REVIEW URRENT C OPINION

Smoothened inhibitors in the treatment of advanced basal cell carcinomas Rainer Kunstfeld

Purpose of review The Hedgehog pathway has been identified as a key element in the development of many forms of cancer. Smoothened (Smo) inhibitors are known to beneficially interfere with the Hedgehog pathway and are currently under investigation as anticancer drugs for many tumor entities. Reviewed here are the most recent developments in clinical research on Smo inhibitors for the treatment of advanced basal cell carcinoma (BCC). Recent findings When reviewing the literature of the past 12 months, it is striking to see the rapid evolution of the field. Compounds that have been presented as powerful new drug candidates 12 months ago have now been discontinued, whereas new ones have emerged. Reports on 13 drug candidates have been identified: one marketed, vismodegib, eight currently under development (phase I–II) and four for which clinical investigation for BCC is currently not being pursued. Summary Smo inhibitors are a promising drug class for the treatment of BCC. To date, most candidates are in early stage development and are expected to enter the market in approximately 5–8 years, if successful. Keywords basal cell carcinoma, hedgehog, Smo inhibitors, smoothened inhibitors

INTRODUCTION Basal cell carcinoma (BCC) is a commonly occurring skin tumor that is generally curable. In some cases, however, it can spread locally or metastasize to distant locations (advanced BCC, aBCC). Cytotoxic chemotherapy is currently not approved for the treatment of advanced disease and new approaches are urgently needed. The Hedgehog pathway has been identified as a key element in the development of many forms of cancer and is found to be altered and activated in almost all BCCs, both sporadic and inherited [1,2]. The inhibition of smoothened (Smo) is currently the best known mechanism for interfering with the Hedgehog pathway. Smo inhibitors represent a promising treatment strategy for aBCC and many drug companies have invested in the development of molecules that target Smo. Reviewed here are the most recent developments in clinical research on Smo inhibitors for the treatment of aBCC, including clinical trials currently ongoing and listed in the WHO International Clinical Trials Registry Platform (WHO ICTRP). www.co-oncology.com

THE HEDGEHOG PATHWAY AND SMOOTHENED INHIBITION A growing body of evidence suggests a role for conserved embryonic signaling pathways such as Hedgehog – named after the spiky appearance of Hedgehog mutant Drosophila melanogaster cells – in the development of human cancers. The Hedgehog signaling pathway is a key regulator of tissue polarity, patterning maintenance, and stem-cell maintenance during embryonic development and is typically silenced in adult tissue [3]. Hyperactivation of this pathway, via either mutation or deregulation, has been associated with tumorigenesis in a wide array of tissues. The Hedgehog Division of General Dermatology, Department of Dermatology, Medical University of Vienna, Vienna, Austria Correspondence to University Professor Dr Rainer Kunstfeld, Division of General Dermatology, Department of Dermatology, Medical University of Vienna, Wa¨hringer Gu¨rtel 18-20, A-1090 Vienna, Austria. Tel: +43 1 40400 6262; fax: +43 1 40400 7699; e-mail: rainer.kunstfeld@ meduniwien.ac.at Curr Opin Oncol 2014, 26:184–195 DOI:10.1097/CCO.0000000000000058 Volume 26  Number 2  March 2014

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Smo inhibitors in the treatment of advanced BCC Kunstfeld

KEY POINTS  The Hedgehog pathway is a key element in the development of many forms of cancer and is found to be altered and activated in almost all BCCs.  Smo inhibition is the best known mechanism for interfering with the Hedgehog pathway, and therefore represents a promising target for the treatment of BCC.  One Smo inhibitor, vismodegib, is available for clinical use, while eight candidates are currently undergoing clinical investigation.  In the pivotal ERIVANCE study, vismodegib showed 30% response (all PR) in aBCC and 43% response (21% CR, 22% PR) in laBCC.  Smo inhibitors cause side-effects such as muscle spasms, dysgeusia, alopecia, loss of appetite, and weight loss.

cascade is normally triggered when Hedgehog pathway ligands (Desert, Indian, or Sonic) bind to the transmembrane receptor Patched (Ptch) to initiate pathway signaling. In the inactive state, Ptch exerts an inhibitory effect on the signal transducer Smo, and no downstream signaling occurs. When Hedgehog ligand binds to Ptch, inhibition of Smo is released and downstream signaling occurs, regulating the expression of the transcription factors Gli1-3 (Fig. 1). The hereditary form of BCC, basal cell nevus syndrome (BCNS) or Gorlin–Goltz syndrome, is caused by germline deletion of one copy of Ptch1 [4] and can lead to hundreds to thousands of BCC tumors in affected individuals [5]. There are currently nine novel Smo inhibitors in clinical development (Table 1), of which one – vismodegib – has obtained marketing authorization in the United States in 2012 and in the European Union, Canada, Switzerland, Australia, Mexico, Israel, and South Korea in 2013. Additionally, a number of established drugs that are already licensed in other indications have been found to inhibit Smo and are under investigation in BCC.

DRUG CANDIDATES CURRENTLY UNDER INVESTIGATION Candidates currently in clinical stage development for BCC are discussed below.

Vismodegib (GDC-0449, Erivedge) The WHO ICTRP currently lists 10 ongoing or recently completed clinical trials investigating the

efficacy of vismodegib in patients with metastatic BCC (mBCC), locally advanced BCC (laBCC), multiple BCCs, BCNS (Table 1). Of the listed trials, three have published results within the review period, including the phase II ERIVANCE and STEVIE studies in mBCC and laBCC, and a phase II study in BCNS (Table 2) [6 ,7,8 ,9 ]. The ERIVANCE study [6 ] included 104 patients (mBCC, n ¼ 33; laBCC, n ¼ 63; excluded from efficacy analysis, n ¼ 8). Patients with mBCC had measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Patients with laBCC had inoperable lesions or were not considered candidates for surgery (recurrence after two or more previous surgical procedures; risk of severe mutilation). Radiation therapy had been unsuccessful or was contraindicated. Patients received vismodegib orally at the standard dose of 150 mg once daily until disease progression, unacceptable toxicity, or discontinuation of the study. Dose interruptions of up to 4 weeks were allowed for toxicity. The primary endpoint was the objective response rate, as assessed by independent review. Response was defined as a decrease of at least 30% in the externally visible or radiographic dimension (if applicable) or complete resolution of ulceration (if present at baseline). Statistical significance was tested versus a null hypothesis of a greater than 10% response rate for mBCC and greater than 20% for laBCC. The major secondary endpoint was duration of response. The independently assessed objective response rate was 30% [95% confidence interval (CI), 16–48; P ¼ 0.001; all partial responses (PR)] in patients with mBCC and 43% (95% CI, 31–56; P < 0.001) in those with laBCC, with complete responses (CRs) in 21% of patients (n ¼ 13). The median duration of response was 7.6 months (range, 2.1–11.1) in both cohorts, with a median progression-free survival of 9.5 months (95% CI, 7.4 to not estimable). Testing of Hedgehog pathway activation by measuring relative expression of Gli1 and Ptch2 was conducted from archival samples of tumor tissue (data available for 76% of patients) versus control samples of normal skin obtained from commercial sources. Analysis showed that expression of Gli1 and Ptch2 was increased versus control samples, to a similar degree in both cohorts, suggesting active Hedgehog signaling. Adverse events documented in greater than 30% of patients were muscle spasms (68%), alopecia (63%), dysgeusia (51%), weight loss (46%), and fatigue (36%). Serious adverse events (SAEs) were reported in 25% of patients, including seven deaths due to adverse events, all of which were considered by the investigators to be unrelated to vismodegib. The 18-month update of ERIVANCE, presented at the 2013 congress of the American

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&&

&

&

&&

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Melanoma and other skin neoplasms

Endoplasmic reticulum and golgi apparatus Skn Hh

Hn-secreting cell

HhN Dispatched

Ligands (IHn, DHh, SHh)

HhN Smo antagonist Robotnikinin Activated Smo

HPI-4

HhN COS Ptch

SuFu β-Arrestin

CDO and brother of CDO

Gli1/2/3 HPI-2/3

Kif3A Gli1/2

Active

HPI 1 Cyclin D, Cyclin E, Myc Gli1, Ptch, HPI

Cytoplasm Active

Gli1/2 Nucleus

FIGURE 1. Hedgehog signaling pathway inhibition. Most pathway inhibitors target smoothened (Smo) or Gli. In the inactive state, the absence of Hedgehog leads to inhibition of Smo by the transmembrane receptor Ptch whereas Gli1/2 are phosphorylated and removed from the cytoplasm through proteosomal degradation. In the active state, Hh is secreted by an adjacent cell and binds to Ptch, allowing Smo activation. Gli1/2 are released from the Smo protein complex and translocate to the nucleus, leading to transcriptional activation of Hh-associated genes. New therapeutic agents have been developed that target Hedgehog and Smo activation and downstream proteins, such as Gli. COS, costal; Hh, Hedgehog; HIP, Hedgehog interacting protein; HPI, Hedgehog protein inhibitor; Ptch, Patched; Smo, smoothened; SuFu, suppressor of fused. Reproduced with permission from [32]. &

Society of Clinical Oncology (ASCO) [8 ], showed an observed response rate of 48.5% for mBCC (all PR) and 60.3% (31.7% CR, 28.6% PR) for laBCC. The duration of response improved from the primary analysis [6 ]: 14.7 months for mBCC and 20.3 months for laBCC. The median overall survival was 30.9 months in mBCC and could not be estimated in laBCC. The adverse event profile remained consistent with the primary analysis. A total of 27 deaths have been reported compared with 16 deaths in the primary analysis. The additional 11 deaths occurred during the survival follow-up &&

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period and were not judged to be treatment-related. The most common reasons for death included progressive disease (n ¼ 15) and adverse events (n ¼ 7). The third interim analysis of the STEVIE study, recently presented at ASCO [9 ], included 300 patients with laBCC (n ¼ 278) or mBCC (n ¼ 22) receiving 150 mg vismodegib orally once daily. The median treatment duration was 176.5 days (range, 1–455). The preliminary best overall response in patients with available data (n ¼ 251) included CR (17.5%), PR (39.8%), stable disease (39.0%), and progressive disease (2.8%). Common treatment-related &

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Drug company

Roche, Genentech, Curis

Drug

Vismodegib (Erivedge, GDC-0449)

1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins BCC (II)

BCC (II)

Loma Linda University

Genentech

BCC (II)

laBCC/ mBCC (II)

F. Hoffmann-La Roche Ltd.

Genentech

Multiple BCCs (II)

Children’s Hospital and Research Center Oakland / Genentech

laBCC/ mBCC (II)

Multiple BCCs (II)

F. Hoffmann-La Roche Ltd.

Genentech

BCC (I)

Stanford University

Study sponsor

Indication (study phase)

Single arm, open label, two-cohort

Single arm, open label, expanded access

Nonrandomized, open label

Randomized, placebocontrolled, double-blind

Single arm, open label

Randomized, open label

Randomized, activecontrolled, double-blind

Single arm, open label

Study design

EUCTR2008-004945-27-DE

NCT01160250

NCT01201915

NCT01543581

EUCTR2011-000195-34-SE/ STEVIE

NCT01556009

EUCTR2012-00330510-AT

NCT01631331

Trial registry number/ study acronym (if available)

Table 1. Overview of ongoing clinical trials investigating smoothened inhibitors for basal cell carcinomasa

May 2012/June 2013

October 2010/August 2013

81

74

May 2009/n.a.

June 2011/n.a.

800

100

April 2012/April 2015

24

July 2010/April 2012

March 2013/n.a.

200

n.a.

June 2012/June 2013

Date of first enrolment/ estimated study completion date

20

Target patient numbers

A pivotal phase II, multicenter, single arm, two-cohort trial evaluating the efficacy and safety of GDC-0449 in patients with advanced basal cell carcinoma

A single-arm, open-label, expanded access study of vismodegib (GDC-0449) in patients with locally advanced or metastatic basal cell carcinoma

A phase II, multicenter, open-label, three-cohort trial evaluating the efficacy and safety of vismodegib (GDC-0449) in operable basal cell carcinoma

Placebo-controlled, double blind study to assess efficacy and safety of oral vismodegib for the treatment of basal cell carcinoma preceding excision by mohs micrographic surgery

A single-arm, open-label, phase II, multicentre study to assess the safety of vismodegib (GDC0449) in patients with locally advanced or metastatic basal cell carcinoma. STEVIE

A phase II randomized, open-label trial comparing the effects of intermittent vismodegib versus photodynamic therapy on the maintenance of benefit following 7 months of continuous vismodegib treatment in patients with multiple basal cell carcinoma

A randomized, double-blinded, regimen controlled, phase II, multicenter study to assess the efficacy and safety of two different vismodegib regimens in patients with multiple basal cell carcinoma

A pilot study to investigate the off label use of vismodegib as an adjuvant to surgery for basal cell carcinoma tumors

Study title

Smo inhibitors in the treatment of advanced BCC Kunstfeld

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188

Drug company

Novartis

Drug

Sonidegib (LDE225)

Table 1 (Continued)

www.co-oncology.com Solid tumors (I)

Novartis Pharmaceuticals

GS (I)

Nonrandomized, open label

laBCC/ mBCC (I)

Stanford University; Novartis Pharmaceuticals

Novartis Pharma

Randomized, double-blind, cross-over

BCNS (II)

Children’s Hospital and Research Center Oakland/Genentech

Randomized, open label

Single arm, open label

EUCTR2008-005506-40-AT

NCT01208831

NCT01529450

NCT00957229

NCT01700049

Single arm, open label

hrBCC/ laBCCb (IIB)

St. Louis University

NCT00833417/ERIVANCE

Genentech

Trial registry number/ study acronym (if available)

Single arm, open label, two-cohort

BCC (II)

Study sponsor Study design

Indication (study phase)

August 2009/ January 2015

February 2012/ November 2014

October 2010/ September 2013

41

22

44

August 2009/n.a.

October 2012/ January 2016

36

15

February 2009/ February 2014

Date of first enrolment/ estimated study completion date

104

Target patient numbers

A double-blind, randomized, vehicle-controlled proof of concept (PoC) study, to evaluate the safety, local tolerability, pharmacokinetics and pharmacodynamics of multiple topical administrations of LDE225 (a specific Smoothened inhibitor) on skin basal cell carcinomas in Gorlin syndrome patients followed by an open label, randomized expansion group to test two different strengths of an improved LDE225 formulation for extended treatment durations – LDE225B2203

An East Asian phase I, multicenter, open-label, dose-escalation study of oral LDE225 in patients with advanced solid tumors

A pilot open-label study to examine the safety and efficacy of oral LDE225 in patients with locally advanced or metastatic basal cell carcinoma who have been previously treated with nonLDE225 Smoothened inhibitor(s)

A randomized, phase II multicenter trial evaluating the efficacy and safety of a systemic Hedgehog pathway antagonist (GDC0449) in patients with basal cell nevus syndrome (BCNS)

ML28485: phase IIB single-site, open-label, nonrandomized study evaluating efficacy of oral vismodegib in various histologic subtypes (infiltrative/ morpheaform, nodular and superficial) of high risk and/or locally advanced basal cell carcinoma

A phase II, multicenter, single-arm, two-cohort trial evaluating the efficacy and safety of vismodegib (GDC-0449) in patients with advanced basal cell carcinoma

Study title

Melanoma and other skin neoplasms

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Drug company

Eli Lilly

Bristol-Myers Squibb, Exelixis

Novartis

Drug

Taladegib (LY2940680)

BMS-833923 (XLI139)

LEQ-506

Table 1 (Continued)

1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins nssBCC (I, II)

laBCC/ mBCC (II)

BCNS (II)

Novartis Pharmaceuticals

Novartis Pharma Services AG

Novartis Pharmaceuticals

Novartis Pharma AG

Novartis Pharmaceuticals

Bristol-Myers Squibb

Bristol-Myers Squibb

Solid tumors, including laBCC/ mBCC (I)

Solid tumors, including NBCCS and sporadic BCC (I)

Solid tumors (I)

Advanced cancer incl. BCC (I)

Solid tumors (I)

Study sponsor

Eli Lilly

Indication (study phase)

Single arm, open label

Single arm, open label, nonrandomized

Single arm, open label

Single arm, nonrandomized

Randomized, double-blind

Nonrandomized, double-blind

Randomized, vehiclecontrolled, double-blind

Single arm, open label

Study design

NCT01106508

NCT00670189

NCT01413906

NCT01226485

EUCTR2010-023819-34-DE

NCT01327053

EUCTR2009-013665-26-GB

NCT00880308

Trial registry number/ study acronym (if available) March 2009/ December 2013

January 2010/n.a.

June 2011/August 2014

April 2011/n.a.

September 2010/June 2014 November 2011/ November 2012 July 2008/July 2013

October 2010/January 2014

48

270

42

70 12 70

71

Date of first enrolment/ estimated study completion date

100

Target patient numbers

A phase I, multicenter, open label, dose escalation study of LEQ506, an oral Smoothened inhibitor, in patients with advanced solid tumors

A phase 1 multiple ascending dose study of BMS-833923 in subjects with advanced or metastatic solid tumors

Phase 1 multiple ascending dose study of BMS-833923 (XL139) in subjects with solid tumors

A study in advanced cancer

A phase II, double-blind, randomized, proof-of-concept, dose-ranging trial evaluating the efficacy, safety and pharmacokinetics of oral LDE225 in treatment of adult patients with nevoid basal cell carcinoma syndrome

Phase II, randomized double-blind study of efficacy and safety of two dose levels of LDE225 in patients with locally advanced or metastatic basal cell carcinoma

A double-blind, randomized, vehicle-controlled proof of concept (PoC) study to evaluate the efficacy, safety, local tolerability, pharmacokinetics and pharmacodynamics of multiple topical administrations of LDE225 (a specific Smoothened inhibitor) on superficial and nodular sporadic skin basal cell carcinomas

A phase I, multicenter, open-label, dose-escalation study of oral LDE225 in patients with advanced solid tumors

Study title

Smo inhibitors in the treatment of advanced BCC Kunstfeld

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190

www.co-oncology.com Maastricht University Medical Center

Millennium Pharmaceuticals, Inc.

Study sponsor

BCC (III)

Solid tumors, including BCC (I)

Indication (study phase)

Randomized, single-blind

Single arm, open label

Study design

NCT01358045

NCT01204073

Trial registry number/ study acronym (if available) October 2010/January 2013

November 2011/May 2013

128

Date of first enrolment/ estimated study completion date

46

Target patient numbers

Topical vitamin D3, diclofenac or a combination of both to treat basal cell carcinoma

A multicenter, open-label, dose-escalation, phase 1 study of TAK-441, an oral Hedgehog signaling pathway inhibitor, in adult patients with advanced nonhematologic malignancies

Study title

Primary analysis 33 30 (all PR) 7.6 25 12

Analysis

Number of patients (n)

Response rate (% of patients)a

Median duration of response (months)

Serious adverse events (% of patients)

Discontinuation due to adverse events (% of patients) n.a.

n.a.

14.7

48.5 (all PR)

n.a.

18-month update

]

12

25

7.6

43 (21 CR, 22 PR)

63

Primary analysis

Noncomparative

&&

laBCC [4,6

18-month update

n.a.

n.a.

20.3

60.3 (31.7 CR, 28.6 PR)

n.a.

12

17.7

n.a.

57.3 (17.5 CR, 39.8 PR)

300

Noncomparative

aBCC [7]

54

38

8

65% reduction in tumor dimensions

41 (26 active, 15 placebo)

Randomized, placebo-controlled

BCNS [5]

CR and PR only. aBCC, advanced basal cell carcinoma; BCC, basal cell carcinoma; BCNS, basal-cell nevus syndrome; CR, complete response; hrBCC, high risk basal cell carcinoma; laBCC, locally advanced basal cell carcinoma; mBCC, metastatic basal cell carcinoma; n.a., not available; PR, partial response.

Noncomparative

Design

]

mBCC [4,6

Trial

&&

Table 2. Summary of recent clinical findings of the smoothened inhibitor vismodegib in basal cell carcinomas

various histologic subtypes (infiltrative/morpheaform, nodular and superficial) of high risk and/or locally advanced basal cell carcinoma.

a

b

BCC, basal cell carcinoma; BCNS, basal cell nevus syndrome; GS, Gorlin syndrome; hrBCC, high risk basal cell carcinoma; laBCC, locally advanced basal cell carcinoma; mBCC, metastatic basal cell carcinoma; MMS, Mohs micrographic surgery; n.a., not available; nssBCC, nodular sporadic skin basal cell carcinoma; PoC, proof of concept; Smo, smoothened. Information taken from World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; http://apps.who.int/trialsearch/default.aspx; accessed 13 June 2013).

a

Millenium

TAK-441

Vitamin D3

Drug company

Drug

Table 1 (Continued)

Melanoma and other skin neoplasms

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Smo inhibitors in the treatment of advanced BCC Kunstfeld

adverse events were consistent with previous findings: muscle spasms (59.3%), alopecia (49.3%), and dysgeusia (41.9%). SAEs occurred in 17.7% of patients. Survival data from vismodegib-treated BCC patients with distant metastasis were obtained from the phase I (n ¼ 16) [10] and the pivotal phase II (n ¼ 29) [6 ] studies and compared with historical data from untreated patients reported in the literature. This revealed a 1-year survival rate of 84.4% (95% CI, 73, 9–95.0%) for vismodegibtreated BCC patients versus 58.6% for untreated patients and a median survival of 2.7 years (95% CI, 2.0 to not estimable) versus 2.0 years [11 ]. The BCNS study [7] included 41 patients with BCNS (at least two major diagnostic criteria and at least 10 surgically eligible BCCs present at study entry or removed during the previous 2 years). Patients were randomly (2 : 1 ratio) assigned to receive oral vismodegib 150 mg daily or placebo for a planned duration of 18 months. The primary endpoint was the rate of appearance of new BCCs that were eligible for surgical resection. Secondary endpoints included a reduction in the rate of appearance of smaller BCCs, reduction in the size of existing surgically eligible BCCs, duration of effect after drug discontinuation, change in Hedgehog target-gene expression in BCCs, and between-group differences in adverse events. At the planned second interim analysis, the data safety and monitoring as well as the institutional review boards recommended ending the placebo treatment owing to statistically significant differences in efficacy in favor of vismodegib. At the cut-off date, patients had been followed for a mean of 8 months (range: 1–15). The per-patient rate of new surgically eligible BCCs was markedly lower in the vismodegib group compared to placebo (mean 2 versus 29 per year; P < 0.001). The size of existing BCCs (sum of the longest diameters) was reduced by 65% in the vismodegib group and by 11% in the placebo group (P ¼ 0.003). Patients receiving vismodegib also had fewer on-study surgical tumor removals compared with placebo recipients (mean 0.31 versus 4.4 per patient; P < 0.001). All tumors responded to vismodegib, with near-complete remissions in some patients. Among patients receiving vismodegib for more than 3 months, 46% of biopsy specimens revealed residual tumors. A post-hoc analysis of seven patients, who had discontinued vismodegib, showed a rate of tumor regrowth of 0.69 new surgically eligible BCCs per month, compared with 2.4 in placebo patients. Hedgehog signaling, as evidenced by Gli1 messenger RNA expression, decreased by 90% (P < 0.001) in patients who had received vismodegib for 1 month. Tumor proliferation, as &&

assessed by Ki67 expression, was also significantly decreased at this time point, with no change in apoptotic activity, as assessed by cleaved caspase 3. Among vismodegib patients, 54% discontinued because of adverse events. Adverse events documented in greater than 30% of patients were dysgeusia (85%), muscle spasms (81%), hair loss (62%), and weight loss (42%). SAEs (grade 3 or 4) occurred in 38% of patients. Most adverse events were mild-to-moderate in severity, and no grade 5 events were observed. Table 3 shows the safety profile of vismodegib.

&

Sonidegib (LDE225) Sonidegib was originally tested as both an oral and a topical formulation [12–14]. In the phase I study investigating this agent in solid tumors [12,13], a maximum tolerated oral dose of 800 mg per day was established. In the cohort of patients with aBCC, one CR with histologic clearance was observed, along with four PRs. Two patients achieved stable disease lasting greater than 4 months. The topical formulation was studied in a total of eight BCNS patients presenting 27 BCCs, who randomly received a 0.75% sonidegib cream or vehicle [14]. Among 13 sonidegib-treated BCCs, there were three CRs and nine PRs, that is, only one tumor did not respond. Apart from one PR, the vehicle produced no clinical responses in any of the 14 treated BCCs [14]. Clinical development of the topical formulation, however, was discontinued because of the incomplete eradication of tumor cells [15]. The oral formulation is currently being investigated in BCC in pilot, phase I and phase II clinical trials in various clinical scenarios (Table 1). A proof-of-concept study in patients with BCNS was recently completed. Phase II studies are also under way investigating the efficacy of sonidegib in patients with aBCC or mBCC, including patients who have previously been treated with other Smo inhibitors. Two additional trials are evaluating the safety, local tolerability, pharmacokinetics and pharmacodynamics of the drug in patients with BCNS and those with sporadic superficial and nodular skin BCCs. No results have been reported to date. Table 3 shows the safety profile of sonidegib.

BMS-833923 (XLI139) A first-in-human, phase I study of BMS-833923 was conducted in patients with advanced or metastatic solid tumors, including two BCNS patients [16]. The study was designed to identify the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics. One

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Melanoma and other skin neoplasms Table 3. Safety of Smo inhibitors Adverse events reported (in >30% of patients)

Drug

Trial

Vismodegib (GDC-0449, Erivedge)

ERIVANCE BCC && & study [6 ,8 ]

Muscle spasms (68%)

SAEsa

Discontinuations for adverse eventsa

25%

12%

17.7%

26%

38%

54%

Not reported

Not reported

Not reported

Not reported

24%

Not reported

Not reported

18.8%

Alopecia (63%) Dysgeusia (51%) Weight loss (46%) Fatigue (36%) STEVIE study [9 ] &

Muscle spasms (59.3%) Alopecia (49.3%) Dysgeusia (41.9%)

BCNS study [7]

Dysgeusia (85%) Muscle spasms (81%) Hair loss (62%) Weight loss (42%)

Sonidegib (LDE225)

Phase I pharmacokinetics and pharmacodynamics study [12,13]

Fatigue

Nausea Vomiting Anorexia Muscle cramp Dysgeusia (No percentages reported) BMS-833923 (XLI139)

Advanced or metastatic solid tumors, including two BCNS patients [16]

Muscle spasms (44%)

Dysgeusia (44%) Taladegib (LY2940680)

Phase I pharmacokinetics and pharmacodynamics study [17]

Fatigue (44%)

Nausea (40%) Vomiting (40%) Dysgeusia (36%) TAK-441

Phase I pharmacokinetics and pharmacodynamics study [18]

Muscle spasms (44%) Dysgeusia (41%) Nausea (41%) Fatigue (38%)

SAE, serious adverse events. a Adverse events, SAEs and discontinuations are listed, whether or not they were considered by the investigators to be related to the treatment with the investigational agent.

of the two participating BCNS patients achieved an ongoing confirmed PR, but experienced drugrelated CTCAE grade 2 lipase elevation and pancreatitis that rapidly resolved when the drug was withheld. Most common adverse events (in greater than 30% of patients) were muscle spasms (44%) and dysgeusia (44%; Table 3). Currently, the compound is undergoing further investigation in solid tumors including BCC in two phase I studies (Table 1). 192

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Taladegib (LY2940680) The activity of taladegib in BCC is currently being investigated in a phase I study (Table 1). Interim data from pharmacokinetics and pharmacodynamics evaluation (25 patients) were reported at the 2012 ENA congress (European Organization for Research and Treatment of Cancer–National Cancer Institute–American Association for Cancer Research) [17]. The maximum tolerated dose was found to be 400 mg once daily. Dose-limiting Volume 26  Number 2  March 2014

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Smo inhibitors in the treatment of advanced BCC Kunstfeld

toxicities were one case of grade 3 hyponatremia at 100 mg once daily and one case each of grade 3 rash and grade 2 confusion, nausea and dehydration at 600 mg once daily. Frequent adverse events (20%) were fatigue (44%), nausea (40%), vomiting (40%), dysgeusia (36%), decreased appetite (28%), and muscle spasms (20%; Table 3). Two patients with BCC achieved PR. Of two patients who had progressive disease while receiving vismodegib, one had a minor response followed by progressive disease at 100 mg, whereas the other had a PR at 600 mg [17]. Final study results are expected in June 2014.

LEQ506 LEQ506 is currently being investigated in a phase I, first-in-human dose-escalation study in patients with advanced solid tumors, including laBCC and mBCC. The study aims to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of LEQ506 given orally on a daily dosing schedule. First study results are expected in January 2014 (Table 1).

of these will undergo clinical studies in patients with BCC.

PI-722 PI-722 has shown low nanomolar Smo inhibition, a favorable pharmacokinetic profile, and in-vivo efficacy. It retains potent activity against the clinically relevant D473H Smo resistance mutation [19].

Monoclonal antibodies Preclinical research is currently being conducted in the area of monoclonal antibodies directed against Smo [20].

DRUG CANDIDATES DISCONTINUED/NOT FURTHER DEVELOPED IN BASAL CELL CARCINOMA Drug candidates that were frequently mentioned in previous reviews of the topic and that have now been discontinued entirely or are not further developed in the indication of BCC, are discussed below.

TAK-441 Results of a phase I dose-escalation study of TAK441 were first presented at the 2012 congress of the European Society of Medical Oncology [18]. Thirtytwo patients were enrolled into the dose-escalation phase and treated with doses ranging from 50 to 1600 mg daily. Dose-limiting toxicities of grade 3 fatigue and muscle spasms were observed in one patient at the 1600 mg dose level. Six individuals discontinued because of adverse events, including a case of fatal cerebral hemorrhage considered drugrelated. The most common treatment-emergent adverse events were muscle spasms (44%), dysgeusia (41%), nausea (41%), fatigue (38%), and constipation (28%; Table 3). The maximum feasible dose was identified as 1600 mg and the maximum tolerated dose has not been reached. Four patients remained on trial for greater than 10 cycles, and three patients were continuing on treatment at the time of reporting. A dose expansion cohort has been initiated at 800 mg in patients with untreated BCC. Another study in BCC patients and patients with nonhematologic malignancies for whom standard treatment was no longer effective or did not offer curative or life-prolonging potential, has recently been completed, but no results have been published so far (Table 1).

Saridegib (IPI-926)

PRECLINICAL CANDIDATES

MK-5710

Some candidates are currently in their preclinical stage. It is too early to know whether any

There was a report in 2011 that this compound was selected for further development. No further

Saridegib initially demonstrated activity in a broad range of malignancies including BCC in preclinical and early clinical research [21]. The clinical data, however, have been disappointing and the originator company discontinued all company-sponsored clinical trials of saridegib in June 2012 [22].

PF-04449913 One phase I study in selected solid tumors, including one patient with BCC, was completed in June 2011 (ClinicalTrials.gov number: NCT01286467). The maximum tolerated dose was established at 320 mg once daily. A best overall response of stable disease was observed in seven patients, including the BCC patient [23]. Currently, development of PF-0449913 is being pursued only in the setting of acute myeloid leukemia [24].

SEN-794 This compound has been shown to be an active Smo inhibitor in preclinical studies. However, a strategic decision has apparently been taken to not develop the drug further in the indication of BCC [25].

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Melanoma and other skin neoplasms

clinical activities have, however, been reported [26].

clinical phase I or II and are expected to enter the market in approximately 5–8 years [31], if successful.

IMPORTANT OTHER HEDGEHOG INHIBITORS NOT TARGETING SMOOTHENED

Acknowledgements Margit Hemetsberger of Hemetsberger medical services, Vienna, Austria, and Julia Balfour, Dundee, Scotland, UK, assisted with the drafting and editing of the manuscript.

For the sake of completeness, important other Hedgehog inhibitors that do not target Smo are discussed below.

Itraconazole In a screening of drugs previously tested in humans, the systemic antimycotic agent itraconazole was found to be a potent Hedgehog inhibitor. It does not directly bind to Smo, but unfolds its inhibitory effect after Ptch, where it prevents the accumulation of Smo in the primary cilium [27]. An exploratory phase II study in 19 patients showed a reduction in tumor size in 23%, a reduction in cell proliferation in 45%, and inhibition of the Hedgehog pathway in 65% of patients [28]. There currently are no active clinical trials investigating itraconazole in BCC. A pilot biomarker study (NCT01108094; Stanford University) was initiated but has suspended participant recruitment.

Vitamin D3 It has long been known that vitamin D3 exhibits potent antitumor activity. Vitamin D3 was also identified as a Hedgehog pathway inhibitor and is thought to exert its effects through direct binding to Smo [29]. Vitamin D3 analogs were shown in vitro to be able to block the Hedgehog pathway directly and exhibited antiproliferative activity against two human cancer cell lines through mechanisms distinct from the Hedgehog or vitamin D receptor pathways [30]. Topical application of calcitriol to inhibit BCC growth or achieve cure is currently under clinical investigation. Results were expected for May 2013, but no published results have been found (Table 1). Regarding novel vitamin D3 analogs, further research is needed to explore their potential as selective Hedgehog inhibitors [30].

CONCLUSION Smo appears to be a promising but challenging target for the treatment of BCC. Compounds that have been presented as powerful new drug candidates 12 months ago, have now been discontinued, while new ones have emerged. One Smo inhibitor, vismodegib, has been approved for this indication. Most other currently tested drug candidates are in 194

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Conflicts of interest The author has no conflicts of interest to declare.

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Smoothened inhibitors in the treatment of advanced basal cell carcinomas.

The Hedgehog pathway has been identified as a key element in the development of many forms of cancer. Smoothened (Smo) inhibitors are known to benefic...
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