OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Sonidegib	956697-53-3	C26-H26-F3-N3-O3

ANNOTATED BIBLIOGRAPHY

References updated: 01 June 2017

Abbreviations used: CK, creatine kinase

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of protein kinase inhibitors such as sonidegib).
• DeLeve LD. Kinase inhibitors. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556-7.

  (Review of hepatotoxicity of cancer chemotherapeutic agents discusses several tyrosine kinase inhibitors including imatinib, gefitinib, erlotinib and crizotinib, but not sonidegib).
• Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.

  (Textbook of pharmacology and therapeutics).
• Pan S, Wu X, Jiang J, Gao W, Wan Y, Cheng D, Han D, et al. Discovery of NVP-LDE225, a potent and selective smoothened antagonist. ACS Med Chem Lett 2010; 1: 130-4. [PMC free article: PMC4007689] [PubMed: 24900187]

  (In vitro demonstration of selective antagonism of the kinase receptor smoothened by a novel series of chemicals identified by high throughput screening for molecules that inhibited the hedgehog signaling pathway).
• Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, Coppola C, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012; 366: 2180-8. [PMC free article: PMC4362529] [PubMed: 22670904]

  (Among 41 patients with basal cell nevus syndrome, vismodegib therapy was associated with a lower rate of new tumors and decrease in size of existing tumors compared to placebo, but was associated with a high rate of side effects and 54% stopped therapy because of side effects; no mention of ALT elevations or hepatotoxicity).
• Rodon J, Tawbi HA, Thomas AL, Stoller RG, Turtschi CP, Baselga J, Sarantopoulos J, et al. A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor sonidegib (LDE225) in patients with advanced solid tumors. Clin Cancer Res 2014; 20: 1900-9. [PubMed: 24523439]

  (Among 103 patients with different forms of advanced cancer treated with increasing doses of sonidegib, dose limiting toxicities were myalgia and increases in serum creatine kinase [CK] levels, while common side effects were muscle spasms, myalgia, gastrointestinal complaints, fatigue and alopecia, ALT elevations occurred in 15% of patients and were above 5 times ULN in 6%).
• Migden MR, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, Herd RM, 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: 716-28. [PubMed: 25981810]

  (Among 230 patients with advanced basal cell carcinoma treated with sonidegib [200 vs 800 mg daily] for a median of 14 months, objective response rates were similar for both doses [36% vs 34%], but adverse event rates were less with the lower dose, including muscle spasms [49% vs 69%] and ALT elevations [1% vs 4%]).
• Minami H, Ando Y, Ma BB, Hsiang Lee J, Momota H, Fujiwara Y, Li L, et al. Phase I, multicenter, open-label, dose-escalation study of sonidegib in Asian patients with advanced solid tumors. Cancer Sci. 2016; 107: 1477-83. [PMC free article: PMC5084670] [PubMed: 27467121]

  (Among 45 Asian adults with advanced cancer treated with increasing doses of sonidegib [400 to 800 mg daily], the most common adverse events were myalgia, fatigue and CK elevations while ALT elevations occurred in 27% and were above 5 times ULN in 14%).
• Lacouture ME, Dréno B, Ascierto PA, Dummer R, Basset-Seguin N, Fife K, Ernst S, et al. Characterization and management of hedgehog pathway inhibitor-related adverse events in patients with advanced basal cell carcinoma. Oncologist 2016; 21: 1218-29. [PMC free article: PMC5061532] [PubMed: 27511905]

  (Review of the adverse events caused by vismodegib and sonidegib including muscle spasms, gastrointestinal complaints and alopecia, but does not discuss ALT elevations or liver related events).
• Dummer R, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, Herd RM, 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: 113-25.e5. [PubMed: 27067394]

  (Among the 230 patients with advanced basal cell cancer enrolled in a clinical trial comparing 200 vs 800 mg doses of sonidegib [Migden 2015], 12 month objective response rates were 58% vs 44% and discontinuation rates for adverse events were 28% vs 37%, mostly for muscle spasms and CK elevations; no mention of ALT elevations or hepatotoxicity).
• Jacobsen AA, Aldahan AS, Hughes OB, Shah VV, Strasswimmer J. Hedgehog pathway inhibitor therapy for locally advanced and metastatic basal cell carcinoma: a systematic review and pooled analysis of interventional studies. JAMA Dermatol 2016; 152: 816-24. [PubMed: 27096888]

  (Systematic review of 11 publications on vismodegib and 2 on sonidegib as therapy for advanced basal cell carcinoma provides summary of efficacy outcomes and rates of side effects, but does not discuss ALT elevations or hepatotoxicity).
• Danial C, Sarin KY, Oro AE, Chang AL. An investigator-initiated open-label trial of sonidegib in advanced basal cell carcinoma patients resistant to vismodegib. Clin Cancer Res 2016; 22: 1325-9. [PMC free article: PMC4794361] [PubMed: 26546616]

  (Among 9 patients with advanced basal cell carcinoma who were resistant to vismodegib therapy and were treated with sonidegib, none had an objective response and side effects included muscle cramps, nausea and CK elevations; ALT levels were not mentioned).
• Sonidegib (Odomzo) for basal cell carcinoma. Med Lett Drugs Ther 2016; 58 (1489): 31-2. [PubMed: 26938701]

  (Concise review of the mechanism of action, efficacy, safety and costs of sonidegib shortly after its approval for use in the US; mentions the common side effects of muscle spasms, CK elevations, gastrointestinal complaints, fatigue and alopecia, but does not mention ALT elevations or hepatotoxicity).
• Casey D, Demko S, Shord S, Zhao H, Chen H, He K, Putman A, et al. FDA approval summary: sonidegib for locally advanced basal cell carcinoma. Clin Cancer Res 2017; 23 (10): 2377-81. [PubMed: 28073840]

  (Summary of result of the clinical trials that formed the basis of the FDA approval of sonidegib for advanced basal cell carcinoma discusses overall safety results and specific issues of musculoskeletal and embryo-fetal toxicities, but not ALT elevations or hepatotoxicity).