Odomzo (Sonidegib), a Hedgehog Pathway Inhibitor, FDA Approved for the Treatment of Patients with Locally Advanced Basal-Cell Carcinoma

March 2016, Vol 9, Seventh Annual Payers' Guide - Web Exclusive
Loretta Fala
Medical Writer

Basal-cell carcinoma is the most common type of skin cancer, accounting for approximately 80% of nonmelanoma skin cancers.1 More than 2.8 million new cases of basal-cell carcinoma are diagnosed annually in the United States, and 3000 people die from this disease annually.2 Furthermore, the prevalence of basal-cell carcinoma is increasing in men and women aged <40 years, and particularly in young women.3,4

Basal-cell carcinoma and squamous-cell carcinoma are categorized as nonmelanoma skin cancers; basal-cell carcinoma is 4 to 5 times more common than squamous-cell carcinoma.4 The annual treatment costs for nonmelanoma skin cancers account for an estimated $4.8 billion in the United States.3

Exposure to ultraviolet light, natural and artificial, increases the risk for all skin cancers.3 In addition to long-term sun exposure, other factors that predispose an individual to basal-cell carcinoma are fair skin and exposure to radiation therapy during childhood.1,5 Additional risk factors for skin cancer include increasing age (≥50 years), a family history of skin cancer, certain inherited syndromes, immune-suppressing drugs, and exposure to high levels of arsenic.5

Basal-cell carcinoma is caused by a mutation in the skin’s basal-cell DNA, and most frequently affects the head and neck area, the trunk, and legs.5 If detected early, basal-cell carcinoma has a favorable prognosis. However, when the disease progresses to the advanced or metastatic stage, it can lead to the disfigurement and involvement of soft tissue, cartilage, and bone, and to mortality in some cases.2,4

The overall 5-year recurrence rate for basal-cell carcinoma is approximately 3.3%.2,6 This high recurrence rate suggests that a considerable number of cases are inoperable or are incurable through surgery.2 Advanced forms of basal-cell carcinoma, including locally advanced and metastatic, may account for 1% to 10% of all cases of this cancer.2

In recent years, researchers have elucidated the role of the hedgehog pathway, a molecular pathway that is active in basal-cell cancers, as well as in other cancers.7,8 The abnormal activation (ie, deregulation) of this pathway is associated with cell proliferation and tumor growth acceleration.7 The hedgehog pathway also has a contributing role in increasing tumor invasiveness.7 The deregulation of hedgehog pathway signaling occurs in approximately 95% of basal-cell carcinoma tumors.9

The treatments for basal-cell carcinoma include surgery, cryosurgery, electrodesiccation and curettage, radiation therapy, photodynamic therapy, laser therapy, topical therapies, and, more recently, oral therapies.5,10 The treatment of locally advanced, recurrent, or metastatic disease is challenging, particularly in patients with substantial morbidity and tissue invasion.9

Relatively few therapeutic options exist for patients with advanced basal-cell carcinoma; they include chemotherapy, radiation therapy, and the hedgehog pathway inhibitors—a class of targeted drugs that represent a major advancement for certain patients with recurring or inoperable basal-cell carcinoma.2,4,9 Until recently, vismodegib (Erivedge) was the only hedgehog pathway inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of adults with metastatic disease, or with locally advanced basal-cell carcinoma that has recurred after surgery, or for the treatment of patients who are not candidates for surgery and radiation therapy.8,11

Sonidegib a New Oral Treatment for Locally Advanced Basal-Cell Carcinoma

On July 24, 2015, sonidegib (Odomzo; Novartis), an oral hedgehog pathway inhibitor, was approved by the FDA for the treatment of patients with locally advanced basal-cell carcinoma that has recurred after surgery or radiation therapy, or for the treatment of patients who are not candidates for surgery or radiation therapy.8,12

Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, said, “Our increasing understanding of molecular pathways involved in cancer has led to approvals of many oncology drugs in difficult-to-treat diseases for which few therapeutic options previously existed. Thanks to a better understanding of the Hedgehog pathway, the FDA has now approved two drugs for the treatment of basal cell carcinoma just in the last three years.”8

Mechanism of Action

Sonidegib is a hedgehog pathway inhibitor.12 By binding to and inhibiting Smoothened, a transmembrane protein that is involved in hedgehog signal transduction, sonidegib suppresses the hedgehog molecular pathway, thereby stopping or reducing the growth of cancerous lesions.8,9,12

Dosage and Administration

The recommended dosage of sonidegib is 200 mg taken orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal. Sonidegib is available as a 200-mg capsule for oral use.12

BOLT: the Pivotal Clinical Trial

The FDA approval of sonidegib was based on the BOLT clinical trial, a multicenter, double-blind, multiple-cohort clinical study that evaluated the safety and effectiveness of sonidegib in patients with locally advanced basal-cell carcinoma (N = 194) or metastatic basal-cell carcinoma (N = 36).9,12 Patients with locally advanced basal-cell carcinoma were required to have postradiotherapy or postsurgical disease recurrence, unresectable lesions, or lesions for which radiotherapy was inappropriate.12 Patients were randomized in a 2:1 ratio to receive sonidegib 200 mg or sonidegib 800 mg orally once daily until disease progression or until unacceptable toxicity.12

The primary efficacy end point in this study was the proportion of patients who achieved an objective response (partial shrinkage or complete tumor disappearance). The key secondary outcome measure was the duration of response.12 A total of 66 patients with locally advanced basal-cell carcinoma (median age, 67 years; 58% aged ≥65 years) were randomized to receive so­nidegib 200 mg daily; these patients were followed for a minimum of 12 months unless sonidegib was discontinued earlier.

Treatment with sonidegib 200 mg demonstrated antitumor activity and a durable objective response rate in the BOLT clinical trial (Table).9 In fact, 58% of patients who received sonidegib 200 mg showed tumor shrinkage or disappearance (95% confidence interval, 45-70), which included complete responses in 3 (5%) patients and partial responses in 35 (53%) patients.12 This effect was maintained for at least 1.9 to 18.6 months; responses lasting 6 months or longer in patients with locally advanced disease were observed in 39% of patients taking sonidegib 200 mg.8,12

Table

A prespecified sensitivity analysis that used a different definition for complete response indicated that treatment with sonidegib resulted in a complete response rate of 20%.12

The results showed no evidence of improved anti­tumor activity among patients with locally advanced basal-cell carcinoma who received sonidegib 800 mg.12

Therefore, only 200 mg of sonidegib is approved by the FDA for patients with locally advanced basal-cell carcinoma.12

Adverse Events

The most common adverse reactions (all grades) occurring in ≥10% of patients who received sonidegib 200 mg in the BOLT clinical trial included muscle spasms (54%), alopecia (53%), dysgeusia (46%), fatigue (41%), nausea (39%), musculoskeletal pain (32%), diarrhea (32%), decreased weight (30%), decreased ap­petite (23%), myalgia (19%), abdominal pain (18%), headache (15%), pain (14%), vomiting (14%), and pruritus (10%).12

Grade 3 adverse reactions in patients who received sonidegib 200 mg included muscle spasms (3%), musculoskeletal pain (1%), headache (1%), fatigue (4%), decreased weight (3%), pain (1%), nausea (1%), diarrhea (1%), vomiting (1%), and decreased appetite (1%). No grade 4 adverse reactions were reported with sonidegib 200 mg.12

Overall, 34% of patients permanently discontinued sonidegib because of adverse reactions, and treatment was temporarily interrupted in 20% of patients.12 Adverse reactions leading to the treatment discontinuation included muscle spasms and dysgeusia (each 5%); asthenia, increased lipase, and nausea (each 4%); and fatigue, decreased appetite, alopecia, and decreased weight (each 3%).12

Drug Interactions

Cytochrome (CY) P3A inhibitors. Sonidegib should not be administered concomitantly with strong CYP3A inhibitors.12 The concomitant administration of moderate CYP3A inhibitors should also be avoided. If a moderate CYP3A inhibitor must be used concomitantly with sonidegib, the moderate CYP3A inhibitor should be administered for less than 14 days, and the patient should be closely monitored, particularly for musculoskeletal reactions.12

CYP3A inducers. Sonidegib should not be administered concomitantly with strong and moderate CYP3A inducers.12

Warnings and Precautions

Boxed warning. Sonidegib was approved with a boxed warning stating that it can cause death or severe birth defects in a fetus when administered to a pregnant woman. Pregnancy status should be verified before starting treatment with sonidegib, and men and women of reproductive potential should be cautioned about these risks and use precautionary measures to prevent pregnancy.8,12

Blood donation. Patients taking sonidegib and for at least 20 months after the last dose of sonidegib should not donate blood or blood products.12

Musculoskeletal adverse reactions. Sonidegib and other hedgehog pathway inhibitors can cause musculoskeletal adverse reactions that may be accompanied by elevations in the serum creatine kinase levels. Serum creatine kinase levels and creatinine kinase levels should be obtained before starting treatment with soni­degib and periodically during treatment. A temporary dose interruption or discontinuation of sonidegib may be required.12

Use in Specific Populations

Pregnancy. Sonidegib’s mechanism of action suggests that it may cause fetal harm when administered to a pregnant woman. Pregnant women should be advised of this risk.12

Lactation. Because the effects of sonidegib on milk production or on breast-fed infants are not known, a nursing woman should be advised not to breast-feed while receiving sonidegib, and for 20 months after the last dose.12

Females and males of reproductive potential. Soni­degib can cause death or severe birth defects in a fetus. Pregnancy status should be verified before starting treatment with sonidegib, and men and women of reproductive potential should be cautioned about these risks.12

Pediatric use. Data are not available on the safety and effectiveness of sonidegib in pediatric patients.12

Geriatric use. No overall differences in the effectiveness of sonidegib were observed in patients aged ≥65 years versus younger patients. A higher incidence of serious adverse events and adverse events requiring dose discontinuation or interruption of sonidegib occurred in patients aged ≥65 years.12

Hepatic impairment. No dosage adjustment of soni­degib is recommended for patients with mild hepatic impairment. Sonidegib has not been evaluated in patients with moderate or severe hepatic impairment.12

Renal impairment. No dosage adjustment of sonideg­ib is recommended in patients with renal impairment.12

Conclusion

Another treatment option became available for patients with locally advanced basal-cell carcinoma or for the treatment of patients who are not candidates for surgery or radiation therapy with the FDA approval of sonidegib, an oral hedgehog pathway inhibitor.

In the BOLT clinical trial, treatment with sonidegib 200 mg demonstrated a 58% objective response rate, which included complete responses in 5% of patients and partial responses in 53% of patients with locally advanced basal-cell carcinoma, a potentially disfiguring and difficult-to-treat skin cancer. The findings from this study also reinforce the association between hedgehog pathway inhibition and tumor response.

References

1. American Society of Clinical Oncology. Skin cancer (non-melanoma): overview. Cancer.Net. www.cancer.net/cancer-types/skin-cancer-non-melanoma/overview. Accessed November 20, 2015.
2. Mohan SV, Chang AL. Advanced basal cell carcinoma: epidemiology and therapeutic innovations. Curr Dermatol Rep. 2014;3:40-45.
3. American Academy of Dermatology. Skin cancer. www.aad.org/media-resources/stats-and-facts/conditions/skin-cancer. Accessed November 17, 2015.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): basal cell skin cancer. Version 1.2016. October 26, 2015. www.nccn.org/professionals/physician_gls/pdf/nmsc.pdf. Accessed November 19, 2015.
5. Mayo Clinic staff. Diseases and conditions: basal cell carcinoma. September 7, 2013. www.mayoclinic.org/diseases-conditions/basal-cell-carcinoma/basics/defini tion/con-20028996?p=1. Accessed November 17, 2015.
6. Chren M-M, Linos E, Torres JS, et al. Tumor recurrence 5 years after treatment of cutaneous basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol. 2013; 133:1188-1196.
7. Gupta S, Takebe N, LoRusso P. Targeting the hedgehog pathway in cancer. Ther Adv Med Oncol. 2010;2:237-250.
8. US Food and Drug Administration. FDA approves new treatment for most common form of advanced skin cancer. Press release. July 24, 2015. www.fda.gov/News Events/Newsroom/PressAnnouncements/ucm455862.htm. Accessed November 17, 2015.
9. 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; 16:716-728.
10. National Cancer Institute. Skin cancer treatment—for health professionals (PDQ®): basal cell carcinoma of the skin treatment. Updated July 15, 2015. www.cancer.gov/types/skin/hp/skin-treatment-pdq#section/_222. Accessed November 27, 2015.
11. Erivedge (vismodegib) capsule [prescribing information]. South San Francisco, CA: Genentech, Inc; May 2015.
12. Odomzo (sonidegib) capsules [prescribing information]. East Hanover, NJ: Novartis; July 2015.

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