In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On July 24, 2015, sonidegib (Odomzo) was approved for treatment of patients with locally advanced basal cell carcinoma recurring after surgery or radiation therapy and patients who are not candidates for surgery or radiation therapy.1,2
The approval was based on demonstration of durable objective responses in a two-arm phase II trial in which 230 patients with locally advanced basal cell carcinoma not amenable to local therapy or metastatic basal cell carcinoma were randomized 2:1 to receive oral sonidegib at 800 mg (n = 151) or 200 mg (n = 79) daily until disease progression or unacceptable toxicity.2,3 In total, 84% of patients had locally advanced disease.
Both 200-mg and 800-mg doses of sonidegib showed antitumour activity in patients with advanced basal cell carcinoma. The 200-mg dose was associated with a more favorable safety profile than the 800-mg dose. The benefit-to-risk profile of 200-mg sonidegib was determined a potentially new treatment option for this difficult-to-treat population of patients with advanced basal cell carcinoma.
Among patients with locally advanced disease randomized to receive 200 mg daily of sonidegib (the approved dose), the median age was 67 years, 58% were male, 89% were white, 67% had an Eastern Cooperative Oncology Group performance status of 0, 76% had received prior treatment for basal cell carcinoma, and 56% had an aggressive histology. None had received prior Hedgehog inhibitor treatment.
Among 66 patients with locally advanced disease who received 200 mg, the objective response rate was 58% (95% confidence interval [CI] = 45%–70%). Among the 38 patients with an objective response, 7 (18%) had subsequent disease progression, with 4 having maintained a response of at least 6 months. At last analysis, the remaining 31 patients had ongoing responses of 1.9+ to 18.6+ months, and the median duration of response had not been reached. The objective response rate among 128 patients with locally advanced disease receiving 800 mg was 44% (95% CI = 35%–53%).
A prespecified sensitivity analysis defining complete response as at least partial response on magnetic resonance imaging or photography and no evidence of tumor on biopsy of the residual lesion indicated a complete response rate of 20%. However, in the study, the classification of complete response required confirmation in multiple biopsy samples, with these results being assessed by an independent review committee. As a result of these more stringent criteria, the complete response rate in the study was only 5%.
How It Works
Sonidegib is an inhibitor of the Hedgehog signaling pathway. It binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction. Most sporadic basal cell carcinomas have mutations in the PTCH1 gene or Smoothened, which lead to activation of signaling and expression of the Hedgehog pathway and its targets.
How It Is Given
The recommended dose of sonidegib is 200 mg once daily on an empty stomach, at least 1 hour before or 2 hours after a meal. Treatment should continue until disease progression or unacceptable toxicity.
Sonidegib treatment should be interrupted for severe or intolerable musculoskeletal adverse reactions, first occurrence of serum creatine kinase elevation between 2.5 and 10 times the upper limit of normal (ULN), and recurrent creatine kinase elevation between 2.5 and 5 times ULN; treatment can be resumed at 200 mg upon resolution of clinical signs and symptoms. Treatment should be permanently discontinued for creatine kinase elevation > 2.5 times ULN with worsening renal function, creatine kinase elevation > 10 times ULN, recurrent creatine kinase elevation > 5 times ULN, and recurrent severe or intolerable musculoskeletal adverse reactions.
Concomitant administration with strong CYP3A inhibitors (eg, saquinavir, telithromycin, ketoconazole, itraconazole) and concomitant use for more than 14 days with moderate CYP3A inhibitors (eg, atazanavir, diltiazem, fluconazole) should be avoided. Concomitant use with strong and moderate CYP3A inducers (eg, carbamazepine, modafinil, phenobarbital, St. John’s wort) should be avoided.
In the phase II trial, the most common clinical adverse events of any grade in patients receiving 200 mg of sonidegib were muscle spasms (54%), alopecia (53%), dysgeusia (46%), fatigue (41%), nausea (39%), musculoskeletal pain (32%), diarrhea (32%), and decreased weight (30%). The most common grade 3 adverse events (no grade 4 events reported) were fatigue (4%), muscle spasms (3%), and decreased weight (3%). Serious adverse events occurred in 18% of patients. Adverse events led to treatment interruption in 20% of patients and treatment discontinuation in 34%, with the most common causes of treatment discontinuation being muscle spasms (5%), dysgeusia (5%), asthenia (4%), increased lipase (4%), and nausea (4%).
The most common laboratory abnormalities of any grade were increased serum creatinine (92%), increased serum creatine kinase (61%), hyperglycemia (51%), and increased lipase (43%). The most common grade 3 or 4 abnormalities were increased lipase (13%), increased serum creatine kinase (8%), hyperglycemia (4%), and increased alanine transaminase and aspartate transaminase (both 4%). Thus, serum creatine kinase levels must be measured and renal function tests performed in all patients prior to starting treatment with sonidegib, periodically during treatment, and as clinically indicated.
The frequencies of common adverse events, serious adverse events, and discontinuation of treatment due to adverse events were higher in patients receiving the 800-mg dose.
Sonidegib has a boxed warning for embryo-fetal risk, as it can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. Thus, the pregnancy status of women of reproductive potential must be verified prior to starting treatment. Women of reproductive potential must be advised to use effective contraception during treatment and for at least 20 months after the last dose. Males must be advised of the potential risk of exposure through semen and encouraged to use condoms with a pregnant partner or a female partner of reproductive potential during treatment and for at least 8 months after the last dose.
Sonidegib also carries warnings/precautions for blood donation and musculoskeletal adverse reactions. Patients should be advised not to donate blood or blood products during treatment or for at least 20 months after the last dose. Women should not breast-feed during treatment or for at least 20 months after the last dose. ■
1. U.S. Food and Drug Administration: Sonidegib. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm455865.htm. Accessed July 28, 2015.
2. Odomzo (sonidegib) capsules prescribing information, Novartis Pharmaceuticals, July 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/205266s000lbl.pdf. Accessed July 28, 2015.
3. Migden MR, et al: Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT). Lancet Oncol 16:716-728, 2015.