Ceritinib (1) – Zykadia®

• Clinical trials
  • The marketing authorisation for ceritinib for this therapeutic indication, which was granted by the European Medicines Agency (EMA) subject to specific conditions, was based on two single-arm studies: the Phase I study X2101 and the Phase II study A2201.
  • A Phase III trial (trial A2303) is currently underway to directly compare ceritinib with chemotherapy using docetaxel or pemetrexed for the therapeutic indication.

Patients for whom treatment with docetaxel or pemetrexed is an option

• For patients for whom treatment with docetaxel or pemetrexed is an option, an additional benefit is not proven.
• In summary, it is concluded that the data submitted are not suitable for assessing the additional benefit of ceritinib compared with the appropriate comparator therapy. The additional benefit of ceritinib compared with the appropriate comparator therapy is therefore not proven.
• mortality
  • In the dossier, the pharmaceutical manufacturer cites, for ceritinib, the results for ALK-positive patients previously treated with crizotinib from the A2201 and X2101 studies (patient population) and, for the appropriate comparator therapy, the analysis by Ou et al. 2014.
  • The data from the analysis by Ou et al. 2014 are not considered suitable for demonstrating an additional benefit of ceritinib over the appropriate comparator therapy, particularly as the subsequent systemic therapy is not specified in detail and it is therefore unclear whether this even represents the appropriate comparator therapy (docetaxel or pemetrexed).
  • no information is available on the patient characteristics of this group from the analysis by Ou et al. 2014, which is why the comparability of the groups compared in the historical control cannot be assessed.
  • The subsequent treatment of patients following progression whilst on crizotinib was not randomised, and the considerations underlying the therapeutic decision regarding continuation of treatment with crizotinib, further systemic therapy or best supportive care are unclear.
  • It cannot be ruled out – as also discussed by the authors of the analysis by Ou et al. – that the observed differences in post-progression survival in this analysis were significantly influenced by prognostic factors.
  • Furthermore, the difference resulting from the historical control when comparing the overall survival results does not appear to be so great that it could not be attributed solely to the bias arising from the historical control.
• Morbidity – symptoms and health-related quality of life
  • For this comparison, the pharmaceutical manufacturer has, in the dossier, compared the results for crizotinib-pretreated patients from the ceritinib trial A2201 with the results for crizotinib-naïve patients from the chemotherapy arm of the PROFILE 1007 trial.
  • This comparison does not allow for an assessment of the additional benefit of ceritinib, particularly as the results from crizotinib-naïve patients are used, whereas prior treatment with crizotinib is a prerequisite according to ceritinib’s authorised therapeutic indication and constitutes a key feature of the present assessment.
  • Even disregarding this aspect, no advantages of ceritinib over the appropriate comparator therapy could be inferred from the historical control presented regarding symptoms and health-related quality of life.
• Side effects
  • For the comparison of adverse events, the pharmaceutical manufacturer has provided data from the ceritinib studies A2201, X2101 (overall population) for ceritinib, and data from the chemotherapy arm of the PROFILE 1007 trial (docetaxel or pemetrexed) for the appropriate comparator therapy.
  • The patients in the chemotherapy arm of the PROFILE 1007 study were ALK-positive, crizotinib-naïve patients; consequently, the potential effects of prior crizotinib treatment have not been taken into account.
  • In this regard, differences in disease progression and patient morbidity must also be taken into account, solely in relation to the timing of treatment with docetaxel or pemetrexed within the treatment sequence.
  • There is insufficient proof to support the assumption that the aforementioned factors have no significant influence on the nature and extent of adverse events under docetaxel or pemetrexed.
  • This historical control is therefore not suitable for assessing the adverse events associated with ceritinib compared with the appropriate comparator therapy (docetaxel or pemetrexed).
  • Furthermore, it should be noted that high rates of serious adverse events (SAEs) and severe adverse events (CTCAE grade ≥ 3) were observed in the ceritinib studies A2201 and X2101.

Patients for whom treatment with docetaxel or pemetrexed is not an option

• For patients for whom treatment with docetaxel or pemetrexed is not an option, additional benefit is not proven.
• For the group of patients for whom treatment with docetaxel or pemetrexed is not an option, no relevant data have been presented to assess the additional benefit of ceritinib compared with the appropriate comparator therapy (best supportive care).

Courtesy translation only, please refer to the German original.