Cemiplimab (3) – Libtayo®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer has submitted the results of the single-arm, open-label, multicentre Phase II trial R2810-ONC-1620 in the dossier.

a) Adults with locally advanced basal cell carcinoma (laBCC) who have previously been treated with a Hedgehog inhibitor and who, during this treatment, have shown disease progression or intolerance to it.

• Hint for a minor additional benefit
• Consequently, taking into account the opinions of medical experts and the current treatment situation for patients with laBCC, the G-BA has determined that cemiplimab offers a patient-relevant advantage in terms of tumour response.
• The extent of the additional benefit of cemiplimab compared with the appropriate comparator therapy, best supportive care, is assessed as minor overall for patients with laBCC.
• mortality
  • The endpoint of overall survival was assessed as a secondary endpoint in the R2810-ONC-1620 study and defined as the time from the start of treatment to death from any cause.
  • Overall, based on the results of the R2810-ONC-1620 study regarding the endpoint of overall survival, no conclusion can be drawn regarding the extent of the additional benefit for the endpoint category of mortality, as no comparative data are available.
  • The overall survival endpoint is presented for supplementary information.
• Morbidity – Objective Response Rate / Clinical Response
  • The objective response rate (ORR) endpoint was assessed as the primary endpoint in the R2810-ONC-1620 study and operationalised as a composite response, incorporating both clinical and radiological response.
  • With regard to the composite response, a response was observed in 28.6% of patients with laBCC and in 21.4% of patients with mBCC.
  • A clinical response was observed in 30% of patients with laBCC.
  • Of the patients with larger lesions (category 1), 23% responded, whilst 44% of those with smaller lesions (category 2) responded to treatment with cemiplimab.
  • In 9 of the patients who responded to treatment with cemiplimab, there was a 100% complete remission of the lesions and resolution of ulcerations (11%).
  • The remaining 15 patients showed a partial remission of grade 2 or 3.
  • In patients with a clinical response in Category 1 (lesion size > 50 mm), the lesion size was reduced by an average of approximately 39 per cent, and in patients with a clinical response in category 2 (lesion size ≤ 50 mm), by an average of approximately 65 per cent.
  • 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 objective response rate (ORR) is regarded as 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 24 out of 81 patients with laBCC (30 %) – including complete remission in 9 patients (11 %) – which are to be regarded as clinically relevant.
  • It can therefore be concluded from the present results that treatment with cemiplimab leads to an increase in clinical response compared with best supportive care in patients with laBCC.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) was defined as the time interval between the start of treatment and the onset of a recurrence or disease progression (photographic or radiological) or the time of death from any cause.
  • As the progression-free survival endpoint comprises various sub-endpoints of differing relevance and severity, its clinical relevance to patients cannot be clearly assessed; consequently, no overall conclusion can be drawn regarding its additional benefit.
  • Notwithstanding this, based on the results of the R2810-ONC-1620 study regarding the progression-free survival endpoint, no conclusion can be drawn regarding the extent of the additional benefit for the mortality endpoint category, as no comparative data are available.
  • The endpoint ‘progression-free survival’ is presented for supplementary information.
• Health-related quality of life
  • Health-related quality of life was assessed in the R2810-ONC-1620 study using the global health status and functional scales of the EORTC QLQ-C30 questionnaire, as well as the SKINDEX-16 questionnaire.
  • The results on health-related quality of life cannot be assessed, as no comparative data are available.
• Side effects
  • Total adverse events (AEs)
  • Adverse events (AEs) occurred in almost all study participants.
  • Serious adverse events (SAEs), severe AEs (CTCAE grade ≥ 3), therapy discontinuations due to AEs and AEs of special interest
  • No comparative data are available for serious adverse events (SAEs), severe AEs (CTCAE grade ≥ 3), therapy discontinuations due to AEs and AEs of particular interest.
  • Overall, based on the results of the R2810-ONC-1620 study on adverse events, no conclusion can be drawn regarding the extent of the additional benefit for the endpoint category ‘adverse events’, as no comparative data are available.
  • The results for the ‘side effects’ endpoint category are presented for supplementary information only.
• Overall assessment
  • In the morbidity endpoint category, a good clinical response was demonstrated for patients with locally advanced basal cell carcinoma (laBCC) for the clinical response component of the composite endpoint objective response rate (ORR).
  • As it can be assumed with sufficient certainty that no relevant effects in terms of clinical response can be achieved with the comparator therapy, Best Supportive Care, a clinical response of this considerable extent is considered clinically relevant for this indication and can be used with sufficient certainty for the benefit assessment.
  • The positive effect on clinical response is offset by adverse events associated with cemiplimab.
  • On balance, therefore, a difference relevant to the benefit assessment—or evaluable data—is available only for clinical response.
  • The results on clinical response allow conclusions to be drawn only for patients with laBCC; for patients with metastatic basal cell carcinoma (mBCC), there are no evaluable data available overall.

b) Adults with metastatic basal cell carcinoma (mBCC) who have previously been treated with a Hedgehog inhibitor and who, during this treatment, have shown disease progression or intolerance to it.

• An additional benefit is not proven.
• For patients with mBCC, there are no data suitable for deriving additional benefit; consequently, it is concluded for these patients that additional benefit is not proven.
• mortality
  • The endpoint of overall survival was assessed as a secondary endpoint in the R2810-ONC-1620 study and defined as the time from the start of treatment to death from any cause.
  • Overall, based on the results of the R2810-ONC-1620 study regarding the endpoint of overall survival, no conclusion can be drawn regarding the extent of the additional benefit for the endpoint category of mortality, as no comparative data are available.
  • The overall survival endpoint is presented for supplementary information.
• Morbidity – Objective Response Rate / Clinical Response
  • The objective response rate (ORR) endpoint was assessed as the primary endpoint in the R2810-ONC-1620 study and operationalised as a composite response, incorporating both clinical and radiological responses.
  • With regard to the composite response, a response was observed in 28.6% of patients with laBCC and in 21.4% of patients with mBCC.
  • For patients with mBCC, the presence of distant metastases means that considering clinical response alone is not sufficient; in order to assess the overall tumour behaviour, radiological response must also be evaluated.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) was defined as the time span between the start of treatment and the onset of a recurrence or disease progression (photographic or radiological) or the time of death from any cause.
  • As the endpoint ‘progression-free survival’ comprises various endpoint categories of differing relevance and severity, its clinical relevance to patients cannot be clearly assessed; consequently, no overall conclusion can be drawn regarding additional benefit.
  • Notwithstanding this, based on the results of the R2810-ONC-1620 study regarding the progression-free survival endpoint, no conclusion can be drawn regarding the extent of the additional benefit for the mortality endpoint category, as no comparative data are available.
  • The endpoint ‘progression-free survival’ is presented for supplementary information.
• Morbidity – Symptoms
  • The results regarding symptoms cannot be assessed, as no comparative data are available.
• Health-related quality of life
  • The results regarding health-related quality of life cannot be assessed, as no comparative data are available.
• Side effects
  • Total adverse events (AEs)
  • Adverse events (AEs) occurred in almost all study participants.
  • Serious adverse events (SAEs), severe AEs (CTCAE grade ≥ 3), therapy discontinuations due to AEs and AEs of special interest
  • No comparative data are available for serious adverse events (SAEs), severe AEs (CTCAE grade ≥ 3), therapy discontinuations due to AEs and AEs of particular interest.
  • Overall, based on the results of the R2810-ONC-1620 study on adverse events, no conclusion can be drawn regarding the extent of the additional benefit for the endpoint category ‘adverse events’, as no comparative data are available.
  • The results for the ‘side effects’ endpoint category are presented for supplementary information only.
• Overall assessment
  • Overall, no evaluable data are available for patients with metastatic basal cell carcinoma (mBCC).

Courtesy translation only, please refer to the German original.