Overall, 1215 patients were included in the STEVIE efficacy and safety analyses, 1119 with laBCC and 96 with mBCC.16 Patients were 57% male with median age of 72 years. At study completion, 147 (12%) patients remained on study treatment; 189 (16%) patients discontinued due to disease progression.16 Investigator-assessed ORR was 69% in laBCC and 37% in mBCC, while CR reached 33% in laBCC and 5% in mBCC (Table 2 and Figure 1).16
Efficacy by age group
A secondary analysis in ERIVANCE patients examined efficacy of vismodegib stratified by age.19 Patients aged ≥65 and <65 years demonstrated ORR by investigator review of 47% and 73% for laBCC, and 36% and 53% for mBCC, respectively. CR amounted to 26% for laBCC and 0% for mBCC in the ≥65 years group, and 36% for laBCC and 0% for mBCC in the <65 years group. The investigators concluded no clinically meaningful differences in efficacy were observed between the age groups.19
Efficacy outcomes from MIKIE
MIKIE enrolled 229 patients, 116 and 113 randomized to the 12-week and 24-week vismodegib regimen, respectively.17 The 12-week regimen group was 70% male with a median age of 62 years, while the 24-week regimen group was 78% male with a median age of 60 years. Overall 64 (55%) and 56 (50%) patients remained on treatment by end of the study, and 3 (2.6%) and 3 (2.7%) patients discontinued due to disease progression, for the 12-week and 24-week regimen groups, respectively.17
Patients in MIKIE achieved mean 63% reduction in number and 83% reduction in size of BCCs on a 12-week vismodegib regimen, and 54% reduction in number and 69% reduction in size of BCCs on a 24-week vismodegib regimen.17 Overall, 66% and 50% of the total number of patients in the 12-week and 24-week regimen groups had a ≥50% reduction in lesion number at the end of treatment, respectively. Absence of recurring or new BCCs at the end of treatment was reported in 77% and 74% of patients in the 12-week and 24-week regimens, respectively.17
Efficacy by tumor histology
Efficacy of sonidegib in aggressive and nonaggressive BCC subtypes was evaluated in a secondary analysis of BOLT results at 42 months.20 Patients with aggressive BCC comprised 49% of the 200 mg and 50% of the 800 mg group, while those with nonaggressive BCC histology comprised 49% and 47% of the 200 and 800 mg groups, respectively.20 Histology was indeterminate in 1% of patients in the 200 mg and 3% of patients in the 800 mg group. ORR by central review was 60% in patients with aggressive and 52% in patients with nonaggressive BCC receiving sonidegib 200 mg. For the 800 mg group, ORR was 45% in patients with aggressive and 47% in patients with nonaggressive BCC.20 Among patients with aggressive BCC subtypes, those with infiltrative and morpheaform subtypes achieved the highest ORRs of 52% in the 200 mg and 37% in the 800 mg group for infiltrative, and 50% in the 200 mg and 75% in the 800 mg group for morpheaform BCC.20
Vismodegib efficacy in different histologic subtypes of high- risk or laBCC was examined in a phase 2b, single-center, prospective case series in 27 patients with a total of 65 BCCs.21
Efficacy by age group
A secondary analysis in ERIVANCE patients examined efficacy of vismodegib stratified by age.19 Patients aged ≥65 and <65 years demonstrated ORR by investigator review of 47% and 73% for laBCC, and 36% and 53% for mBCC, respectively. CR amounted to 26% for laBCC and 0% for mBCC in the ≥65 years group, and 36% for laBCC and 0% for mBCC in the <65 years group. The investigators concluded no clinically meaningful differences in efficacy were observed between the age groups.19
Efficacy outcomes from MIKIE
MIKIE enrolled 229 patients, 116 and 113 randomized to the 12-week and 24-week vismodegib regimen, respectively.17 The 12-week regimen group was 70% male with a median age of 62 years, while the 24-week regimen group was 78% male with a median age of 60 years. Overall 64 (55%) and 56 (50%) patients remained on treatment by end of the study, and 3 (2.6%) and 3 (2.7%) patients discontinued due to disease progression, for the 12-week and 24-week regimen groups, respectively.17
Patients in MIKIE achieved mean 63% reduction in number and 83% reduction in size of BCCs on a 12-week vismodegib regimen, and 54% reduction in number and 69% reduction in size of BCCs on a 24-week vismodegib regimen.17 Overall, 66% and 50% of the total number of patients in the 12-week and 24-week regimen groups had a ≥50% reduction in lesion number at the end of treatment, respectively. Absence of recurring or new BCCs at the end of treatment was reported in 77% and 74% of patients in the 12-week and 24-week regimens, respectively.17
Efficacy by tumor histology
Efficacy of sonidegib in aggressive and nonaggressive BCC subtypes was evaluated in a secondary analysis of BOLT results at 42 months.20 Patients with aggressive BCC comprised 49% of the 200 mg and 50% of the 800 mg group, while those with nonaggressive BCC histology comprised 49% and 47% of the 200 and 800 mg groups, respectively.20 Histology was indeterminate in 1% of patients in the 200 mg and 3% of patients in the 800 mg group. ORR by central review was 60% in patients with aggressive and 52% in patients with nonaggressive BCC receiving sonidegib 200 mg. For the 800 mg group, ORR was 45% in patients with aggressive and 47% in patients with nonaggressive BCC.20 Among patients with aggressive BCC subtypes, those with infiltrative and morpheaform subtypes achieved the highest ORRs of 52% in the 200 mg and 37% in the 800 mg group for infiltrative, and 50% in the 200 mg and 75% in the 800 mg group for morpheaform BCC.20
Vismodegib efficacy in different histologic subtypes of high- risk or laBCC was examined in a phase 2b, single-center, prospective case series in 27 patients with a total of 65 BCCs.21
Examined lesions were 45% nodular, 37% infiltrative, and 15% superficial. Histological clearance after 12 weeks of treatment with vismodegib 150 mg QD was 45% in nodular, 75% in infiltrative, and 50% in superficial BCCs. Clinical clearance at 24 weeks was 83% for nodular, 92% in infiltrative, and 90% for superficial BCCs.21 Another case series examined histologic changes in BCCs during vismodegib treatment and concluded vismodegib can promote a shift toward metatypical or squamous differentiation in patients with PR, and keratinization in patients with CR and PR.22
Relapse following complete response
Two retrospective studies examined relapse after discontinuation of vismodegib treatment in patients who achieved CR.23,24 In the first study, 116 patients with laBCC, including those previously enrolled in STEVIE and MIKIE, reported a median (95% confidence interval [CI]) relapse-free survival of 18 (13–24) months after CR and end of vismodegib treatment.23 After 36 months of follow-up, the relapse-free rate was 35%.23 The second study in 35 patients with advanced BCC who received 6 months of vismodegib treatment reported a 31% relapse rate after a 6-month follow-up.24
There are no published studies evaluating relapse following discontinuation of sonidegib in patients who achieved CR.
Safety
Adverse events
At the time of BOLT completion, median duration of exposure to sonidegib was 11 months for the approved 200 mg dose.11 Overall, 77 (98%) of BOLT patients receiving sonidegib 200 mg experienced an AE, with grade ≥3 AEs reported in 34 (43%) patients, and grade ≥3 AEs related to study treatment reported in 25 (32%) patients. Four (5%) patients experienced a serious AE (SAE) considered related to study treatment. AEs led to discontinuation in 24 (30%) patients.11 Most common AEs (% of patients with grade ≤2 and grade ≥3 AEs) included muscle spasms (52% and 3%), alopecia (49% and 0%), and dysgeusia (44% and 0%,Table 3).
Median duration of exposure to vismodegib 150 mg QD was 13 months at the end of ERIVANCE, and all patients experienced an AE.12 Of these, 58 (56%) patients experienced grade ≥3 AEs, and 9 (9%) experienced SAEs considered related to study treatment. Discontinuations due to AEs were reported for 22 (21%) patients, and the most common AEs were muscle spasms in 74 (71%) patients, alopecia in 69 (66%) patients, and dysgeusia in 58 (56%) patients (Table 3).12
In STEVIE, median duration of exposure to vismodegib 150 mg QD was 9 months and a total of 1192 (98%) patients experienced an AE.16 Grade ≥3 AEs were reported in 531 (45%) patients, and SAEs in 289 (24%) patients. AEs led to discontinuation in 380 (31%) patients.16 Muscles spasms in 807 (66%) patients, alopecia in 747 (62%) patients, and dysgeusia in 663 (55%) patients were the most common AEs (Table 3).
For all patients in MIKIE, exposure to vismodegib 150 mg QD was approximately 48 weeks.17 A total of 113 (99%) and 110 (97%) patients experienced grade ≤2 AEs, 30 (26%) and 36 (32%) experienced grade 3 AEs, and 3 (3%) and 4 (4%) experienced grade 4 AEs, for the 12-week and 24-week regimen groups, respectively. SAEs related to study treatment occurred in 6 (5%) on the 12-week and 2 (2%) patients on the 24-week regimen. Discontinuations due to AEs were reported in 23 (20%) patients on the 12-week regimen and 30 (27%) patients on the 24-week regimen.17 The most common AE was muscle spasms reported as grade ≤2 in 79 (69%) and 81 (72%) patients, and as grade 3 in 4 (4%) and 12 (11%) patients, for the 12-week and 24-week regimen groups, respectively (Table 3). Dysgeusia was second most common, reported as grade ≤2 in 74 (65%) and 73 (65%) patients, and 1 (1%) and 2 (2%) patients, for the 12-week and 24-week regimen groups, respectively. Alopecia was only grade ≤2, reported in 72 (63%) patients on a 12-week regimen and 73 (65%) patients on a 24-week regimen.
Based on published literature to date from the pivotal BOLT and ERIVANCE studies, sonidegib had a slightly lower incidence of most AEs, and AEs reported related to study treatment were slightly less frequent and less severe compared with vismodegib at final analysis.12,15,25
Safety by age group
In a secondary analysis of vismodegib safety in ERIVANCE patients stratified by age, median exposure to study drug was 9 months in patients ≥65 years and 10 months in patients <65 years.19 All patients in both age groups experienced ≥1 AE, and grade ≥3 AEs were reported in 24 (51%) patients aged ≥65 and 20 (35%) patients aged <65 years. AEs led to discontinuation in 7 (15%) and 6 (11%) patients, for the ≥65 and <65 groups, respectively. Most common AEs (n [%] of patients aged ≥65 vs <65 years) included muscle spasms (30 [64%] vs 41 [72%]), dysgeusia (24 [51%] vs 29 [51%]), and alopecia (23 [49%] vs 43 [75%]).19
Muscle spasms and creatine kinase elevation
Creatine kinase is an enzyme found in abundance in muscle tissue, where it reversibly phosphorylates creatine using adenosine triphosphate as a phosphate source.26 In the event of cellular stress or damage, such as during spasmic contractions, muscle cells can release their content into the bloodstream, resulting in serum CK elevation.27
The exact relationship between muscle spasms and Hedgehog inhibition is not known, but it is hypothesized that noncanonical Hedgehog signaling may lead to calcium influx into the muscle
Relapse following complete response
Two retrospective studies examined relapse after discontinuation of vismodegib treatment in patients who achieved CR.23,24 In the first study, 116 patients with laBCC, including those previously enrolled in STEVIE and MIKIE, reported a median (95% confidence interval [CI]) relapse-free survival of 18 (13–24) months after CR and end of vismodegib treatment.23 After 36 months of follow-up, the relapse-free rate was 35%.23 The second study in 35 patients with advanced BCC who received 6 months of vismodegib treatment reported a 31% relapse rate after a 6-month follow-up.24
There are no published studies evaluating relapse following discontinuation of sonidegib in patients who achieved CR.
Safety
Adverse events
At the time of BOLT completion, median duration of exposure to sonidegib was 11 months for the approved 200 mg dose.11 Overall, 77 (98%) of BOLT patients receiving sonidegib 200 mg experienced an AE, with grade ≥3 AEs reported in 34 (43%) patients, and grade ≥3 AEs related to study treatment reported in 25 (32%) patients. Four (5%) patients experienced a serious AE (SAE) considered related to study treatment. AEs led to discontinuation in 24 (30%) patients.11 Most common AEs (% of patients with grade ≤2 and grade ≥3 AEs) included muscle spasms (52% and 3%), alopecia (49% and 0%), and dysgeusia (44% and 0%,Table 3).
Median duration of exposure to vismodegib 150 mg QD was 13 months at the end of ERIVANCE, and all patients experienced an AE.12 Of these, 58 (56%) patients experienced grade ≥3 AEs, and 9 (9%) experienced SAEs considered related to study treatment. Discontinuations due to AEs were reported for 22 (21%) patients, and the most common AEs were muscle spasms in 74 (71%) patients, alopecia in 69 (66%) patients, and dysgeusia in 58 (56%) patients (Table 3).12
In STEVIE, median duration of exposure to vismodegib 150 mg QD was 9 months and a total of 1192 (98%) patients experienced an AE.16 Grade ≥3 AEs were reported in 531 (45%) patients, and SAEs in 289 (24%) patients. AEs led to discontinuation in 380 (31%) patients.16 Muscles spasms in 807 (66%) patients, alopecia in 747 (62%) patients, and dysgeusia in 663 (55%) patients were the most common AEs (Table 3).
For all patients in MIKIE, exposure to vismodegib 150 mg QD was approximately 48 weeks.17 A total of 113 (99%) and 110 (97%) patients experienced grade ≤2 AEs, 30 (26%) and 36 (32%) experienced grade 3 AEs, and 3 (3%) and 4 (4%) experienced grade 4 AEs, for the 12-week and 24-week regimen groups, respectively. SAEs related to study treatment occurred in 6 (5%) on the 12-week and 2 (2%) patients on the 24-week regimen. Discontinuations due to AEs were reported in 23 (20%) patients on the 12-week regimen and 30 (27%) patients on the 24-week regimen.17 The most common AE was muscle spasms reported as grade ≤2 in 79 (69%) and 81 (72%) patients, and as grade 3 in 4 (4%) and 12 (11%) patients, for the 12-week and 24-week regimen groups, respectively (Table 3). Dysgeusia was second most common, reported as grade ≤2 in 74 (65%) and 73 (65%) patients, and 1 (1%) and 2 (2%) patients, for the 12-week and 24-week regimen groups, respectively. Alopecia was only grade ≤2, reported in 72 (63%) patients on a 12-week regimen and 73 (65%) patients on a 24-week regimen.
Based on published literature to date from the pivotal BOLT and ERIVANCE studies, sonidegib had a slightly lower incidence of most AEs, and AEs reported related to study treatment were slightly less frequent and less severe compared with vismodegib at final analysis.12,15,25
Safety by age group
In a secondary analysis of vismodegib safety in ERIVANCE patients stratified by age, median exposure to study drug was 9 months in patients ≥65 years and 10 months in patients <65 years.19 All patients in both age groups experienced ≥1 AE, and grade ≥3 AEs were reported in 24 (51%) patients aged ≥65 and 20 (35%) patients aged <65 years. AEs led to discontinuation in 7 (15%) and 6 (11%) patients, for the ≥65 and <65 groups, respectively. Most common AEs (n [%] of patients aged ≥65 vs <65 years) included muscle spasms (30 [64%] vs 41 [72%]), dysgeusia (24 [51%] vs 29 [51%]), and alopecia (23 [49%] vs 43 [75%]).19
Muscle spasms and creatine kinase elevation
Creatine kinase is an enzyme found in abundance in muscle tissue, where it reversibly phosphorylates creatine using adenosine triphosphate as a phosphate source.26 In the event of cellular stress or damage, such as during spasmic contractions, muscle cells can release their content into the bloodstream, resulting in serum CK elevation.27
The exact relationship between muscle spasms and Hedgehog inhibition is not known, but it is hypothesized that noncanonical Hedgehog signaling may lead to calcium influx into the muscle
