Alectinib (1) – Alecensa®

a) Patients for whom treatment with docetaxel, pemetrexed or ceritinib is an option

• For patients for whom treatment with docetaxel, pemetrexed or ceritinib is an option, there is a hint of a minor additional benefit compared with docetaxel or pemetrexed.
• The G-BA classifies the extent of the additional benefit of alectinib as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• Compared with the appropriate comparator therapy, docetaxel or pemetrexed, there is, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, there is a moderate – and not merely minor – improvement in the therapy-relevant benefit, as a significant reduction in adverse events is achieved.
• mortality
  • For the endpoint of overall survival, there is no statistically significant difference between the treatment groups in the study (hazard ratio: 0.89 [0.35; 2.24], p-value = 0.797). An additional benefit of alectinib compared with docetaxel or pemetrexed chemotherapy is therefore not proven for overall survival.
  • The assessment takes into account that, at the time of the analysis, 68.6% of patients in the chemotherapy treatment group had switched to follow-up treatment with alectinib (‘cross-over’), which means that the result for overall survival is subject to potentially significant bias.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) was statistically significantly longer in patients treated with alectinib. The median PFS for these patients was 7.1 months versus 1.6 months for patients treated with chemotherapy (hazard ratio: 0.32 [0.17; 0.59], p-value = 0.0001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. In this study, the ‘mortality’ component of the endpoint was assessed via the ‘overall survival’ endpoint as a standalone endpoint. The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (in accordance with RECIST 1.1). Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
• quality of life
  • Health-related quality of life was assessed in this study using the five functional scales and the scale for general health status/quality of life from the EORTC-QLQ-C30 questionnaire. The assessment is based on the evaluation of ‘time to deterioration in health-related quality of life’ using responder analyses.
  • No significant difference was observed between the study arms for any health-related quality of life endpoint. An additional benefit of alectinib compared with docetaxel or pemetrexed chemotherapy is therefore not proven for the health-related quality of life endpoint.
• Side effects
  • Overall, adverse events occurred in 77.1% of patients in the alectinib arm and 85.3% of patients in the chemotherapy arm.
  • For serious adverse events (SAEs) and for the endpoint ‘therapy discontinuation due to adverse events’, the survival analysis showed no statistically significant difference between the treatment groups.
  • With regard to the endpoint ‘severe adverse events’, the analysis of time to first occurrence showed a statistically significant advantage of alectinib over chemotherapy (hazard ratio: 0.36 [0.17; 0.76], p-value = 0.005).
  • In the overall assessment of the endpoints relating to adverse events, there is a significant advantage for treatment with alectinib over chemotherapy with docetaxel or pemetrexed, as a reduction in severe adverse events is achieved.
• Overall assessment
  • Data are available from the ALK study to assess the additional benefit of alectinib in the treatment of advanced, anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC) following prior treatment with crizotinib, the ALUR study provides results on mortality (overall survival), morbidity, health-related quality of life and side effects compared with chemotherapy using docetaxel or pemetrexed.
  • An additional benefit for treatment with alectinib in terms of overall survival is not proven. The assessment takes into account that, at the time of the analysis, 68.6% of patients in the chemotherapy group had switched to follow-up treatment with alectinib (‘cross-over’), meaning that the overall survival result is subject to potentially significant bias.
  • With regard to symptoms, there is no statistically significant difference between alectinib and chemotherapy for the majority of endpoints. For individual non-serious/non-severe symptoms or subsequent complications where a statistically significant difference is observed, the positive effects of alectinib predominate.
  • For the endpoint of health-related quality of life, there are no statistically significant differences between the treatment groups; consequently, an additional benefit is not proven for this endpoint.
  • With regard to side effects, alectinib shows a positive effect compared with docetaxel or pemetrexed for the endpoint ‘severe adverse events (CTCAE grade ≥ 3)’. With regard to the endpoints ‘therapy discontinuation due to adverse events’ and ‘serious adverse events (SAE)’, no significant differences were observed between the treatment groups.
  • Overall, a minor additional benefit of alectinib over chemotherapy with docetaxel or pemetrexed is observed for the treatment of advanced, ALK-positive NSCLC in patients previously treated with crizotinib.

b) Patients for whom treatment with docetaxel, pemetrexed or ceritinib is not an option

• For patients for whom treatment with docetaxel, pemetrexed or ceritinib is not an option, an additional benefit is not proven.
• For the group of patients for whom treatment with docetaxel, pemetrexed or ceritinib is not an option, no relevant data were submitted for the assessment of the additional benefit of alectinib compared with the appropriate comparator therapy (best supportive care).

Courtesy translation only, please refer to the German original.