BackgroundPatients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult‐to‐treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial.ObjectiveTo evaluate long‐term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18‐ and 30‐month analyses.MethodsBOLT (NCT01327053, ClinicalTrials.gov), a double‐blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI‐treatment–naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review.ResultsWith 30 months of follow‐up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200‐mg arm died. Median overall survival was not reached in either population; 2‐year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non‐aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%).ConclusionSonidegib continued to demonstrate long‐term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.

No dose adjustment is needed for mild hepatic impairment, mild and moderate renal impairment, age, weight, gender, or ethnicity. This population PK model adequately characterizes sonidegib PK characteristics and can be used for various simulations and applications.

These results suggest that pasireotide is a promising option in patients with dumping syndrome after bariatric or upper gastrointestinal cancer surgery.

Sonidegib (Odomzo) is an orally available Smoothened inhibitor for the treatment of advanced basal cell carcinoma. Sonidegib was found to be metabolized primarily by cytochrome P450 (CYP)3A in vitro. The effect of multiple doses of the strong CYP3A perpetrators, ketoconazole (KTZ) and rifampin (RIF), on sonidegib pharmacokinetics (PK) after a single 800 mg dose in healthy subjects was therefore assessed. These data were used to verify a physiologically-based pharmacokinetic (PBPK) model developed to 1) bridge the clinical drugdrug interaction (DDI) study of sonidegib with KTZ and RIF in healthy subjects to the marketed dose (200 mg) in patients 2) predict acute (14 days) versus long-term dosing of the perpetrators with sonidegib at steady state and 3) predict the effect of moderate CYP3A perpetrators on sonidegib exposure in patients. Treatment of healthy subjects with KTZ resulted in an increased sonidegib exposure of 2.25- and 1.49-fold (area under the curve and maximal concentration respectively), and RIF decreased exposure by 72% and 54%, respectively. The model simulated the single- and/or multiple-dose PK of sonidegib (healthy subjects and patients) within ∼50% of observed values. The effect of KTZ and RIF on sonidegib in healthy subjects was also simulated well, and the predicted DDI in patients was slightly less and independent of sonidegib dose. At steady state, sonidegib was predicted to have a higher DDI magnitude with strong or moderate CYP3A perpetrators compared with a single dose. Different dosing regimens of sondigeb with the perpetrators were also simulated and provided guidance to the current dosing recommendations incorporated in the product label.

Sonidegib selectively inhibits smoothened protein, suppresses the growth of Hedgehog pathway-dependent tumors, and has recently been approved in the indication of locally advanced basal cell carcinoma. A comprehensive exposure-response analysis was conducted to further characterize the relationship of sonidegib exposure to efficacy and safety. Minimum observed plasma concentration at predose (C ), peak concentration (C ), and area under the curve were used as exposure endpoints. Exposure-efficacy analyses included data from 190 patients who received sonidegib 200 mg or 800 mg once daily in the primary efficacy study. Objective response rate (ORR) (complete response [CR] or partial response [PR]), progression-free survival (PFS), and time to tumor response (TTR) were assessed by logistic regression, Cox regression, and Kaplan-Meier analyses. Exposure-safety (creatine phosphokinase [CK] elevation) analyses included data from 336 patients pooled from 4 clinical trials and included doses across ranges of 100 to 3000 mg once daily and 250 to 750 mg twice daily. Similar plasma exposure was observed between responders and nonresponders. The logistic regression model of week 5 C vs ORR indicated no relationship between sonidegib exposure resulting from 200 mg or 800 mg doses and the probability of CR or PR. A similar conclusion of no exposure-efficacy relationship was drawn from the PFS and TTR analyses. Increased exposure was associated with a greater risk of grade 3 or 4 CK elevation, with lower risk in females than in males when C was used in the model. These analyses support the sonidegib dose recommendation for registration and are consistent with clinical observations.

AIMSThis study aimed to evaluate the impact of esomeprazole on the pharmacokinetics of sonidegib. METHODSThis Phase I study evaluated the impact of the proton pump inhibitor (PPI) esomeprazole on the oral absorption and pharmacokinetics (PKs) of a single dose of sonidegib under fasted conditions. A total of 42 healthy subjects were enrolled to receive either sonidegib alone (200 mg single dose) or sonidegib in combination with esomeprazole (40 mg pre-treatment 5 days and combination were given on day 6). Primary PK parameters assessed in the study were area under the concentration-time curve (AUC) from 0-14 days and 0-7 days and maximum observed plasma concentration (C max ). RESULTSThe plasma exposure (AUC0-14d, AUC0-7d and C max ) of a single 200 mg oral dose of sonidegib was decreased by 32-38% when sonidegib was co-administered with esomeprazole compared with sonidegib alone, with no apparent change in elimination slope and t max . Baseline gastric pH was similar between the two arms. CONCLUSIONSThese results suggest a modest reduction in the extent of sonidegib absorption by esomeprazole. There was no obvious metabolic drug-drug interaction between the two agents. Both sonidegib and esomeprazole were well tolerated in the study population. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Sonidegib is a newly approved drug in various regions globally for treating locally advanced basal cell carcinoma which cannot be treated with curative surgery or radiation therapy.• Drugs having pH-dependent solubility may have drug-drug interaction with gastric pH agents (e.g., PPI, H 2 blocker) when in combination.• In vitro, sonidegib follows pH-dependent solubility, with lower solubility at higher pH.• Gastric pH agents are commonly used in cancer patients. British Journal of Clinical Pharmacology WHAT THIS STUDY ADDS• This study investigates the effect of a proton pump inhibitor on the oral absorption and pharmacokinetics of sonidegib.• The exposure changes observed when sonidegib is given in combination with esomeprazole are not considered to be clinically relevant.

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Overall, sonidegib exposures were similar or decreased in the hepatic impairment groups compared with the normal group, and sonidegib was generally well-tolerated in all subjects. Dose adjustment is not considered necessary for subjects with mild, moderate, or severe hepatic impairment.