A review of the safety, efficacy, and administration of hedgehog inhibitors for the treatment of advanced basal cell carcinoma: an expert consensus panel
DOI:
https://doi.org/10.5070/s3cn8t86Keywords:
basal cell carcinoma, expert consensus, hedgehog inhibitors, Skin cancer, sonidegib, treatmentAbstract
Background: Hedgehog inhibitors (HHIs) are approved for the treatment of locally advanced BCCs in patients who are not surgical candidates or have had recurrence following surgical treatment. This expert consensus panel further characterizes the efficacy and safety of HHIs while also providing clinical guidance on their appropriate dosing, laboratory monitoring, and supplementation.
Methods: A comprehensive literature review was completed on November 1, 2024 using the keywords “basal cell carcinoma,” “hedgehog inhibitor,” “sonidegib,” and “vismodegib”. An expert panel of nine dermatologists reviewed and assigned levels of evidence to the relevant articles and created consensus statements regarding HHIs, with correlating strength of recommendations, using the modified Delphi process.
Results: Of the 304 articles identified, 23 articles met the selection criteria and were included for review. The panel unanimously adopted nine consensus statements and recommendations, of which three were given a strength of recommendation of “A”, two were given a “B”, and four were given a “C”.
Conclusion: Sonidegib and vismodegib have similar efficacy in treating advanced BCC, but sonidegib has lower rates and a greater delay in onset of AEs. Sonidegib has a significantly greater volume of distribution and half-life than those of vismodegib. Dosing interruptions have not been shown to reduce the efficacy of HHIs, and L-carnitine supplementation can help reduce the incidence of muscle spasms.
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1. McDaniel B, Badri T, Steele RB. Basal Cell Carcinoma. [Updated 2024 Mar 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482439/
2. McCusker M, Basset-Seguin N, Dummer R, Lewis K, Schadendorf D, Sekulic A, Hou J, Wang L, Yue H, Hauschild A. Metastatic basal cell carcinoma: prognosis dependent on anatomic site and spread of disease. Eur J Cancer. 2014 Mar;50(4):774-83. doi: 10.1016/j.ejca.2013.12.013. Epub 2014 Jan 9. PMID: 24412051.
3. Migden MR, Chang ALS, Dirix L, Stratigos AJ, Lear JT. Emerging trends in the treatment of advanced basal cell carcinoma. Cancer Treat Rev. 2018;64:1-10. doi:10.1016/j.ctrv.2017.12.009
4. Mohan SV, Chang ALS. Advanced Basal Cell Carcinoma: Epidemiology and Therapeutic Innovations. Curr Dermatol Rep. 2014;3(1):40-45. doi:10.1007/s13671-014-0069-y
5. Habashy S, Jafri A, Osman HO, Thomas NE, Udekwe S, Heindl SE. Hedgehog Pathway Inhibitors: Clinical Implications and Resistance in the Treatment of Basal Cell Carcinoma. Cureus. 2021 Mar 12;13(3):e13859. doi: 10.7759/cureus.13859. PMID: 33754119; PMCID: PMC7971714.
6. Brancaccio G, Pea F, Moscarella E, Argenziano G. Sonidegib for the Treatment of Advanced Basal Cell Carcinoma. Front Oncol. 2020 Oct 30;10:582866. doi: 10.3389/fonc.2020.582866. PMID: 33194718; PMCID: PMC7662670.
7. Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): A Patient-Centered Approach to Grading Evidence in the Medical Literature. J Am Board Fam Med. 2004;17(1):59-67. doi:10.3122/jabfm.17.1.59
8. Hsu CC, Sandford B. The Delphi technique: making sense of consensus. Published online 1-8 2007.
9. Shah, M., Miller, L., Casquejo, R., Chao, T., DiRugierro, D., Gautier, K., Glover, H., Kucera, K., Nguyen, A., Pansch, L.A., Volz, J., Young, M.S., Burshtein, J. and Zakria, D. 2024. Topical Cycling: The Obstacles to Moving Forward with Systemic Psoriasis Therapies and How to Characterize the Systemic Ready Patient. SKIN The Journal of Cutaneous Medicine. 8, 1 (Jan. 2024), 1217–1231. DOI:https://doi.org/10.25251/skin.8.1.2.
10. Burshtein J, Shah M, Zakria D, Armstrong AW, Golant AK, Gottlieb AB, Weinberg JM, Kircik L, Han G, Langley RG, Neimann AL, Lebwohl M. Safety of Bimekizumab for Plaque Psoriasis: An Expert Consensus Panel. J Drugs Dermatol. 2024 Aug 1;23(8):592-599. doi: 10.36849/JDD.8246. PMID: 39093660.
11. Burshtein J, Shah M, Zakria D, Lockshin B, Crowley J, Merola JF, Gordon K, Shahriari M, Korman NJ, Chovatiya R, Kalb R, Lebwohl M. The Efficacy and Safety of Bimekizumab for Plaque Psoriasis: An Expert Consensus Panel. Dermatol Ther (Heidelb). 2024 Feb;14(2):323-339. doi: 10.1007/s13555-024-01099-y. Epub 2024 Feb 10. PMID: 38340237; PMCID: PMC10891030.
12. Zakria, D., Shah, M., Burshtein, J., Berman, B., Bhatia, N., Ceilley, R., Farberg, A., Lebwohl, M., Merritt, D., Nouri, K., Stein Gold, L. and Rigel, D. 2024. The Role of Field Cancerization in Selecting Therapies for Actinic Keratosis: An Expert Consensus Panel. SKIN The Journal of Cutaneous Medicine. 8, 3 (May 2024), 1478–1487. DOI:https://doi.org/10.25251/skin.8.3.1.
13. Cannon JGD, Tran DC, Li S, Chang AS. Levocarnitine for vismodegib-associated muscle spasms: a pilot randomized, double-blind, placebo-controlled, investigator-initiated trial. J Eur Acad Dermatol Venereol. 2018;32(7):e298-e299. doi:10.1111/jdv.14844
14. Dréno B, Kunstfeld R, Hauschild A, et al. Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial. Lancet Oncol. 2017;18(3):404-412. doi:10.1016/S1470-2045(17)30072-4
15. Dummer R, Guminski A, Gutzmer R, et al. The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): A phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol. 2016;75(1):113-125.e5. doi:10.1016/j.jaad.2016.02.1226
16. Dummer R, Guminksi A, Gutzmer R, et al. Long-term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study. Br J Dermatol. 2020;182(6):1369-1378. doi:10.1111/bjd.18552
17. Dummer R, Lear JT, Guminski A, Leow LJ, Squittieri N, Migden M. Efficacy of sonidegib in histologic subtypes of advanced basal cell carcinoma: Results from the final analysis of the randomized phase 2 Basal Cell Carcinoma Outcomes With LDE225 Treatment (BOLT) trial at 42 months. J Am Acad Dermatol. 2021;84(4):1162-1164. doi:10.1016/j.jaad.2020.08.042
18. Lear JT, Migden MR, Lewis KD, et al. Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study. J Eur Acad Dermatol Venereol. 2018;32(3):372-381. doi:10.1111/jdv.14542
19. Lewis K, Dummer R, Farberg AS, Guminski A, Squittieri N, Migden M. Effects of Sonidegib Following Dose Reduction and Treatment Interruption in Patients with Advanced Basal Cell Carcinoma During 42-Month BOLT Trial. Dermatol Ther (Heidelb). 2021;11(6):2225-2234. doi:10.1007/s13555-021-00619-4
20. Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16(6):716-728. doi:10.1016/S1470-2045(15)70100-2
21. Sekulic A, Migden MR, Lewis K, et al. Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC. J Am Acad Dermatol. 2015;72(6):1021-1026.e8. doi:10.1016/j.jaad.2015.03.021
22. Cantisani C, Musolff N, Longo C, et al. Dynamic optical coherence tomography evaluation in locally advanced basal cell carcinoma during sonidegib treatment. J Eur Acad Dermatol Venereol. 2024;38(5):967-973. doi:10.1111/jdv.19806
23. Gutzmer R, Loquai C, Robert C, et al. Key Clinical Adverse Events in Patients with Advanced Basal Cell Carcinoma Treated with Sonidegib or Vismodegib: A Post Hoc Analysis. Dermatol Ther (Heidelb). 2021;11(5):1839-1849. doi:10.1007/s13555-021-00588-8
24. Gutzmer R, Leiter U, Mohr P, et al. Interim analysis of the multinational, post-authorization safety study (NISSO) to assess the long-term safety of sonidegib in patients with locally advanced basal cell carcinoma. BMC Cancer. 2024;24(1):1401. doi:10.1186/s12885-024-13101-z
25. Murgia G, Valtellini L, Denaro N, et al. Gorlin Syndrome-Associated Basal Cell Carcinomas Treated with Vismodegib or Sonidegib: A Retrospective Study. Cancers (Basel). 2024;16(12):2166. doi:10.3390/cancers16122166
26. Nguyen A, Xie P, Litvinov IV, Lefrançois P. Efficacy and Safety of Sonic Hedgehog Inhibitors in Basal Cell Carcinomas: An Updated Systematic Review and Meta-analysis (2009-2022). Am J Clin Dermatol. 2023;24(3):359-374. doi:10.1007/s40257-023-00763-x
27. Odom D, Mladsi D, Purser M, et al. A Matching-Adjusted Indirect Comparison of Sonidegib and Vismodegib in Advanced Basal Cell Carcinoma. J Skin Cancer. 2017;2017:6121760. doi:10.1155/2017/6121760
28. Basset-Séguin N, Hauschild A, Kunstfeld R, et al. Vismodegib in patients with advanced basal cell carcinoma: Primary analysis of STEVIE, an international, open-label trial. Eur J Cancer. 2017;86:334-348. doi:10.1016/j.ejca.2017.08.022
29. Soon SL, Ibrahim SF, Arron ST. A randomized phase II study evaluating vismodegib as neoadjuvant treatment of basal cell carcinoma preceding Mohs micrographic surgery: results and lessons learned. Br J Dermatol. 2019;181(1):208-209. doi:10.1111/bjd.17623
30. Truong K, Peera M, Liu R, et al. Real-world data on the efficacy and safety of hedgehog pathway inhibitors in patients with basal cell carcinoma: Experience of a tertiary Australian centre. Australas J Dermatol. Published online October 25, 2024. doi:10.1111/ajd.14373
31. Dinehart MS, McMurray S, Dinehart SM, Lebwohl M. L-Carnitine Reduces Muscle Cramps in Patients Taking Vismodegib. SKIN. 2018;2(2):90-95.
32. Lear JT, Morris LM, Ness DB, Lewis LD. Pharmacokinetics and pharmacodynamics of Hedgehog pathway inhibitors used in the treatment of advanced or treatment-refractory basal cell carcinoma. Expert Rev Clin Pharmacol. 2023;16(12):1211-1220. doi:10.1080/17512433.2023.2285849
33. Patel S, Armbruster H, Pardo G, et al. Hedgehog pathway inhibitors for locally advanced and metastatic basal cell carcinoma: A real-world single-center retrospective review. PLoS One. 2024;19(4):e0297531. doi:10.1371/journal.pone.0297531
34. Villani A, Fabbrocini G, Costa C, Scalvenzi M. Sonidegib: Safety and Efficacy in Treatment of Advanced Basal Cell Carcinoma. Dermatol Ther (Heidelb). 2020;10(3):401-412. doi:10.1007/s13555-020-00378-8
35. Villani A, Scalvenzi M, Micali G, et al. Efficacy and safety of sonidegib for the management of basal cell carcinoma: a drug safety evaluation. Expert Opin Drug Saf. 2023;22(7):525-531. doi:10.1080/14740338.2023.2227089
36. Sekulic A, Migden MR, Oro AE, et al. Efficacy and Safety of Vismodegib in Advanced Basal-Cell Carcinoma. N Engl J Med. 2012;366(23):2171-2179. doi:10.1056/NEJMoa1113713
37. Sekulic A, Migden MR, Basset-Seguin N, et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study [published correction appears in BMC Cancer. 2019 Apr 18;19(1):366. doi: 10.1186/s12885-019-5568-6.]. BMC Cancer. 2017;17(1):332. Published 2017 May 16. doi:10.1186/s12885-017-3286-5
38. Ally MS, Aasi S, Wysong A, Teng C, Anderson E, Bailey-Healy I, Oro A, Kim J, Chang AL, Tang JY. An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. J Am Acad Dermatol. 2014 Nov;71(5):904-911.e1. doi: 10.1016/j.jaad.2014.05.020. Epub 2014 Jun 11. PMID: 24929884.
39. Bertrand N, Guerreschi P, Basset-Seguin N, Saiag P, Dupuy A, Dalac-Rat S, Dziwniel V, Depoortère C, Duhamel A, Mortier L. Vismodegib in neoadjuvant treatment of locally advanced basal cell carcinoma: First results of a multicenter, open-label, phase 2 trial (VISMONEO study): Neoadjuvant Vismodegib in Locally Advanced Basal Cell Carcinoma. EClinicalMedicine. 2021 Apr 26;35:100844. doi: 10.1016/j.eclinm.2021.100844. PMID: 33997740; PMCID: PMC8093898.
40. Peris K, Fargnoli MC, Kaufmann R, et al. European consensus-based interdisciplinary guideline for diagnosis and treatment of basal cell carcinoma-update 2023. Eur J Cancer. 2023;192:113254. doi:10.1016/j.ejca.2023.113254
41. Moreno-Arrones OM, Béa-Ardebol S, Mayo-Martinez F, et al. Sonidegib as a Locally Advanced Basal Cell Carcinoma Therapy in Real-life Clinical Setting: A National Multicentre Study. Actas Dermosifiliogr. 2023;114(7):565-571. doi:10.1016/j.ad.2023.04.022
42. Bossi P, Ascierto PA, Basset-Seguin N, et al. Long-term strategies for management of advanced basal cell carcinoma with hedgehog inhibitors. Crit Rev Oncol Hematol. 2023;189:104066. doi:10.1016/j.critrevonc.2023.104066
43. Venturi F, Trane L, Silvestri F, Zuccaro B, Magnaterra E, De Giorgi V. Tolerance of sonidegib after intolerance of vismodegib-Experience in two patients with nevoid basal cell carcinoma syndrome (Gorlin syndrome). Skin Health Dis. 2023 Jun 14;3(5):e260. doi: 10.1002/ski2.260. PMID: 37799353; PMCID: PMC10549827.
44. Lear JT, Dummer R, Guminski A. Using drug scheduling to manage adverse events associated with hedgehog pathway inhibitors for basal cell carcinoma. Oncotarget. 2021 Dec 21;12(26):2531-2540. doi: 10.18632/oncotarget.28145. PMID: 34966484; PMCID: PMC8711575.
45. Dummer R, Ascierto PA, Basset-Seguin N, Dréno B, Garbe C, Gutzmer R, Hauschild A, Krattinger R, Lear JT, Malvehy J, Schadendorf D, Grob JJ. Sonidegib and vismodegib in the treatment of patients with locally advanced basal cell carcinoma: a joint expert opinion. J Eur Acad Dermatol Venereol. 2020 Sep;34(9):1944-1956. doi: 10.1111/jdv.16230. Epub 2020 Mar 4. PMID: 31990414.
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Copyright (c) 2025 Milaan Shah, Lauren Debusk, Angela Rosenberg, Joshua Burshtein, Danny Zakria, Mohammed Dany, Scott Dinehart, Mark Lebwohl, Jesse Lewin, George Monks, Michael Mortazie, Todd Schlesinger, Shannon Trotter, Darrell Rigel (Author)

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