Exposure‐Response Analysis of Sonidegib (LDE225), an Oral Inhibitor of the Hedgehog Signaling Pathway, for Effectiveness and Safety in Patients With Advanced Solid Tumors

Abstract

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.

Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas

“…Following 4 weeks of treatment, Ber-EP4 and BCL-2 expression in tumors decreased, while HLA expression was upregulated on residual tumor cells, leading to the recruitment of CD8 + cytotoxic T cells into the tumor mass. Analysis with quantitative polymerase chain reaction revealed that expression of immune response-regulating genes was altered, which is consistent with our previous study that the Hh pathway is responsible for suppressing the immune response, and SMO antagonists relieve the suppression 52,53. Although this study was severely limited by the low number of patients treated with sonidegib, the result supports the role of Hh signaling for the immune suppressive microenvironment as well as the possibility to combine immune modifiers with Hh signaling inhibition to achieve extended tumor control.…”

“…Both responders and nonresponders showed similar plasma concentration levels, but there was no correlation between the dosage and probability of tumor response. Similarly, increasing exposure did not show an improvement in progression-free survival nor in time to tumor response 52. Thus, patients who fail to respond to lower doses may not benefit from an increase in dose.…”

“…Grade 1/2 muscle spasms, dysgeusia, nausea, and alopecia were the most common causes of discontinuation. CK elevation was the most common grade 3/4 event, occurring in 6% of patients taking the 200 mg dose; women show a lower risk of CK abnormality than men 52. Furthermore, CK elevations were observed at low doses in Japanese patients, which resulted in their lower MTD of sonidegib 48,49.…”

To Take or Not to Take With Meals? Unraveling Issues Related to Food Effects Labeling for Oral Antineoplastic Drugs

“…Previously published population PK and exposure‐toxicity models of sonidegib were used to simulate (n = 100) scenarios of taking sonidegib in different ways with respect to food . It was known that sonidegib had a 5‐ to 7‐fold increase in exposure with a high‐fat, high‐caloric meal.…”

“…Briefly, a 2‐compartment model with first‐order absorption with lag‐time, linear elimination, and bioavailability that increased by 5.74‐fold in fed condition was used to simulate the steady state trough plasma concentration on cycle 2 day 1 of sonidegib therapy . This simulated PK metric was used in an exposure‐toxicity model to drive the probability of developing a grade 3/4 creatine kinase (CK) elevation according to Equations and , where π(x) is the probability of developing grade 3/4 CK elevation, β 0 , β 1 , and β 2 are the intercept (−2.58) and slopes (0.10 for C min and −0.92 for female) in the logistic regression, and C min is the steady‐state trough plasma concentration (ng/mL) on cycle 2 day 1.…”