Key clinical-trial evidence for vismodegib

Introduction

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

ERIVANCE BCC was an international, single-arm, multicentre, two-cohort, open-label Phase II study that enrolled 104 patients with advanced BCC, including locally advanced BCC (n = 71) and metastasized BCC (33).

Locally advanced BCC patients 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.

Metastasised 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 150mg vismodegib orally, once daily until disease progression or intolerable toxicity.

The primary analysis was conducted 9 months after completion of accrual.

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

The median progression-free survival (PFS) by independent review for both metastatic and locally advanced BCC patients was 9.5 months.

In addition, 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 shrank tumours or healed visible lesions, or prevented them from growing any further for more than 24 weeks.

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

Key results are tabulated below.

In the metastatic BCC cohort, tumour response was assessed according to the Response Evaluation Criteria in Solid tumours (RECIST) version 1.0.

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

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

In the locally advanced BCC cohort, tumour response evaluation included measurement of the externally assessable tumour (including scar), assessment for ulceration in photographs, radiographic assessment of target lesions (if appropriate), and tumour biopsy.

Disease progression was defined as any of the following:

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

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

• ≥ 30% reduction in lesion size [sum of the longest diameter (SLD)] from baseline in target lesions by radiographic assessment
• ≥ 30% reduction in SLD from baseline in the 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 sampling tumour biopsy.

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

• One hundred four patients with measurable advanced BCC received oral vismodegib 150 mg once daily until disease progression or intolerable toxicity.
• At data cutoff (39 months after completion of accrual), 8 patients were receiving the study drug.
• 69 patients (66%) remained in survival follow-up.
• Median duration (range) of treatment with vismodegib was 12.9 (0.7–47.8) months (13.3 [0.7–39.1] months in the metastatic BCC (mBCC) cohort and 12.7 [1.1–47.8] months in the locally advanced (la)BCC cohort).
• Investigator-assessed overall response rate (ORR) which was the primary endpoint was 48.5% in the mBCC group (all partial responses) and 60.3% in the laBCC group (20 patients had a complete response and 18 patients had a partial response).
• 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 of treatment-related adverse events (TEAEs) 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 frequent being weight decrease (8.7%), followed by muscle spasms (5.8%). Other grade ≥ 3 adverse events including fatigue, decreased appetite, diarrhoea, and SCC, occurred in < 5% of patients.
• This long-term study of vismodegib involving 39 months of observation after the completion of patient accrual in the ERIVANCE BCC trial reinforces the clinical usefulness 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 study (STEVIE)-post approval study

• This study assessed safety and efficacy of vismodegib—a first-in-class Hedgehog pathway inhibitor demonstrating clinical benefit in advanced basal cell carcinoma (BCC)—in a patient population representative of clinical practice.
• In this multicentre, open-label trial, adult patients with histologically confirmed laBCC or mBCC were recruited from regional referral centres or specialist clinics.
• Patients received oral vismodegib 150 mg/d until progressive disease, unacceptable toxicity, or withdrawal.
• The primary objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with assessments on day 1 of each treatment cycle (28 days) by principal investigator and coinvestigators at the site.
• Efficacy variables were assessed as secondary endpoints.

Safety

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

Efficacy

• Patients with histologically confirmed BCC who received at least one dose of study drug were included in the efficacy analysis.
• Median follow-up was 17.9 months, and 1161 patients in the efficacy-evaluable population had histologically confirmed measurable disease.
• Overall response rates (investigator-assessed) in patients with histologically confirmed measurable baseline disease were 68.5% (95% confidence interval (CI) 65.7–71.3) in patients with laBCC and 36.9% (95% CI 26.6–48.1) in patients with mBCC.
• Response rates in patients with Gorlin syndrome (basal cell naevus 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 and mBCC, respectively.

The primary analysis of STEVIE demonstrated that:

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

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