Vismodegib (2) – Erivedge®

• Clinical trials
  • For the follow-up assessment of vismodegib, the pharmaceutical manufacturer submitted the up-to-date data sets from the interventional Phase II trials ERIVANCE (SHH4476g; 30-month update dated 30 May 2013) and STEVIE (MO25616; data cut-off involving 500 patients dated 6 November 2013).
  • In addition, the single-arm, open-label Phase II trial US-EAP (SHH4811g) and the Phase I trial SHH3925g, which were submitted in the first dossier, are included once again.

a) Adult patients with symptomatic metastatic basal cell carcinoma

• For adult patients with symptomatic metastatic basal cell carcinoma, additional benefit is not proven compared to the appropriate comparator therapy.
• The four intervention studies are not suitable for demonstrating additional benefit in the patient population of ‘patients with symptomatic metastatic basal cell carcinoma’, as the inclusion criteria do not correspond to this target population.
• According to the SmPC, vismodegib has marketing authorisation for the treatment of symptomatic metastatic basal cell carcinoma (BCC). According to the studies’ inclusion criteria, only patients with histologically confirmed metastatic basal cell carcinoma were studied, without taking symptoms into account.
• The dossier presented data on all patients with metastatic basal cell carcinoma; however, the pharmaceutical manufacturer once again did not present a separate analysis of patients with symptomatic metastasis in the current dossier, due to the unclear distinction between patients with symptomatic metastatic BCC and those with asymptomatic metastatic BCC.
• Consequently, there are no usable data available to derive an additional benefit for this patient population.

b) Adult patients with locally advanced basal cell carcinoma for whom neither surgery nor radiotherapy is suitable

• Mortality – overall survival
  • In the ERIVANCE trial, ‘overall survival’ was assessed as a secondary endpoint. The number of deaths at the time of the final confirmatory analysis was nine patients (12.7 per cent) and rose to 16 (22.5 per cent) by the latest data cut-off (30-month update, May 2015). The median overall survival had not yet been reached.
  • To assess the extent of this effect, the pharmaceutical manufacturer carried out an historical control with best supportive care based on case reports. The effect of best supportive care on overall survival is defined as unknown, as the pharmaceutical manufacturer was unable to identify any observational data for quantification.
  • On the basis of the available data, it is therefore not possible to draw any conclusions regarding the extent of the additional benefit for the endpoint of overall survival compared with the appropriate comparator therapy (best supportive care).
• Morbidity – Objective response rate
  • The objective response rate is a composite endpoint comprising the following morbidity parameters: Assessment of clinical response, comprising external tumour size, degree of ulceration (in patients who presented with ulceration at baseline) and the occurrence of new lesions, and was additionally assessed using imaging procedures in accordance with RECIST criteria (RECIST 1.0) for lesions that could be visualised in this way.
  • At the time of the final confirmatory data cut-off, at patient level, 27 of the 63 laBCCin the efficacy-evaluable population, 27 laBCC patients were classified as responders at the patient level, and 44 out of 116 lesions were classified as responders at the lesion level by the IRF assessment.
  • Of the 27 responders, 22 out of 63 laBCC patients (35%) showed a clinical response. In five of the 27 laBCC patients classified as responders by the IRF, the response was confirmed on the basis of radiographic criteria.
  • Among the 22 laBCC patients with a clinical response, ten patients had an IRF-assessed partial tumour response (PR) and twelve patients had an IRF-assessed complete tumour response (CR).
  • In the indication of locally advanced basal cell carcinoma, a special case arises in that, due to the good external visibility of the tumour lesions and ulcerations—which in some cases manifest as clearly visible disfigurements and may also be accompanied by an olfactory component— the endpoint ‘objective response rate’ (ORR) is considered a patient-relevant endpoint, provided that appropriate operationalisation demonstrates that tumour size and tumour ulcerations are reduced to a relevant extent.
  • The analysis made possible by presenting the individual components of the ORR showed results in the form of a significant reduction in tumours and tumour ulcerations due to a clinical response in 22 out of 63 laBCC patients (35 %) – including complete remission in four patients (6 %) – which are to be regarded as clinically relevant.
  • To assess the extent of the effect of treatment with vismodegib, the pharmaceutical manufacturer carried out a historical control. The efficacy of best supportive care in terms of complete or partial response was deemed to be non-existent due to a lack of reports in the literature and, in the view of clinical experts, the absence of spontaneous remissions; it was therefore concluded that there was an increase in objective response with vismodegib treatment compared with the appropriate comparator therapy.
  • A rate of spontaneous remissions comparable to that observed in the finalconfirmatory data cut-off of the ERIVANCE study—where complete remission was observed in four out of 63 laBCC patients (6 %) from the group of 22 patients with a clinical response—is not proven in the literature.
• quality of life
  • The generic SF-36 questionnaire was used in the ERIVANCE study to assess health-related quality of life.
  • Data on general quality of life using the SF-36 were collected and presented at the final confirmatory data cut-off and at the 6- and 12-month updates, with changes in scores from baseline reported in each case.
  • To assess the extent of the additional benefit, the pharmaceutical manufacturer carried out a historical control with best supportive care based on case reports. The effect of best supportive care on health-related quality of life is defined by the pharmaceutical manufacturer as unknown, as no observational data could be identified for quantification.
  • On the basis of the available data on quality of life, it is therefore not possible to draw any conclusions regarding the additional benefit of vismodegib compared with the appropriate comparator therapy.
• Side effects
  • The positive effects of vismodegib are offset by adverse events.
  • In the ERIVANCE trial, all patients experienced at least one adverse event. Serious adverse events occurred in 26.8% of patients at the time of the final confirmatory data cut-off. 15.5% of patients discontinued treatment with vismodegib due to adverse events at this point.
  • At the 30-month update, the proportion of patients experiencing serious adverse events had risen to 39.4%. At the same time, the treatment discontinuation rate due to adverse events rose to 25.4%.
  • Adverse events of CTCAE grade 3 or higher occurred in 46.5% of patients at the time of the final confirmatory data cut-off. 28.2% of patients were affected by a CTCAE grade 3 event, 9.9% by a CTCAE grade 4 event and 8.5% by a CTCAE grade 5 event.
  • By the 30-month update, the proportion of patients had risen to 60.6% for the overall analysis of adverse events of Grade 3 and above. At this point, the proportion of CTCAE Grade 3 patients was 35.2 per cent, the proportion of CTCAE Grade 4 patients was 15.5 per cent, and the proportion of CTCAE Grade 5 patients was 9.9 per cent.
  • The most common adverse event of CTCAE grade 3 or higher was weight loss.
  • At the time of the final confirmatory data cut-off, the most common adverse events were muscle spasms (70.4%), hair loss (66.2%) and taste disturbances (45.1%).
  • Neoplasms were observed in 22.5% of patients; 12.7% of patients with locally advanced basal cell carcinoma had squamous cell carcinoma.

Courtesy translation only, please refer to the German original.