setting of posttreatment scarring, fibrosis, and ill-defined lesion borders.11 Evaluation per mRECIST integrated histology from multiple biopsies across lesion surface area, MRI according to RECIST v1.1, and standard and annotated color photography using bidimensional WHO criteria. According to mRECIST, criteria for CR included negative histology; MRI confirmation, if available; and CR, or PR or SD with tumor scarring or fibrosis only per lesion photograph.15 Criteria for PR included negative histology; CR, PR, or SD per MRI, if available; and CR, PR, or SD with tumor scarring or fibrosis only per lesion photograph. Criteria for SD included positive or unknown histology; CR, PR, or SD per MRI, if available; and SD per lesion photograph if available.15 Additionally, a prespecified analysis of BOLT results for patients with laBCC at 42 months was performed using a similar methodology to that used in the ERIVANCE trials in order to produce more comparative results for sonidegib vs vismodegib.
In ERIVANCE, CR was defined as absence of residual BCC in a biopsy specimen.14 Criteria for PR included decrease of ≥30% in the externally visible or radiographic dimension of the tumor, or the complete resolution of ulceration if present at baseline. Progressive disease (PD) was defined as ≥20% increase in the externally visible or radiographic dimension, or the appearance of new ulceration or a new lesion. An increase or decrease in tumor size insufficient to adjudicate PR or PD was designated as SD. Externally visible tumor dimension measurements included scarring, and tumor response was confirmed 4 weeks after initial documentation.14
Safety assessments included adverse events (AEs) graded for toxicity using CommonTerminology Criteria for Adverse Events (CTCAE) version 4.03 for BOLT and 3.0 for ERIVANCE.11,12 In BOLT creatine kinase (CK) levels were monitored ≤72 h from the first sonidegib dose, every week during the first 2 months, and every 4 weeks thereafter.11
Other Major Clinical Studies of Vismodegib Basal Cell Carcinoma
STEVIE (SafeTy Events in VIsmodEgib) was a phase 2, single-arm, open-label, multicenter study evaluating safety and efficacy of vismodegib in patients with advanced BCC in a setting representative of clinical practice (Table 1).16 Eligible patients were ≥18 years old with an ECOG performance status ≤2 and histologically confirmed diagnosis of mBCC or laBCC not amenable to or appropriate for surgery and previously treated with radiotherapy, if appropriate.16 Patients with both measurable and nonmeasurable disease per RECIST v1.1 were eligible to enroll if additional criteria were met. All patients received vismodegib 150 mg QD until disease progression, unacceptable toxicity, withdrawal of consent, study termination, or death.Treatment interruptions of ≤8 weeks were permitted to manage toxicity or if patients were unable to swallow capsules. The primary endpoint was safety, assessed by AE monitoring and grading for toxicity using CTCAE version 4.0, physical examination, ECOG performance status, vital signs, and laboratory testing. Secondary efficacy assessments included investigator-assessed ORR, DOR, TTR, PFS, and OS. Tumor response was assessed by physical examination using RECIST v1.1 every 4–8 weeks. CT and MRI were performed every 8–16 weeks, if necessary.16
MIKIE was a phase 2, randomized, double-blind, regimen- controlled, multicenter study evaluating the efficacy and safety of intermittent doses of vismodegib in patients with multiple BCCs (Table 1).17 The study enrolled patients ≥18 years old with ECOG performance status ≤2 and >6 clinically evident BCCs amenable to surgery, and without any laBCC or mBCC tumors. Target BCCs (3 per patient) were ≥5 mm in their longest diameter, and at least 1 was histologically confirmed. Patients were randomized 1:1 into 2 treatment regimen groups. The 12-week regimen group received vismodegib 150 mg QD for 12 weeks, then 3 consecutive cycles of placebo QD for 8 weeks followed by vismodegib 150 mg QD for 12 weeks. The 24-week regimen group received vismodegib 150 mg QD for 24 weeks, then 3 consecutive cycles of placebo QD for 8 weeks followed by vismodegib 150 mg QD for 8 weeks. Both treatment groups were followed for 52 weeks after the end of the treatment period at week 73. The primary efficacy endpoint was percent decrease in number of BCCs at week 73.17 Secondary efficacy endpoints included percent decrease in total size of target lesions, recurrence of appearance of new lesions, and ≥50% decrease in number of lesions.17 Tumor response was assessed by physical examination and BCC counting every 8 weeks. AEs were classified using Medical Dictionary for Regulatory Activities v18.0.17
Despite key differences in study design and primary endpoints for the STEVIE and MIKIE trials as compared with BOLT and ERIVANCE, we believe the findings from these phase 2 trials provide value and are important trials to include when comparing efficacy and safety of sonidegib and vismodegib based on published literature to date.
Efficacy
Clinical efficacy
BOLT enrolled 79 patients in the sonidegib 200 mg group (66 with laBCC and 13 with mBCC) and 151 patients in the 800 mg group (128 with laBCC and 23 with mBCC).11 The study population was 61% and 64% male with median age of 67 and 65 years, for the sonidegib 200 and 800 mg groups, respectively. At 42 months, 6 (8%) patients in the 200 mg group and 5 (3%) in the 800 mg group remained on treatment. Overall, 29 (37%) and 24 (16%) patients discontinued due to disease progression in the 200 and 800 mg groups, respectively.11
In the BOLT final analysis at 42 months, patients achieved ORR
In ERIVANCE, CR was defined as absence of residual BCC in a biopsy specimen.14 Criteria for PR included decrease of ≥30% in the externally visible or radiographic dimension of the tumor, or the complete resolution of ulceration if present at baseline. Progressive disease (PD) was defined as ≥20% increase in the externally visible or radiographic dimension, or the appearance of new ulceration or a new lesion. An increase or decrease in tumor size insufficient to adjudicate PR or PD was designated as SD. Externally visible tumor dimension measurements included scarring, and tumor response was confirmed 4 weeks after initial documentation.14
Safety assessments included adverse events (AEs) graded for toxicity using CommonTerminology Criteria for Adverse Events (CTCAE) version 4.03 for BOLT and 3.0 for ERIVANCE.11,12 In BOLT creatine kinase (CK) levels were monitored ≤72 h from the first sonidegib dose, every week during the first 2 months, and every 4 weeks thereafter.11
Other Major Clinical Studies of Vismodegib Basal Cell Carcinoma
STEVIE (SafeTy Events in VIsmodEgib) was a phase 2, single-arm, open-label, multicenter study evaluating safety and efficacy of vismodegib in patients with advanced BCC in a setting representative of clinical practice (Table 1).16 Eligible patients were ≥18 years old with an ECOG performance status ≤2 and histologically confirmed diagnosis of mBCC or laBCC not amenable to or appropriate for surgery and previously treated with radiotherapy, if appropriate.16 Patients with both measurable and nonmeasurable disease per RECIST v1.1 were eligible to enroll if additional criteria were met. All patients received vismodegib 150 mg QD until disease progression, unacceptable toxicity, withdrawal of consent, study termination, or death.Treatment interruptions of ≤8 weeks were permitted to manage toxicity or if patients were unable to swallow capsules. The primary endpoint was safety, assessed by AE monitoring and grading for toxicity using CTCAE version 4.0, physical examination, ECOG performance status, vital signs, and laboratory testing. Secondary efficacy assessments included investigator-assessed ORR, DOR, TTR, PFS, and OS. Tumor response was assessed by physical examination using RECIST v1.1 every 4–8 weeks. CT and MRI were performed every 8–16 weeks, if necessary.16
MIKIE was a phase 2, randomized, double-blind, regimen- controlled, multicenter study evaluating the efficacy and safety of intermittent doses of vismodegib in patients with multiple BCCs (Table 1).17 The study enrolled patients ≥18 years old with ECOG performance status ≤2 and >6 clinically evident BCCs amenable to surgery, and without any laBCC or mBCC tumors. Target BCCs (3 per patient) were ≥5 mm in their longest diameter, and at least 1 was histologically confirmed. Patients were randomized 1:1 into 2 treatment regimen groups. The 12-week regimen group received vismodegib 150 mg QD for 12 weeks, then 3 consecutive cycles of placebo QD for 8 weeks followed by vismodegib 150 mg QD for 12 weeks. The 24-week regimen group received vismodegib 150 mg QD for 24 weeks, then 3 consecutive cycles of placebo QD for 8 weeks followed by vismodegib 150 mg QD for 8 weeks. Both treatment groups were followed for 52 weeks after the end of the treatment period at week 73. The primary efficacy endpoint was percent decrease in number of BCCs at week 73.17 Secondary efficacy endpoints included percent decrease in total size of target lesions, recurrence of appearance of new lesions, and ≥50% decrease in number of lesions.17 Tumor response was assessed by physical examination and BCC counting every 8 weeks. AEs were classified using Medical Dictionary for Regulatory Activities v18.0.17
Despite key differences in study design and primary endpoints for the STEVIE and MIKIE trials as compared with BOLT and ERIVANCE, we believe the findings from these phase 2 trials provide value and are important trials to include when comparing efficacy and safety of sonidegib and vismodegib based on published literature to date.
Efficacy
Clinical efficacy
BOLT enrolled 79 patients in the sonidegib 200 mg group (66 with laBCC and 13 with mBCC) and 151 patients in the 800 mg group (128 with laBCC and 23 with mBCC).11 The study population was 61% and 64% male with median age of 67 and 65 years, for the sonidegib 200 and 800 mg groups, respectively. At 42 months, 6 (8%) patients in the 200 mg group and 5 (3%) in the 800 mg group remained on treatment. Overall, 29 (37%) and 24 (16%) patients discontinued due to disease progression in the 200 and 800 mg groups, respectively.11
In the BOLT final analysis at 42 months, patients achieved ORR
