Alectinib (2) – Alecensa®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer cites in the dossier the results of the ongoing randomised, open-label, controlled Phase III trial ALEX, in which alectinib is compared with the appropriate comparator therapy, crizotinib.

a) Alecensa is used as monotherapy for the first-line treatment of anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC) in adult patients.

• Hint for a non-quantifiable additional benefit
• In summary, due to the uncertainty described at the endpoint level regarding the certainty of the findings (probability of additional benefit), at most a hint of the observed additional benefit can be derived.
• mortality
  • For the endpoint of overall survival, there was no statistically significant difference between the treatment arms (hazard ratio = 0.76 [0.48; 1.20], p-value = 0.241).
  • The median survival time had not been reached in either study arm.
  • An additional benefit of alectinib over crizotinib in terms of overall survival is therefore not proven.
• Morbidity – Progression-free survival (PFS)
  • A statistically significant difference in favour of alectinib was observed for progression-free survival (PFS) (hazard ratio = 0.50 [0.36; 0.70], p-value < 0.0001).
  • The median PFS was 25.7 months for patients in the alectinib arm and 10.4 months for patients in the crizotinib arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint for patients.
• quality of life
  • The functional scales of the EORTC-QLQ-C30 questionnaire were used to assess health-related quality of life.
  • For both analyses, no statistically significant differences were observed between the treatment arms.
  • An additional benefit of alectinib compared with crizotinib is therefore not proven for the quality of life endpoint category.
• Side effects
  • Adverse events (AEs) occurred at least once in almost every patient in both study arms.
  • For the endpoints ‘serious adverse events (SAEs)’, ‘severe AEs (CTCAE grade ≥ 3)’ and ‘therapy discontinuation due to AEs’, there are no statistically significant differences between the treatment arms.
  • Statistically significant differences between alectinib and crizotinib were observed for certain specific adverse events: for the endpoints ‘gastrointestinal disorders’, ‘eye diseases’, ‘benign, malignant and unspecified neoplasms (including cysts and polyps)’ and ‘nervous system disorders’, an advantage of alectinib over crizotinib was observed.
  • Furthermore, alectinib shows an advantage over crizotinib for the endpoint ‘torsade de pointes/QT prolongation’.
  • Statistically significant disadvantages of alectinib compared with crizotinib are evident for the specific adverse events “disorders of the kidneys and urinary tract” and “myalgia”.
  • Overall, for the endpoint category of side effects, statistically significant differences between the study arms are therefore found exclusively in the specific adverse events, which demonstrate both advantages and disadvantages of alectinib compared with crizotinib.
• Overall assessment
  • For the assessment of the additional benefit of alectinib as first-line treatment for anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC) NSCLC) in adult patients, the ALEX trial provides results on mortality (overall survival), morbidity, health-related quality of life and side effects compared with crizotinib.
  • An additional benefit of treatment with alectinib is not proven for overall survival, as no statistically significant difference was observed between the treatment arms.
  • For the patient population examined here, ‘time to CNS progression’ represents a patient-relevant endpoint. A statistically significant positive effect of alectinib compared with crizotinib was observed for the endpoint ‘time to CNS progression’. However, in view of the methodological uncertainties outlined and the limitations in assessing the immediate significance of the observed effect, the extent of the advantage cannot be quantified for the overall assessment of the additional benefit.
  • With regard to health status, as measured using the EQ-5D VAS, there is no statistically significant difference between alectinib and crizotinib.
  • With regard to side effects, there is neither an advantage nor a disadvantage for alectinib in terms of the endpoints ‘serious adverse events (SAE)’, ‘severe adverse events (CTCAE grade ≥ 3)’ and ‘therapy discontinuation due to AEs’. There are statistically significant advantages as well as disadvantages of alectinib compared with crizotinib for specific adverse events.
  • Overall, the determination of additional benefit is based on the endpoint ‘time to CNS progression’, which also takes into account the patients’ clinical and neurological symptoms in accordance with the RANO criteria. The G-BA classifies the extent of the additional benefit of alectinib, based on the criteria in Section 5(7) of the AM-NutzenV, as non-quantifiable for the endpoint ‘time to CNS progression’ due to the uncertainties described in the scientific evidence base.

Courtesy translation only, please refer to the German original.