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Hedgehog pathway inhibition in advanced basal cell carcinoma: latest evidence and clinical usefulness:

Hedgehog pathway inhibition in advanced basal cell carcinoma: latest evidence and clinical... 653605 TAM0010.1177/1758834016653605Therapeutic Advances in Medical OncologyS Silapunt, L Chen research-article2016 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Hedgehog pathway inhibition in advanced 2016, Vol. 8(5) 375 –382 DOI: 10.1177/ basal cell carcinoma: latest evidence and © The Author(s), 2016. Reprints and permissions: clinical usefulness http://www.sagepub.co.uk/ journalsPermissions.nav Sirunya Silapunt, Leon Chen and Michael R. Migden Abstract: Treatment of locally advanced basal cell carcinomas (laBCCs) with large, aggressive, destructive, and disfiguring tumors, or metastatic disease is challenging. Dysregulation of the Hedgehog (Hh) signaling pathway has been identified in the vast majority of basal cell carcinomas (BCCs). There are two United States Food and Drug Administration (US FDA)-approved Hh pathway inhibitors (HPIs) that exhibit antitumor activity in advanced BCC with an acceptable safety profile. Common adverse effects include muscle spasms, dysgeusia, alopecia, fatigue, nausea and weight loss. Keywords: basal cell carcinoma, Hedgehog pathway inhibitor, sonidegib, vismodegib Correspondence to: Introduction receptor-targeted molecules in the Hh pathway Michael R. Migden, MD More than 2.8 million new cases of basal cell car- has led to the approval of two Hh pathway inhibi- Departments of Dermatology and Head cinoma (BCC), the most common human can- tors (HPIs) vismodegib and sonidegib by the & Neck Surgery, The cer, are diagnosed each year in the United States United States Food and Drug Administration University of Texas MD Anderson Cancer Center, and contribute to over 3000 deaths [Madan et al. (US FDA) (Figure 1). 1515 Holcombe Boulevard, 2010; Mohan and Chang, 2014]. Most BCCs are Unit 1452, Houston, TX 77030, USA effectively treated with surgical excision, Mohs Vismodegib (Erivedge Capsule, Genentech, Inc., mrmigden@mdanderson. surgery, destruction or topical therapy. A study of USA) was approved by the US FDA in January org facial BCCs found 5-year recurrence rates after 2012 for the treatment of adults with metastatic Sirunya Silapunt, MD Department of excision or Mohs surgery were 2.5–4.1% for pri- basal cell carcinoma (mBCC) or with locally Dermatology, the mary tumors, and 2.4–12.1% for recurrent advanced basal cell carcinoma (laBCC) that has University of Texas McGovern Medical School tumors [Mosterd et al. 2008]. When BCC is not recurred following surgery or who are not candi- at Houston, Houston, TX, promptly treated, extensive local tissue invasion dates for surgery or radiation. The US FDA USA and destruction in addition to rare occurrence of approval of vismodegib was based on the demon- Leon Chen, MD Department of metastasis can lead to significant morbidity and stration of objective response rate (ORR) from the Dermatology, The mortality. Surgery and radiation therapy to treat ERIVANCE clinical trial, a multicenter, single- University of Texas McGovern Medical School advanced cases may cause unacceptable disfig- arm, two-cohort, clinical trial, evaluating the treat- at Houston, Houston, TX, urement or morbidity. ment of 150 mg of vismodegib daily in patients USA with laBCC or mBCC [Sekulic et al. 2012]. The pathogenesis of BCC has been elucidated including identification of aberrant Hedgehog Sonidegib (Odomzo Capsules, Novartis (Hh) pathway signaling and the associated muta- Pharmaceuticals Corp., USA) was approved by tions of Patched-1 (PTCH1) and Smoothened the US FDA in July 2015 for the treatment of (SMO) genes [Gailani et  al. 1996; Hahn et  al. patients, 18 years or older, with laBCC that has 1996; Johnson et al. 1996; Aszterbaum et al. 1998; recurred following surgery or radiation therapy, Xie et al. 1998; Epstein, 2008]. Aberrant Hh path- or those who are not candidates for surgery or way signaling has been detected in patients with radiation therapy. The US FDA approval of son- nevoid BCC syndrome as well as in over 95% of idegib was based on the demonstration of durable patients with sporadic BCCs [Gailani et al. 1996; ORR from the BOLT clinical trial, a phase II, Xie et al. 1998; Epstein, 2008]. The discovery of multicenter, randomized and double-blinded http://tam.sagepub.com 375 Therapeutic Advances in Medical Oncology 8(5) Figure 1. When Hh signaling ligand is present and binds to the 12 transmembrane protein PTCH1, the 7 membrane spanning receptor SMO is no longer inhibited via PTCH1-mediated inhibition and allows transcription factor Gli1 to enter the cell nucleus, stimulating cell division and tumorigenesis. Both vismodegib and sonidegib bind SMO and inhibit the Hh pathway reactivation. Hh, Hedgehog; PTCH1, Patched-1 mutation; SMO, Smoothened mutation. clinical trial, evaluating the treatment with two The first SMO antagonist reported in literature is different doses of sonidegib in patients with a naturally occurring alkaloid called cyclopamine laBCC or mBCC [Migden et al. 2015]. found in the corn lily [Cooper et  al. 1998]. Cyclopamine was identified to be the culprit This article will provide an overview of clinical responsible for the midline single-eyed appear- use of HPIs in advanced BCC. ance of many lambs born by corn lily-consuming ewes in the 1950s. Cyclopamine was found to bind SMO and inhibits the activation of down- Drug development stream Hh target genes that are essential for The Hh pathway was discovered during the inves- proper embryonic development [Incardona et al. tigation of Drosophila melanogaster embryogenesis 1998]. In preclinical mouse models, cyclopamine [Nusslein-Volhard and Wieschaus, 1980]. The has been shown to induce the remission of medul- activation of the Hh pathway during embryogen- loblastoma via Hh signaling inhibition [Sanchez esis ensures proper development of the embry- et  al. 2005]. Despite its ability to interfere with onic cells; however, the Hh pathway remains the Hh pathway signaling, cyclopamine’s subop- quiescent in adult tissues. In the absence of the timal aqueous solubility and chemical stability Hh ligand signal, the cell-surface transmembrane limit its therapeutic usefulness in clinical research protein PTCH-1 keeps the activity of the 7-mem- [Winkler et al. 2009]. brane-spanning receptor, SMO, suppressed [Stone et  al. 1996; Xie et  al. 1998]. However, GDC-0449 (vismodegib) is a first-in-class, small- when the Hh signaling ligand is present and molecule inhibitor of SMO that selectively inhib- bound to PTCH-1, SMO is no longer inhibited its the Hh signaling pathway by binding to SMO, and allows the transcription factor Gli to enter the therefore inhibiting the aberrant activation of the cell nucleus, promoting cell division and tumori- Hh pathway. GDC-0449 has greater potency and genesis [Aszterbaum et al. 1998]. more favorable pharmaceutical properties than 376 http://tam.sagepub.com S Silapunt, L Chen et al. cyclopamine. In 2009, a phase I study of GDC- Warning and precaution 0449 (vismodegib) showed a 58% response rate HPIs are contraindicated in women who are either among 33 patients with laBCC and mBCC [Von pregnant or breastfeeding as it may cause death or Hoff et  al. 2009]. The median duration of severe birth defects in developing fetus because Hh response was 12.8 months [Von Hoff et al. 2009]. signaling plays a pivotal role in the embryonic The recommended dose of vismodegib was 150 developmental pathway. Reproductive toxicology mg/day, based on the achievement of maximal studies in rats demonstrated that vismodegib expo- plasma concentration and pharmacodynamic sure during organogenesis results in embryo-fetal response [Lorusso et al. 2011a]. death at higher exposures and severe birth defects at exposures within the range achieved with the LDE225 (sonidegib), discovered in 2010, is a recommended human dose [Genentech, Inc., potent selective SMO antagonist with high tissue 2012]. Although no human data on the effects of penetration and the ability to cross the blood– HPIs on fetal development have been reported, brain barrier with good oral bioavailability [Pan pregnancy status should be verified prior to the ini- et  al. 2010]. In a phase I study in 103 patients tiation of HPIs. Highly effective contraception with advanced BCC and other solid tumors, the should be used during treatment and for up to 7 maximum tolerated dose was determined to be months after the last dose of vismodegib, and for at 800 mg daily and 250 mg twice daily after testing least 20 months after the last dose of sonidegib. various of dosages [Rodon et al. 2014]. No clini- Male patients should use condoms during treat- cal advantage was observed with twice-daily dos- ment with HPIs, and for at least 2 months after the ing over once daily dosing; therefore, the once last dose of vismodegib, or 8 months after the last daily dosing regimen is currently recommended dose of sonidegib. Healthcare providers should [Rodon et al. 2014]. report to pharmaceutical company any cases of exposure during pregnancy (either direct exposure LDE225 0.75% topical cream was investigated in in female patients or through seminal fluid from 27 BCCs treated twice daily for 4 weeks [Skvara male patients), and should encourage pregnant et al. 2011]. In the treatment group (13 of 27); 3 women to participate in the Erivedge or Odomzo BCCs had a complete response, 9 BCCs had a pregnancy pharmacovigilance program to collect partial response, and one BCC had no clinical information on pregnancy outcomes. response. A mean tumor volume reduction was 56%. In the control group (14 of 27), 13 BCCs Currently there are no data available regarding showed no clinical response, and 1 BCC had the presence of HPIs in human milk, however, a partial response. A phase II study with a breastfeeding is not advisable during treatment SLIGHTLY larger sample size showed insuffi- and for at least 20 months after the last dose of cient efficacy with investigational topical formula- sonidegib. Because both the ERIVANCE BCC tion and treatment conditions. and BOLT trials were conducted in the adult population, the safety and effectiveness of HPIs have not been established in pediatric patients. Metabolism and drug interactions Patients should not donate blood or blood prod- The major metabolic pathways of vismodegib ucts while taking HPIs and for at least 7 months include oxidation, glucuronidation and pyridine after the last dose of vismodegib or 20 months ring cleavage [Genentech, Inc., 2012]. Vismodegib after the last dose of sonidegib. Serum creatinine elimination involves multiple pathways predomi- kinase (CK) levels and renal function tests nated by the hepatic route as 82% of the adminis- should be obtained prior to initiating and peri- tered dose was recovered in the feces and 4.4% odically during sonidegib treatment [Novartis was recovered in the urine [Genentech, Inc., Pharmaceuticals Corp., 2015]. 2012]. No change in vismodegib level was observed in patients concomitantly treated with CYP3A4 inhibitors and CYP3A4 inducers. In Administration and formulations contrast, sonidegib is mainly metabolized by the The recommended dose for vismodegib is 150 hepatic enzyme CYP3A, therefore, it should not mg orally daily, and it may be taken with or with- be used in patients taking CYP3A inhibitors or out food. In the pharmacokinetic dose-scheduling CYP3A inducers due to potential drug interaction study of vismodegib, it showed that any reduction [Novartis Pharmaceuticals Corp., 2015]. in vismodegib dose or frequency could result in http://tam.sagepub.com 377 Therapeutic Advances in Medical Oncology 8(5) suboptimal unbound drug concentration and appetite [Sekulic et al. 2012]. Of the 104 patients therefore compromise the maximum clinical ben- enrolled, 13 (12%) had an adverse event leading efit. Dose reduction is not indicated for vismod- to discontinuation of the study drug with muscle egib [Lorusso et al. 2011b]. spasm being the most commonly reported event that contributed to study drug discontinuation, The sonidegib dose is 200 mg orally daily taken which occurred in 2 individuals. Serious adverse on an empty stomach, at least 1 hour before or 2 events of any grade were reported in 26 patients hours after a meal. (25%). Grade 5 (fatal) adverse events reported in 7 patients (6 with laBCC and 1 with mBCC) were due to hypovolemic shock, myocardial Clinical uses of Hh pathway inhibitors infarction, meningeal disease and ischemic stroke that were responsible for 1 death each and 3 Vismodegib patients died from unknown causes. These 7 In the ERIVANCE clinical trial, a multicenter, patients had clinically significant risk factors or international, two-cohort, nonrandomized study, coexisting conditions at baseline. No association a total of 104 patients with mBCC and laBCC with the study drug was identified. who had inoperable disease or for whom surgery was inappropriate were enrolled and received 150 An additional 12-month follow-up in the phase mg of oral vismodegib daily. The primary end II, multinational, multicenter, nonrandomized, point of the ERIVANCE trial was the indepen- two-cohort study, confirms the efficacy and safety dently assessed ORR. For laBCC, the objective of vismodegib in the management of advanced response was defined as a decrease of 30% or BCC [Sekulic et  al. 2015]. Median follow-up more in the externally visible (including residual time, including the primary analysis and the addi- scarring) or radiographic dimension, or complete tional 12-month follow up, was 21.7 months in resolution of ulceration if present at baseline. the laBCC group and 22.4 months in the mBCC Progressive disease was defined as an increase of group. The ORR increased from 42.9% to 47.6% 20% or more in the externally visible or radio- in patients with the laBCC, and from 30.3% to graphic dimension, new ulceration, or a new 33.3% in patients with mBCC. All responders lesion. For patients with multiple target lesions, (33.3%) in the mBCC group had partial response, the sum of the longest diameters was used to and 22.2% and 25.4% of responders in the laBCC determine response and progression. The group had complete and partial response respec- Response Evaluation Criteria in Solid Tumors tively. Median duration of response in patients (RECIST) was used for mBCC [Therasse et  al. with laBCC increased from 7.6 to 9.5 months 2000]. Patients received vismodegib until disease (Table 1). progression, unacceptable toxic effects, or dis- continuation of the study. The mean duration of No new safety signals emerged with extended treatment was approximately 10 months. treatment duration. Muscle spasms, dysgeusia and alopecia remained the most common adverse In 63 patients with laBCC, the ORR (including events in both the primary and the 12-month both complete and partial response) was 43%, update analysis. Amenorrhea was reported in 2 with complete responses in 13 (21%) patients patients with laBCC. As of the 12-month update, (defined as the absence of residual BCC on assess- of the 104 patients enrolled, 75 patients discon- ment of a biopsy specimen). The ORR of 33 tinued treatment mainly due to patient decision, patients with mBCC was 30%, and all responses disease progression and adverse events. The most were partial. The median duration of response was common adverse events leading to treatment dis- 7.6 months in both groups [Sekulic et al. 2012]. continuation included muscle spasms, weight loss and dysgeusia. Adverse events occurring in more than 20% of patients were muscle spasms (68%), alopecia Almost half of patients had grade 1 (mild) to (63%), dysgeusia (taste disturbance, 51%), grade 2 (moderate) adverse events, and 51.9% of weight loss (46%), fatigue (36%), nausea (29%), patients had adverse events grade 3 or higher. decrease in appetite (23%), and diarrhea (22%). Serious adverse events (31.7% of patients) Adverse events of grade 3 (severe or medically increased modestly compared with those at pri- significant) or grade 4 (life threatening) included mary analysis (25% of patients). No death muscle spasms, weight loss, fatigue, and loss of occurred as the result of adverse events. 378 http://tam.sagepub.com S Silapunt, L Chen et al. Table 1. Response rate comparison in sonidegib and vismodegib. BOLT (200 mg BOLT (800 mg ERIVANCE (150 mg sonidegib) sonidegib) vismodegib) Primary analysis Primary analysis Primary analysis 12-month update laBCC mBCC laBCC mBCC laBCC mBCC laBCC mBCC (n = 42) (n = 13) (n = 93) (n = 23) (n = 63) (n = 33) (n = 63) (n = 33) Proportion of patients 18 2 35 4 27 10 30 11 with objective response (43%) (15%) (38%) (17%) (43%) (30%) (48%) (33%) Central review (BOLT); Independent review (ERIVANCE) Complete response 2 0 0 0 13 0 14 0 (5%) (21%) (22%) Partial response 16 2 35 4 14 10 16 11 (38%) (15%) (38%) (17%) (22%) (30%) (25%) (33%) Disease control, % 93% 92% 80% 83% 81% 94% 83% 94% laBCC, locally advanced basal cell carcinoma; mBCC, metastatic basal cell carcinoma. Sonidegib an objective response were noted among the 93 In the BOLT trial, a multicenter, randomized, with laBCC and 4 (17%) among the 23 with double-blind, phase II study, patients with mBCC. A reduction in Gli1 expression was seen laBCC not amenable to curative surgery or radia- in patients with disease control (those with either tion, or mBCC were randomized in a 1:2 ratio to complete response, partial response or stable receive sonidegib 200 mg daily (lowest effica- disease) (Table 1). cious dose) or 800 mg daily (maximum tolerated once daily dosing). RECIST [Therasse et  al. The most common adverse events included mus- 2000] and modified RECIST was used to assess cle spasms, alopecia, dysgeusia (taste distur- mBCC and laBCC, respectively [Migden et  al. bance), nausea, elevated blood CK and fatigue 2015; Eisenhauer et al. 2009]. The primary end- [Migden et al. 2015]. Muscle spasm was the most point was the proportion of patients who achieved common reported adverse event in 49% and 67% an objective response (complete or partial of patients in the 200 mg and 800 mg group response) with data collected up to 6 months respectively, and the most common adverse event after randomization of the last patient. In the set- resulting in treatment discontinuation. Alopecia ting of symptoms indicating potential toxicity, was reported in 43% of patients in the 200 mg dose interruptions or reductions were permitted. group and 55% of patients in 800 mg group. Of the 230 patients enrolled, 194 with laBCC Taste disturbance was reported in 38% and 59% and 36 with mBCC, 79 were in the 200 mg son- of patients in the 200 mg and 800 mg group idegib group, and 151 were in the 800 mg son- respectively. Adverse events generally occurred idegib group. The median durations of treatment less frequently in the 200 mg group than in the were 8.9 months in the 200 mg dose group and 800 mg group. 6.5 months in the 800 mg dose group dose. Median follow up was 13.9 months. The most common grade 3–4 adverse events (severe, medical significant or life threatening) In the primary efficacy analysis population, 20 were elevated serum CK (6% in the 200 mg group (36%) of 55 patients receiving 200 mg sonidegib versus 13% in the 800 mg group) and elevated and 39 (34%) of 116 receiving 800 mg sonidegib lipase (5% of patients in both groups). Increasing achieved an objective response per central sonidegib dose and exposure were associated with review. In the 200 mg sonidegib group, 18 (43%) increased CK level. Serious adverse events were patients who achieved an objective response reported in 14% of patients in the 200 mg son- were noted among the 42 with laBCC and two idegib group and 30% in the 800 mg sonidegib (15%) among the 13 with mBCC. In the 800 mg group. Rhabdomyolysis and elevated serum CK sonidegib group, 35 (38%) patients who achieved were the most frequently reported serious adverse http://tam.sagepub.com 379 Therapeutic Advances in Medical Oncology 8(5) events which both occurred in 1% of patients in [Ozkul, 2007]. No clear relationship between the the 200 mg group and 3% of patients in 800 mg incidence of muscle cramps or spasm and elevated group. However, these reported rhabdomyolysis CK has been established [Migden et  al. 2015]. cases did not meet the criteria defined by the Increased CK level is likely of skeletal muscle ori- Independent Safety Review Committee and gin owing to the lack of evidence of cardiac muscle Adjudication Committee as CK concentrations injury. Sonidegib is mainly metabolized by the more than ten times higher than baseline plus a hepatic enzyme CYP3A so drug interactions with 1.5-fold increase in creatinine concentration in CYP3A inhibitor can potentially increase the risk serum from baseline [Migden et  al. 2015]. for further muscle toxicity [Zollinger et al. 2014]. Secondary malignancies were noted in 6% (200 mg) and 7% (800 mg) of patients. Overall, 4 Taste disturbances are well reported in patients patients in the 800 mg group died while taking treated with HPIs and some patients even discon- study treatment, but none of these deaths was tinued the treatment because of this undesirable deemed to be related to sonidegib. side effect [Dessinioti et  al. 2014]. Chorda tym- pani nerve responses to taste stimuli were mark- Although both groups demonstrated similar effi- edly reduced or absent in mice treated with cacy, the 200 mg sonidegib group was found to LDE225 for up to 28 days [Kumari et al. 2015]. have longer duration of treatment, lower rate of Vismodegib-treated mice were found to have adverse events, and lower discontinuation rate. reductions in taste bud size, taste cells per taste The overall benefit-to-risk profile is more favora- bud, and multiple taste-modulatory factors in the ble with 200 mg than 800 mg sonidegib group. taste cells [Yang et al. 2015]. Regarding dysgeusia Quality of life was assessed based on two health and weight loss, one study suggested the benefit of questionnaires; the Quality of Life Questionnaires nutritional screening prior to initiation of vismod- C30 (QLQ-C30) and the Head and Neck Cancer egib, and nutritional monitoring and management Module 35 (H&N35). The findings demon- during the treatment [Le Moigne et al. 2016]. strated the tolerability of sonidegib and improve- ment in or maintenance of quality of life in most Alopecia is a well-known adverse effect of HPIs. patients with laBCC and mBCC. The Hh pathway has an essential role during hair follicle morphogenesis, where it is required for nor- Additional follow up of the BOLT clinical trial mal advancement beyond the hair germ stage of was ongoing at the time this review article was development [Chiang et al. 1999]. Although HPI- submitted. induced alopecia appears to be reversible in most cases; 4 of 65 patients were reported to have persis- tent alopecia after stopping vismodegib [Alkeraye Safety and tolerability et al. 2015]. Death was reported in both HPI stud- Both HPIs share similar adverse effects which ies, however, a relationship between study drug include muscle spasms, dysgeusia (taste distur- and the deaths has not been established. bance), alopecia, fatigue, nausea and weight loss. The vast majority of adverse effects were mild-to- moderate in severity. Treatment-related adverse Drug resistance effects were manageable and most were reversible Patients with treatment resistance to an SMO after discontinuation of drug. The most frequent inhibitor may also fail other SMO inhibitors. A adverse events leading to discontinuation of HPI study of 9 patients with advanced BCCs that were treatment were muscle spasms, dysgeusia and previously resistant to treatment with vismodegib weight loss. demonstrated resistance with sonidegib [Danial et al. 2015]. Genomic analysis of tumor biopsies HPI-induced muscle contraction and muscle fiber revealed that vismodegib resistance is associated twitching is thought to be the result of calcium with Hh pathway reactivation, predominantly influx [Teperino et  al. 2012]. A study found caused by SMO mutations, and to a lesser extent amlodipine, a calcium channel blocker, reduced through mutation in suppressor of fused (SUFU), the frequency of vismodegib-induced muscle and gain-of-function mutations in Gli2 [Sharpe cramps [Ally et  al. 2015]. This is the result of et  al. 2015]. SMO mutations were identified in blocking voltage-gated calcium channels and 50% (22 of 44) of resistant BCCs [Atwood et al. inhibiting the transport of extracellular calcium 2015]. The findings suggest that a combination into muscle which is required for contraction of therapies targeting both SMO and downstream 380 http://tam.sagepub.com S Silapunt, L Chen et al. the majority of drug resistance in basal cell carcinoma. components of the Hh pathway may be required Cancer Cell 27: 342–353. to overcome drug resistance. Chiang, C., Swan, R., Grachtchouk, M., Bolinger, M., Litingtung, Y., Robertson, E. et al. (1999) Conclusion Essential role for sonic hedgehog during hair follicle HPIs provide a promising treatment for patients morphogenesis. Dev Biol 205: 1–9. with advanced BCCs. Both vismodegib and son- Cooper, M., Porter, J., Young, K. and Beachy, P. idegib demonstrated similar overall efficacy, (1998) Teratogen-mediated inhibition of target tissue safety and tolerability. Vismodegib, the first HPI response to SHH signaling. Science 280: 1603–1607. approved in the US, produced an ORR of 47.6% Danial, C., Sarin, K., Oro, A. and Chang, A. (2015) in patients with laBCC and 33.3% in patients An investigator-initiated open-label trial of sonidegib with mBCC in the additional 12-month follow in advanced basal cell carcinoma patients resistant to up. Sonigegib, the second HPI approved a few vismodegib. Clin Cancer Res 6 November 2015. [Epub years later for laBCC, demonstrated an objective ahead of print]. response in 36% of patients receiving 200 mg rec- Dessinioti, C., Plaka, M. and Stratigos, A. (2014) ommended dose. An additional 12 months of Vismodegib for the treatment of basal cell carcinoma: follow-up data was pending. results and implications of the ERIVANCE BCC trial. Future Oncol 10: 927–936. Future studies might include assessment of HPIs Eisenhauer, E., Therasse, P., Bogaerts, J., Schwartz, in combination with other treatment modalities L., Sargent, D., Ford, R. et al. (2009) New response to accomplish tumor control, and potential use of evaluation criteria in solid tumours: revised RECIST HPIs in advance of surgery to minimize potential guideline (version 1.1). Eur J Cancer 45: 228–247. postoperative disfigurement. Future effort is also needed to investigate the underlying mechanisms Epstein, E. (2008) Basal cell carcinomas: attack of the of actions for drug resistance. hedgehog. Nat Rev Cancer 8: 743–754. Gailani, M., Stahle-Backdahl, M., Leffell, D., Glynn, Funding M., Zaphiropoulos, P., Pressman, C. et al. (1996) The The author(s) received no financial support for role of the human homologue of Drosophila patched in the research, authorship, and/or publication of sporadic basal cell carcinomas. Nat Genet 14: 78–81. this article. Genentech, Inc. (2012) Erivedge (Vismodegib) Package Insert. San Francisco, CA: Genentech, Inc. 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653605 TAM0010.1177/1758834016653605Therapeutic Advances in Medical OncologyS Silapunt, L Chen research-article2016 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Hedgehog pathway inhibition in advanced 2016, Vol. 8(5) 375 –382 DOI: 10.1177/ basal cell carcinoma: latest evidence and © The Author(s), 2016. Reprints and permissions: clinical usefulness http://www.sagepub.co.uk/ journalsPermissions.nav Sirunya Silapunt, Leon Chen and Michael R. Migden Abstract: Treatment of locally advanced basal cell carcinomas (laBCCs) with large, aggressive, destructive, and disfiguring tumors, or metastatic disease is challenging. Dysregulation of the Hedgehog (Hh) signaling pathway has been identified in the vast majority of basal cell carcinomas (BCCs). There are two United States Food and Drug Administration (US FDA)-approved Hh pathway inhibitors (HPIs) that exhibit antitumor activity in advanced BCC with an acceptable safety profile. Common adverse effects include muscle spasms, dysgeusia, alopecia, fatigue, nausea and weight loss. Keywords: basal cell carcinoma, Hedgehog pathway inhibitor, sonidegib, vismodegib Correspondence to: Introduction receptor-targeted molecules in the Hh pathway Michael R. Migden, MD More than 2.8 million new cases of basal cell car- has led to the approval of two Hh pathway inhibi- Departments of Dermatology and Head cinoma (BCC), the most common human can- tors (HPIs) vismodegib and sonidegib by the & Neck Surgery, The cer, are diagnosed each year in the United States United States Food and Drug Administration University of Texas MD Anderson Cancer Center, and contribute to over 3000 deaths [Madan et al. (US FDA) (Figure 1). 1515 Holcombe Boulevard, 2010; Mohan and Chang, 2014]. Most BCCs are Unit 1452, Houston, TX 77030, USA effectively treated with surgical excision, Mohs Vismodegib (Erivedge Capsule, Genentech, Inc., mrmigden@mdanderson. surgery, destruction or topical therapy. A study of USA) was approved by the US FDA in January org facial BCCs found 5-year recurrence rates after 2012 for the treatment of adults with metastatic Sirunya Silapunt, MD Department of excision or Mohs surgery were 2.5–4.1% for pri- basal cell carcinoma (mBCC) or with locally Dermatology, the mary tumors, and 2.4–12.1% for recurrent advanced basal cell carcinoma (laBCC) that has University of Texas McGovern Medical School tumors [Mosterd et al. 2008]. When BCC is not recurred following surgery or who are not candi- at Houston, Houston, TX, promptly treated, extensive local tissue invasion dates for surgery or radiation. The US FDA USA and destruction in addition to rare occurrence of approval of vismodegib was based on the demon- Leon Chen, MD Department of metastasis can lead to significant morbidity and stration of objective response rate (ORR) from the Dermatology, The mortality. Surgery and radiation therapy to treat ERIVANCE clinical trial, a multicenter, single- University of Texas McGovern Medical School advanced cases may cause unacceptable disfig- arm, two-cohort, clinical trial, evaluating the treat- at Houston, Houston, TX, urement or morbidity. ment of 150 mg of vismodegib daily in patients USA with laBCC or mBCC [Sekulic et al. 2012]. The pathogenesis of BCC has been elucidated including identification of aberrant Hedgehog Sonidegib (Odomzo Capsules, Novartis (Hh) pathway signaling and the associated muta- Pharmaceuticals Corp., USA) was approved by tions of Patched-1 (PTCH1) and Smoothened the US FDA in July 2015 for the treatment of (SMO) genes [Gailani et  al. 1996; Hahn et  al. patients, 18 years or older, with laBCC that has 1996; Johnson et al. 1996; Aszterbaum et al. 1998; recurred following surgery or radiation therapy, Xie et al. 1998; Epstein, 2008]. Aberrant Hh path- or those who are not candidates for surgery or way signaling has been detected in patients with radiation therapy. The US FDA approval of son- nevoid BCC syndrome as well as in over 95% of idegib was based on the demonstration of durable patients with sporadic BCCs [Gailani et al. 1996; ORR from the BOLT clinical trial, a phase II, Xie et al. 1998; Epstein, 2008]. The discovery of multicenter, randomized and double-blinded http://tam.sagepub.com 375 Therapeutic Advances in Medical Oncology 8(5) Figure 1. When Hh signaling ligand is present and binds to the 12 transmembrane protein PTCH1, the 7 membrane spanning receptor SMO is no longer inhibited via PTCH1-mediated inhibition and allows transcription factor Gli1 to enter the cell nucleus, stimulating cell division and tumorigenesis. Both vismodegib and sonidegib bind SMO and inhibit the Hh pathway reactivation. Hh, Hedgehog; PTCH1, Patched-1 mutation; SMO, Smoothened mutation. clinical trial, evaluating the treatment with two The first SMO antagonist reported in literature is different doses of sonidegib in patients with a naturally occurring alkaloid called cyclopamine laBCC or mBCC [Migden et al. 2015]. found in the corn lily [Cooper et  al. 1998]. Cyclopamine was identified to be the culprit This article will provide an overview of clinical responsible for the midline single-eyed appear- use of HPIs in advanced BCC. ance of many lambs born by corn lily-consuming ewes in the 1950s. Cyclopamine was found to bind SMO and inhibits the activation of down- Drug development stream Hh target genes that are essential for The Hh pathway was discovered during the inves- proper embryonic development [Incardona et al. tigation of Drosophila melanogaster embryogenesis 1998]. In preclinical mouse models, cyclopamine [Nusslein-Volhard and Wieschaus, 1980]. The has been shown to induce the remission of medul- activation of the Hh pathway during embryogen- loblastoma via Hh signaling inhibition [Sanchez esis ensures proper development of the embry- et  al. 2005]. Despite its ability to interfere with onic cells; however, the Hh pathway remains the Hh pathway signaling, cyclopamine’s subop- quiescent in adult tissues. In the absence of the timal aqueous solubility and chemical stability Hh ligand signal, the cell-surface transmembrane limit its therapeutic usefulness in clinical research protein PTCH-1 keeps the activity of the 7-mem- [Winkler et al. 2009]. brane-spanning receptor, SMO, suppressed [Stone et  al. 1996; Xie et  al. 1998]. However, GDC-0449 (vismodegib) is a first-in-class, small- when the Hh signaling ligand is present and molecule inhibitor of SMO that selectively inhib- bound to PTCH-1, SMO is no longer inhibited its the Hh signaling pathway by binding to SMO, and allows the transcription factor Gli to enter the therefore inhibiting the aberrant activation of the cell nucleus, promoting cell division and tumori- Hh pathway. GDC-0449 has greater potency and genesis [Aszterbaum et al. 1998]. more favorable pharmaceutical properties than 376 http://tam.sagepub.com S Silapunt, L Chen et al. cyclopamine. In 2009, a phase I study of GDC- Warning and precaution 0449 (vismodegib) showed a 58% response rate HPIs are contraindicated in women who are either among 33 patients with laBCC and mBCC [Von pregnant or breastfeeding as it may cause death or Hoff et  al. 2009]. The median duration of severe birth defects in developing fetus because Hh response was 12.8 months [Von Hoff et al. 2009]. signaling plays a pivotal role in the embryonic The recommended dose of vismodegib was 150 developmental pathway. Reproductive toxicology mg/day, based on the achievement of maximal studies in rats demonstrated that vismodegib expo- plasma concentration and pharmacodynamic sure during organogenesis results in embryo-fetal response [Lorusso et al. 2011a]. death at higher exposures and severe birth defects at exposures within the range achieved with the LDE225 (sonidegib), discovered in 2010, is a recommended human dose [Genentech, Inc., potent selective SMO antagonist with high tissue 2012]. Although no human data on the effects of penetration and the ability to cross the blood– HPIs on fetal development have been reported, brain barrier with good oral bioavailability [Pan pregnancy status should be verified prior to the ini- et  al. 2010]. In a phase I study in 103 patients tiation of HPIs. Highly effective contraception with advanced BCC and other solid tumors, the should be used during treatment and for up to 7 maximum tolerated dose was determined to be months after the last dose of vismodegib, and for at 800 mg daily and 250 mg twice daily after testing least 20 months after the last dose of sonidegib. various of dosages [Rodon et al. 2014]. No clini- Male patients should use condoms during treat- cal advantage was observed with twice-daily dos- ment with HPIs, and for at least 2 months after the ing over once daily dosing; therefore, the once last dose of vismodegib, or 8 months after the last daily dosing regimen is currently recommended dose of sonidegib. Healthcare providers should [Rodon et al. 2014]. report to pharmaceutical company any cases of exposure during pregnancy (either direct exposure LDE225 0.75% topical cream was investigated in in female patients or through seminal fluid from 27 BCCs treated twice daily for 4 weeks [Skvara male patients), and should encourage pregnant et al. 2011]. In the treatment group (13 of 27); 3 women to participate in the Erivedge or Odomzo BCCs had a complete response, 9 BCCs had a pregnancy pharmacovigilance program to collect partial response, and one BCC had no clinical information on pregnancy outcomes. response. A mean tumor volume reduction was 56%. In the control group (14 of 27), 13 BCCs Currently there are no data available regarding showed no clinical response, and 1 BCC had the presence of HPIs in human milk, however, a partial response. A phase II study with a breastfeeding is not advisable during treatment SLIGHTLY larger sample size showed insuffi- and for at least 20 months after the last dose of cient efficacy with investigational topical formula- sonidegib. Because both the ERIVANCE BCC tion and treatment conditions. and BOLT trials were conducted in the adult population, the safety and effectiveness of HPIs have not been established in pediatric patients. Metabolism and drug interactions Patients should not donate blood or blood prod- The major metabolic pathways of vismodegib ucts while taking HPIs and for at least 7 months include oxidation, glucuronidation and pyridine after the last dose of vismodegib or 20 months ring cleavage [Genentech, Inc., 2012]. Vismodegib after the last dose of sonidegib. Serum creatinine elimination involves multiple pathways predomi- kinase (CK) levels and renal function tests nated by the hepatic route as 82% of the adminis- should be obtained prior to initiating and peri- tered dose was recovered in the feces and 4.4% odically during sonidegib treatment [Novartis was recovered in the urine [Genentech, Inc., Pharmaceuticals Corp., 2015]. 2012]. No change in vismodegib level was observed in patients concomitantly treated with CYP3A4 inhibitors and CYP3A4 inducers. In Administration and formulations contrast, sonidegib is mainly metabolized by the The recommended dose for vismodegib is 150 hepatic enzyme CYP3A, therefore, it should not mg orally daily, and it may be taken with or with- be used in patients taking CYP3A inhibitors or out food. In the pharmacokinetic dose-scheduling CYP3A inducers due to potential drug interaction study of vismodegib, it showed that any reduction [Novartis Pharmaceuticals Corp., 2015]. in vismodegib dose or frequency could result in http://tam.sagepub.com 377 Therapeutic Advances in Medical Oncology 8(5) suboptimal unbound drug concentration and appetite [Sekulic et al. 2012]. Of the 104 patients therefore compromise the maximum clinical ben- enrolled, 13 (12%) had an adverse event leading efit. Dose reduction is not indicated for vismod- to discontinuation of the study drug with muscle egib [Lorusso et al. 2011b]. spasm being the most commonly reported event that contributed to study drug discontinuation, The sonidegib dose is 200 mg orally daily taken which occurred in 2 individuals. Serious adverse on an empty stomach, at least 1 hour before or 2 events of any grade were reported in 26 patients hours after a meal. (25%). Grade 5 (fatal) adverse events reported in 7 patients (6 with laBCC and 1 with mBCC) were due to hypovolemic shock, myocardial Clinical uses of Hh pathway inhibitors infarction, meningeal disease and ischemic stroke that were responsible for 1 death each and 3 Vismodegib patients died from unknown causes. These 7 In the ERIVANCE clinical trial, a multicenter, patients had clinically significant risk factors or international, two-cohort, nonrandomized study, coexisting conditions at baseline. No association a total of 104 patients with mBCC and laBCC with the study drug was identified. who had inoperable disease or for whom surgery was inappropriate were enrolled and received 150 An additional 12-month follow-up in the phase mg of oral vismodegib daily. The primary end II, multinational, multicenter, nonrandomized, point of the ERIVANCE trial was the indepen- two-cohort study, confirms the efficacy and safety dently assessed ORR. For laBCC, the objective of vismodegib in the management of advanced response was defined as a decrease of 30% or BCC [Sekulic et  al. 2015]. Median follow-up more in the externally visible (including residual time, including the primary analysis and the addi- scarring) or radiographic dimension, or complete tional 12-month follow up, was 21.7 months in resolution of ulceration if present at baseline. the laBCC group and 22.4 months in the mBCC Progressive disease was defined as an increase of group. The ORR increased from 42.9% to 47.6% 20% or more in the externally visible or radio- in patients with the laBCC, and from 30.3% to graphic dimension, new ulceration, or a new 33.3% in patients with mBCC. All responders lesion. For patients with multiple target lesions, (33.3%) in the mBCC group had partial response, the sum of the longest diameters was used to and 22.2% and 25.4% of responders in the laBCC determine response and progression. The group had complete and partial response respec- Response Evaluation Criteria in Solid Tumors tively. Median duration of response in patients (RECIST) was used for mBCC [Therasse et  al. with laBCC increased from 7.6 to 9.5 months 2000]. Patients received vismodegib until disease (Table 1). progression, unacceptable toxic effects, or dis- continuation of the study. The mean duration of No new safety signals emerged with extended treatment was approximately 10 months. treatment duration. Muscle spasms, dysgeusia and alopecia remained the most common adverse In 63 patients with laBCC, the ORR (including events in both the primary and the 12-month both complete and partial response) was 43%, update analysis. Amenorrhea was reported in 2 with complete responses in 13 (21%) patients patients with laBCC. As of the 12-month update, (defined as the absence of residual BCC on assess- of the 104 patients enrolled, 75 patients discon- ment of a biopsy specimen). The ORR of 33 tinued treatment mainly due to patient decision, patients with mBCC was 30%, and all responses disease progression and adverse events. The most were partial. The median duration of response was common adverse events leading to treatment dis- 7.6 months in both groups [Sekulic et al. 2012]. continuation included muscle spasms, weight loss and dysgeusia. Adverse events occurring in more than 20% of patients were muscle spasms (68%), alopecia Almost half of patients had grade 1 (mild) to (63%), dysgeusia (taste disturbance, 51%), grade 2 (moderate) adverse events, and 51.9% of weight loss (46%), fatigue (36%), nausea (29%), patients had adverse events grade 3 or higher. decrease in appetite (23%), and diarrhea (22%). Serious adverse events (31.7% of patients) Adverse events of grade 3 (severe or medically increased modestly compared with those at pri- significant) or grade 4 (life threatening) included mary analysis (25% of patients). No death muscle spasms, weight loss, fatigue, and loss of occurred as the result of adverse events. 378 http://tam.sagepub.com S Silapunt, L Chen et al. Table 1. Response rate comparison in sonidegib and vismodegib. BOLT (200 mg BOLT (800 mg ERIVANCE (150 mg sonidegib) sonidegib) vismodegib) Primary analysis Primary analysis Primary analysis 12-month update laBCC mBCC laBCC mBCC laBCC mBCC laBCC mBCC (n = 42) (n = 13) (n = 93) (n = 23) (n = 63) (n = 33) (n = 63) (n = 33) Proportion of patients 18 2 35 4 27 10 30 11 with objective response (43%) (15%) (38%) (17%) (43%) (30%) (48%) (33%) Central review (BOLT); Independent review (ERIVANCE) Complete response 2 0 0 0 13 0 14 0 (5%) (21%) (22%) Partial response 16 2 35 4 14 10 16 11 (38%) (15%) (38%) (17%) (22%) (30%) (25%) (33%) Disease control, % 93% 92% 80% 83% 81% 94% 83% 94% laBCC, locally advanced basal cell carcinoma; mBCC, metastatic basal cell carcinoma. Sonidegib an objective response were noted among the 93 In the BOLT trial, a multicenter, randomized, with laBCC and 4 (17%) among the 23 with double-blind, phase II study, patients with mBCC. A reduction in Gli1 expression was seen laBCC not amenable to curative surgery or radia- in patients with disease control (those with either tion, or mBCC were randomized in a 1:2 ratio to complete response, partial response or stable receive sonidegib 200 mg daily (lowest effica- disease) (Table 1). cious dose) or 800 mg daily (maximum tolerated once daily dosing). RECIST [Therasse et  al. The most common adverse events included mus- 2000] and modified RECIST was used to assess cle spasms, alopecia, dysgeusia (taste distur- mBCC and laBCC, respectively [Migden et  al. bance), nausea, elevated blood CK and fatigue 2015; Eisenhauer et al. 2009]. The primary end- [Migden et al. 2015]. Muscle spasm was the most point was the proportion of patients who achieved common reported adverse event in 49% and 67% an objective response (complete or partial of patients in the 200 mg and 800 mg group response) with data collected up to 6 months respectively, and the most common adverse event after randomization of the last patient. In the set- resulting in treatment discontinuation. Alopecia ting of symptoms indicating potential toxicity, was reported in 43% of patients in the 200 mg dose interruptions or reductions were permitted. group and 55% of patients in 800 mg group. Of the 230 patients enrolled, 194 with laBCC Taste disturbance was reported in 38% and 59% and 36 with mBCC, 79 were in the 200 mg son- of patients in the 200 mg and 800 mg group idegib group, and 151 were in the 800 mg son- respectively. Adverse events generally occurred idegib group. The median durations of treatment less frequently in the 200 mg group than in the were 8.9 months in the 200 mg dose group and 800 mg group. 6.5 months in the 800 mg dose group dose. Median follow up was 13.9 months. The most common grade 3–4 adverse events (severe, medical significant or life threatening) In the primary efficacy analysis population, 20 were elevated serum CK (6% in the 200 mg group (36%) of 55 patients receiving 200 mg sonidegib versus 13% in the 800 mg group) and elevated and 39 (34%) of 116 receiving 800 mg sonidegib lipase (5% of patients in both groups). Increasing achieved an objective response per central sonidegib dose and exposure were associated with review. In the 200 mg sonidegib group, 18 (43%) increased CK level. Serious adverse events were patients who achieved an objective response reported in 14% of patients in the 200 mg son- were noted among the 42 with laBCC and two idegib group and 30% in the 800 mg sonidegib (15%) among the 13 with mBCC. In the 800 mg group. Rhabdomyolysis and elevated serum CK sonidegib group, 35 (38%) patients who achieved were the most frequently reported serious adverse http://tam.sagepub.com 379 Therapeutic Advances in Medical Oncology 8(5) events which both occurred in 1% of patients in [Ozkul, 2007]. No clear relationship between the the 200 mg group and 3% of patients in 800 mg incidence of muscle cramps or spasm and elevated group. However, these reported rhabdomyolysis CK has been established [Migden et  al. 2015]. cases did not meet the criteria defined by the Increased CK level is likely of skeletal muscle ori- Independent Safety Review Committee and gin owing to the lack of evidence of cardiac muscle Adjudication Committee as CK concentrations injury. Sonidegib is mainly metabolized by the more than ten times higher than baseline plus a hepatic enzyme CYP3A so drug interactions with 1.5-fold increase in creatinine concentration in CYP3A inhibitor can potentially increase the risk serum from baseline [Migden et  al. 2015]. for further muscle toxicity [Zollinger et al. 2014]. Secondary malignancies were noted in 6% (200 mg) and 7% (800 mg) of patients. Overall, 4 Taste disturbances are well reported in patients patients in the 800 mg group died while taking treated with HPIs and some patients even discon- study treatment, but none of these deaths was tinued the treatment because of this undesirable deemed to be related to sonidegib. side effect [Dessinioti et  al. 2014]. Chorda tym- pani nerve responses to taste stimuli were mark- Although both groups demonstrated similar effi- edly reduced or absent in mice treated with cacy, the 200 mg sonidegib group was found to LDE225 for up to 28 days [Kumari et al. 2015]. have longer duration of treatment, lower rate of Vismodegib-treated mice were found to have adverse events, and lower discontinuation rate. reductions in taste bud size, taste cells per taste The overall benefit-to-risk profile is more favora- bud, and multiple taste-modulatory factors in the ble with 200 mg than 800 mg sonidegib group. taste cells [Yang et al. 2015]. Regarding dysgeusia Quality of life was assessed based on two health and weight loss, one study suggested the benefit of questionnaires; the Quality of Life Questionnaires nutritional screening prior to initiation of vismod- C30 (QLQ-C30) and the Head and Neck Cancer egib, and nutritional monitoring and management Module 35 (H&N35). The findings demon- during the treatment [Le Moigne et al. 2016]. strated the tolerability of sonidegib and improve- ment in or maintenance of quality of life in most Alopecia is a well-known adverse effect of HPIs. patients with laBCC and mBCC. The Hh pathway has an essential role during hair follicle morphogenesis, where it is required for nor- Additional follow up of the BOLT clinical trial mal advancement beyond the hair germ stage of was ongoing at the time this review article was development [Chiang et al. 1999]. Although HPI- submitted. induced alopecia appears to be reversible in most cases; 4 of 65 patients were reported to have persis- tent alopecia after stopping vismodegib [Alkeraye Safety and tolerability et al. 2015]. Death was reported in both HPI stud- Both HPIs share similar adverse effects which ies, however, a relationship between study drug include muscle spasms, dysgeusia (taste distur- and the deaths has not been established. bance), alopecia, fatigue, nausea and weight loss. The vast majority of adverse effects were mild-to- moderate in severity. Treatment-related adverse Drug resistance effects were manageable and most were reversible Patients with treatment resistance to an SMO after discontinuation of drug. The most frequent inhibitor may also fail other SMO inhibitors. A adverse events leading to discontinuation of HPI study of 9 patients with advanced BCCs that were treatment were muscle spasms, dysgeusia and previously resistant to treatment with vismodegib weight loss. demonstrated resistance with sonidegib [Danial et al. 2015]. Genomic analysis of tumor biopsies HPI-induced muscle contraction and muscle fiber revealed that vismodegib resistance is associated twitching is thought to be the result of calcium with Hh pathway reactivation, predominantly influx [Teperino et  al. 2012]. A study found caused by SMO mutations, and to a lesser extent amlodipine, a calcium channel blocker, reduced through mutation in suppressor of fused (SUFU), the frequency of vismodegib-induced muscle and gain-of-function mutations in Gli2 [Sharpe cramps [Ally et  al. 2015]. This is the result of et  al. 2015]. SMO mutations were identified in blocking voltage-gated calcium channels and 50% (22 of 44) of resistant BCCs [Atwood et al. inhibiting the transport of extracellular calcium 2015]. The findings suggest that a combination into muscle which is required for contraction of therapies targeting both SMO and downstream 380 http://tam.sagepub.com S Silapunt, L Chen et al. the majority of drug resistance in basal cell carcinoma. components of the Hh pathway may be required Cancer Cell 27: 342–353. to overcome drug resistance. Chiang, C., Swan, R., Grachtchouk, M., Bolinger, M., Litingtung, Y., Robertson, E. et al. (1999) Conclusion Essential role for sonic hedgehog during hair follicle HPIs provide a promising treatment for patients morphogenesis. Dev Biol 205: 1–9. with advanced BCCs. Both vismodegib and son- Cooper, M., Porter, J., Young, K. and Beachy, P. idegib demonstrated similar overall efficacy, (1998) Teratogen-mediated inhibition of target tissue safety and tolerability. Vismodegib, the first HPI response to SHH signaling. Science 280: 1603–1607. approved in the US, produced an ORR of 47.6% Danial, C., Sarin, K., Oro, A. and Chang, A. 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Journal

Therapeutic Advances in Medical Oncology – SAGE

Published: Jun 29, 2016

Keywords: basal cell carcinoma; Hedgehog pathway inhibitor; sonidegib; vismodegib

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