A Phase II single-arm, multicentre, two-cohort, open-label efficacy and safety trial of vismodegib enrolled 104 patients with advanced BCC (71 with locally advanced and 33 with metastatic disease). Patients were enrolled at 31 sites in the US, Europe, and Australia. Patients were defined as having locally advanced BCC if they had lesions considered inappropriate for surgery (ie, inoperable or likely to result in considerable morbidity or deformity). Radiotherapy had either been unsuccessful in these patients or was contraindicated. Patients received 150 mg of vismodegib once daily until disease progression, unacceptable toxicity, or study discontinuation. A total of 8 patients in the locally-advanced cohort were excluded from the efficacy analysis because the independent pathologist did not identify BCC in baseline biopsy specimens.2 Among the patients with locally-advanced disease included in the efficacy analysis, 38% were deemed to have inoperable lesions, while surgery was considered inappropriate in the remainder; of these 25% had multiple recurrences, surgery was likely to result in significant morbidity or deformity in 51%, and both reasons were applicable in 14%. Of the locally-advanced group, 89% had undergone prior surgery, 27% radiation, and 11% systemic or topical therapy.2 The most frequent sites of target lesions in the metastatic cohort were the lung (67%) and lymph nodes (21%). Nearly all patients with metastatic disease had undergone prior surgery, while 58% had undergone radiation therapy and 30% prior systemic therapy.2 The primary endpoint – objective response rate as assessed by independent review – was met in both cohorts. For patients with locally-advanced disease, response was defined as a decrease of 30% or more in the visible or radiographic dimension (if applicable) or complete resolution of ulceration (if present at baseline). The Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.0 were used to assess response in patients with metastatic disease.2 The objective response rate was 43% in the locallyadvanced cohort, a figure significantly greater than the null hypothesis of 20% (P < 0.001). Among the 63 patients included in the efficacy analysis, 13 (21%) had a complete response (defined as the absence of residual BCC on biopsy). In the metastatic cohort 30% of patients (significantly more than the null hypothesis of 10%; P = 0.001) met the criteria for an objective response according to independent review. Investigator assessments placed the response rate at 45%. Concordance between this assess© 2015 The Australasian College of Dermatologists
ment and that of the independent reviewers was 79%. Median progression-free survival (PFS) for both cohorts was 9.5 months, as adjudged by the independent reviewers. A 24-month update included a total of 96 patients. The investigator-assessed objective response rate for locallyadvanced BBC patients was 60.3% (n = 38) and 48.5% (n = 16) for the metastatic cohort, similar to response rates reported in the primary analysis. The median duration of response was 26.2 and 14.8 months, respectively, while median PFS was 12.9 and 9.3 months, respectively. Twoyear overall survival rate was 85.4% and 62.3% for the locally-advanced and metastatic cohorts, respectively.22 Gorlin syndrome Another study compared vismodegib to placebo in 41 patients with Gorlin syndrome. Patients took vismodegib 150 mg or placebo once a day and were followed for a mean of eight months. Vismodegib significantly reduced the mean number of new lesions compared with placebo (2 vs 29 per patient per year; P < 0.001). It also reduced the mean diameter of existing clinically significant lesions compared with placebo (−65% vs −11%; P = 0.003). No tumours progressed during treatment with vismodegib.23 At 1 month, the Hh target-gene expression by BCC was reduced by 90% and tumour-cell proliferation diminished. In 83% of biopsy samples taken from sites of clinicallyregressed lesions, no residual BCC was detectable.23 SafeTy Events in VIsmodEgib (STEVIE) The 3rd interim analysis of this ongoing Phase II study, focusing on the safety of vismodegib in patients with advanced BCC, reported on 278 patients with locally-advanced disease and 22 with metastatic disease. Median treatment duration, including vismodegib interruption, was 176.5 days.24 Secondary endpoints included objective response rates. Among patients with available tumour assessments (n = 251), 17.5% experienced complete response, 39.8% had a partial response, 39% had stable disease, 2.8% had progressive disease, and 0.8% were unevaluable.24
Safety In the Phase I study, vismodegib was generally welltolerated. The most frequently occurring adverse events (occurring in >30% of patients) were muscle spasms, dysgeusia, fatigue, alopecia, and nausea.21 In the ERIVANCE study, by the data cut-off point, half of the patients had discontinued therapy. Disease progression was responsible for discontinuation in 18% of the metastatic BCC cohort. Patient decision was the most common reason in the locally-advanced patients (25%); however, the reasons were not documented.2 Muscle spasms, alopecia, and dysgeusia were the most commonly reported adverse events (Fig. 2).2 Hair loss and dysgeusia are adverse events attributable to the role of hedgehog signalling in the process of hair renewal and taste bud maintenance.25,26 A total of 57% of patients experienced only Grade 1 to Grade 2 adverse events, while serious adverse events were reported in 25% of patients. Seven
Treatment of advanced BCC
Percent of patients
30 20 10
Figure 2 Adverse events reported in ≥20% of all patients according to Grade.2* *The highest grade of event is reported here for each patient.
Grade 3 or 4 3
0 Muscle Alopecia Dysgeuisa Decrease Fatigue spasms in weight
Reasons for discontinuation24
Nausea Decrease Diarrhoea in appetite
Table 3 Clinical responses to interventions for adverse events with vismodegib28
Any Patient or investigator request Adverse events Disease progression Death*
131 41 35 18 13
*7 due to AEs assessed as unrelated to study drug; 3 due to AEs not possible to be assessed; 3 due to disease progression.
deaths occurred, all considered to be unrelated to vismodegib by site investigators.2 In the study dedicated to Gorlin syndrome, patients in the vismodegib group routinely experienced Grade 1 or 2 adverse events of dysgeusia, muscle cramps, hair loss, and weight loss. Overall, 54% of vismodegib-treated patients discontinued treatment due to adverse events.23 In the interim STEVIE safety analysis, common treatment-emergent adverse events (TEAEs) were typically Grade 2 or less and included muscle spasm (59.3%); alopecia (49.3%); and dysgeusia (41.0%). A total of 53 (17.7%) patients experienced serious TEAEs and 131 (43.7%) discontinued from the study (Table 2).24 Managing adverse events Mouse studies suggested that inhibition of the Hh signalling pathway interferes with hair growth.26,27 The pathway also contributes to normal adult olfactory, stomach, and muscle function.28 Thus the most common averse events associated with vismodegib – alopecia, dysgeusia, and muscle spasm – appear to be directly linked to Hh pathway inhibition.28 In a study of 22 patients treated with vismodegib for advanced BCC, each patient who experienced an adverse event was advised to respond according to the theoretical mechanism by which the drug blocks normal Hh pathways in the affected body system. Thus, for alopecia, patients used zinc-based shampoo and/or minoxidil foam to stabilise calcium flux in normal hair disrupted by administration of vismodegib. Patients experiencing dysgeusia used zinc lozenges to release calcium accumulation in taste bud cells. To
Number of patients responding
Alopecia Dysgeusia Nausea Muscle cramps
11/12 14/16 5/5 10/10
promote arrested olfactory Hh pathways, patients drank caffeinated beverages and to combat nausea (presumed to be due to reduced stomach acid production) they drank acidic liquids with each meal. Calcium channel-blocking agents, magnesium, or adequate hydration were used to relieve muscle cramps by blocking calcium retention associated with disruption of muscle-dependent Hh pathways.28 Table 3 shows the number of patients whose adverse events were stabilised, improved, resolved, or prevented by the intervention. Not all patients experiencing these events followed the treatment recommendations and of those who did, compliance varied. All patients were able to control the adverse events within tolerable levels and no patients discontinued vismodegib because of adverse events.28
Special populations The efficacy and safety of vismodegib have not been studied in patients with renal or hepatic disease. Based on population pharmacokinetic analysis of pooled data from five clinical studies, renal function (creatinine clearance) or hepatic function (ALT, AST, total protein, or total bilirubin) do not appear to affect the pharmacokinetics of vismodegib. In a pooled safety analysis that included 138 patients from the pivotal Phase II trial and three other studies, treatment-emergent Grade 3 laboratory abnormalities were hyponatraemia (4.3%), hypokalaemia (1.4%), and azotaemia (2.8%).29 Because Hh pathway inhibitors have been demonstrated to be embryotoxic and/or teratogenic in multiple animal species, pregnant women must not take vismodegib, nor is its use recommended in lactating women.29 © 2015 The Australasian College of Dermatologists
P Foley et al.
The large number of clinical trials underway investigating SMO inhibitors in treating Hh-dependent cancers highlights the intense interest in this class of agents. A host of SMO inhibitors are currently in development that may be used to treat BCC in the near future.30 Reports of tumour regrowth after an initial positive response to vismodegib have raised the question of whether resistance may be an issue with SMO inhibitors. Reasons for tumour regrowth are currently unclear; however, it has been suggested that in some cases a single BCC lesion may be heterogeneous on a cellular or molecular level.31 It is critical that research into the mechanisms of resistance to SMO inhibition be continued. Many ongoing trials are actively collecting tissue samples from progressing lesions for the purposes of molecular analysis. Evaluation of one patient who had progressed on vismodegib demonstrated mutation in the SMO molecule, interfering with vismodegib binding. This finding suggests that agents that bind to both wild type and mutant SMO may be the solution to overcoming vismodegib resistance. In addition, targeting downstream molecules in the Hh pathway, such as Gli, or other pathways known to contribute to Hh inhibitor resistance could be a further means of addressing resistance. Meanwhile, clinicians should perform regular skin checks on treated patients, even in situations when the original lesions appears to have disappeared. When identified and biopsied early, these secondarily resistant BCCs are more likely to be treated effectively.31 Finally, evaluating SMO inhibitors earlier in the disease course as adjuvants or neoadjuvants to traditional therapeutic approaches should be a priority.30
Professor Foley was an investigator in the STEVIE clinical trial. He has also received travel grants and speaker honoraria from Roche Products Pty Ltd.
CONCLUSIONS The identification of the Hh pathway’s role in BCC and the development of drugs that can target it has been a major breakthrough in the treatment of advanced BCC. Extensive study of the first-in-class agent vismodegib has seen this therapy approved for use in a number of countries. The efficacy of vismodegib in locally-advanced and metastatic BCC is encouraging. Clinicians prescribing this agent should educate patients about the simple interventions that can be used to address the most common side effects, thereby promoting compliance and increasing the chances of patients achieving satisfactory outcomes. Other agents with a similar mechanism of action to vismodegib are on the horizon and are expected to further expand the options for patients with advanced BCC.
The author would like to thank Jo Stratmoen for editorial assistance in preparing this paper. © 2015 The Australasian College of Dermatologists
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© 2015 The Australasian College of Dermatologists