Key evidence from clinical trials for vismodegib

Introduction

The approval of vismodegib was based on the results of the fundamental ERIVANCE Basal cell carcinoma (BCC) study.

ERIVANCE BCC was an international, single-arm, multicenter, two-cohort group, open Phase II study that included 104 patients with advanced BCC, including locally advanced BCC (n = 71) and BCC with metastasis (33).

Patients with locally advanced BCC had lesions that were inappropriate for surgery (inoperable, or for whom surgery would result in substantial deformity) and for which radiotherapy was unsuccessful or contraindicated.

Metastasized BCC was defined as BCC that had spread to other parts of the body, including the lymph nodes, lungs, bones and / or internal organs.

The 31 study sites were located in the United States, Australia, and Europe. Study participants received vismodegib 150 mg orally, once daily until disease progression or intolerable toxicity.

the primary The analysis was performed 9 months after completion of the accumulation.

The trial showed that vismodegib substantially reduced visible healed tumors or lesions (objective response rate or ORR) in 43% of patients with locally advanced BCC and 30% of patients with metastatic BCC, as assessed by an independent review, the primary endpoint of the study.

The median progression-free survival (PFS) based on an independent review for patients with locally advanced and metastatic BCC was 9.5 months.

Furthermore, the clinical benefit rate (defined as patients who had a clinical response as well as those who experienced disease stability for more than 24 weeks) was 75% in patients treated with vismodegib.

In these patients, vismodegib shrunk the tumors or healed the visible lesions, or prevented them from growing further for more than 24 weeks.

The ORR assessed by the study investigators, a secondary endpoint, was 60% for locally advanced BCC and 46% for metastatic BCC.

The key results are tabulated below.

In the metastatic cohort of BCC, tumor the response was assessed according to the Response Assessment Criteria in Solid tumors (RECIST) version 1.0.

RECIST is a set of published rules that define when Cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("disease progression") during treatments.

The criteria were published in February 2000 by an international collaboration that includes the European Organization for Research and Treatment of Cancer (EORTC), the National Cancer Institute of the United States, and the National Cancer Institute's Clinical Trials Group. Canada.

In the locally advanced BCC cohort, evaluation of tumor response included measurement of externally evaluable tumor (including scar), evaluation for ulceration on photographs, radiographic evaluation of target lesions (if applicable) and tumor biopsy.

Disease progression was defined as any of the following:

• ≥ 20% increase in injury size in target lesions (either by radiography or by externally visible dimension)
• New ulceration of persistent target lesions without evidence of healing for at least 2 weeks
• new lesions by radiographic evaluation or physical examination
• progression of non-target lesions by RECIST.

The objective response in locally advanced BCC required at least one of the following criteria and the absence of any criteria for disease progression:

• ≥30% reduction in lesion size [sum of the longest diameter (SLD)] from base in target lesions by radiographic evaluation
• Reduction ≥ 30% in SLD from baseline in externally visible dimension of target lesions
• complete resolution of ulceration in all target lesions.

Complete response in locally advanced BCC was defined as objective response (as defined above) with no residual BCC on tumor biopsy sampling.

Long-term update (39 months) of the ERIVANCE BCC trial

• One hundred and four patients with measurable advanced BCC received oral vismodegib 150 mg once daily until disease progression or intolerable toxicity.
• At the data cutoff (39 months after completion of accumulation), 8 patients were receiving study drug.
• 69 patients (66%) remained in survival follow-up.
• The median duration (range) of vismodegib treatment was 12.9 (0.7–47.8) months (13.3 [0.7–39.1] months in the metastatic BCC cohort (mBCC) and 12.7 [1.1 –47.8] months in the locally advanced cohort (the) BCC).
• The investigator-assessed overall response rate (ORR), which was the primary end point, was 48.5% in the mBCC group (all partial responses) and 60.3% in the BCC group (20 patients had a response complete and 18 patients had a partial response).
• The median duration of response was 14.8 months (mBCC) and 26.2 months (laBCC).
• Median overall survival was 33.4 months in the mBCC cohort and not estimable in the laBCC cohort.
• the incidence related treatment adverse events (TEAE) increased between the time of the primary analysis and this final data cutoff date.
• The most common TEAEs of any grade were muscle spasms (71.2%), alopecia (66.3%), dysgeusia (distortion of the sense of taste; 55.8%), weight decrease (51.9%), fatigue (43.3%) and nausea (32.7%).
• Overall, grade ≥ 3 adverse events were reported in 58 patients (55.8%), the most common being weight loss (8.7%), followed by muscle spasms (5.8%). Other Grade ≥ 3 adverse events, including fatigue, decreased appetite, diarrhea, and SCC, occurred in <5% of patients.
• This long-term study of vismodegib that includes 39 months of observation after completing patient accumulation in the ERIVANCE BCC trial reinforces the clinical utility of vismodegib in patients with advanced BCC for whom treatment options are limited and demonstrate the durability of response and long-term safety of vismodegib.

The SafeTy Events in VIsmodEgib (STEVIE) study - post-approval study

• This study evaluated the safety and effectiveness of vismodegib, a first-class Hedgehog pathway inhibitor demonstrating clinical benefit in advanced basal cell carcinoma (BCC), in a patient population representative of clinical practice.
• In this open multicenter trial, adult patients with histologically Confirmed LaBCC or mBCC were recruited from regional referral centers or specialized clinics.
• Patients received oral vismodegib 150 mg / day until progressive illness, unacceptable toxicity, or withdrawal.
• The main objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with evaluations on day 1 of each treatment cycle (28 days) by the principal investigator and co-investigators at the site.
• Efficacy variables were assessed as secondary end points.

Safety

• The safety evaluable population included all patients who received at least one dose of study drug.
• Evaluable adult patients (north = 1215, 1119 locally advanced; 96 mBCC) from 36 countries were treated; 147 patients (12%) remained in study at the time of reporting. The median duration of treatment (range) was 8.6 (0-44) months.
• Treatment-related serious adverse events (TEAE) occurred in 289 patients (23.8%) and included increased hepatic enzyme, cutaneous scaly cell carcinoma and general deterioration of physical health.
• Most patients (1192 [98%]) had ≥ 1 TEAE under study; The most common TEAEs (> 20% incidence) were:
  • muscle spasms (807 [66%])
  • alopecia (747 [62%])
  • dysgeusia (663 [55%])
  • weight decrease (493 [41%])
  • decreased appetite (303 [25%])
  • asthenia (291 [24%])
• Exposure ≥ 12 months did not lead to an increased incidence or severity of new TEAEs.

Effectiveness

• Patients with histologically confirmed BCC who received at least one dose of study drug were included in the efficacy analysis.
• The median follow-up was 17.9 months, and 1,161 patients in the efficacy evaluable population had histologically confirmed measurable disease.
• Overall response rates (as assessed by the investigator) in patients with histologically confirmed measurable baseline disease were 68.5% (95% confidence interval (CI): 65.7-71.3) in patients with BCC and 36, 9% (95% CI: 26.6-48.1) in patients with CCMb.
• Response rates in Gorlin patients syndrome (basal cell nevus syndrome) and histologically confirmed measurable disease were 81.7% (95% CI 75.8-86.7) and 80.0% (95% CI 28.4-99.5) in patients with locally advanced MCC and mBCC, respectively.

STEVIE's primary analysis demonstrated that:

• vismodegib is tolerable in typical patients in clinical practice
• long-term exposure was not associated with worsening severity / frequency of TEAs
• Investigator-assessed response rates showed a high tumor rate control.