Osimertinib (3) – Tagrisso®

• Clinical trials
  • FLAURA is a multicentre, double-blind, randomised controlled trial comparing osimertinib with erlotinib or gefitinib.

a) Adult patients with locally advanced or metastatic NSCLC harbouring the activating EGFR mutations L858R or del 19

• There is a hint of a considerable additional benefit.
• Consequently, osimertinib is found to provide considerable additional benefit compared with erlotinib and gefitinib for first-line treatment of adult patients with locally advanced or metastatic NSCLC harbouring the activating EGFR mutations L858R or del 19.
• In summary, due to the uncertainties described at the endpoint level regarding the certainty of the findings (probability of additional benefit), at most a hint of the established additional benefit can be inferred.
• mortality
  • In the FLAURA trial, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • For overall survival, a statistically significant advantage for osimertinib was observed between the two treatment arms (hazard ratio (HR): 0.63 [95% confidence interval (CI): 0.45; 0.88]; p-value = 0.006).
  • However, the results for the overall survival endpoint are based on a minor number of deaths; the interpretability is therefore limited.
  • For the mortality endpoint category, the available results indicate an additional benefit of osimertinib compared with gefitinib and erlotinib.
• Morbidity – Progression-free survival (PFS)
  • For progression-free survival (PFS), there is a statistically significant difference in favour of osimertinib (HR = 0.46 [0.37; 0.57], p-value < 0.001). The median PFS in patients in the osimertinib arm was 18.9 months and in patients in the comparator arm 10.2 months, resulting in an absolute difference of 8.7 months.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (according to RECIST 1.1).
• Morbidity – Symptoms
  • In the FLAURA study, the symptom scales from the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires were used to record symptoms.
  • Statistically significant differences in favour of osimertinib were observed for the endpoints of nausea and vomiting, as well as haemoptysis, on the EORTC-QLQ-C30 symptom scale, and for the endpoint of alopecia on the EORTC-QLQ-LC13 symptom scale.
  • However, a statistically significant difference in favour of osimertinib was observed only for the alopecia endpoint on the EORTC-QLQ-LC13, where the confidence interval for Hedges’ g lies entirely outside the irrelevance range, indicating a relevant effect (mean difference = −5.18 [−7.33; −3.03]; p < 0.001 and a Hedges’ g: −0.42 [−0.60; −0.25]).
• Health-related quality of life
  • For the endpoints of cognitive functioning, emotional functioning and social functioning on the EORTC-QLQ-C30 functional scales, statistically significant differences were observed in favour of osimertinib.
  • However, as the corresponding confidence intervals for Hedges’ g do not lie entirely outside the irrelevance range, there is no significant effect.
• Side effects
  • Adverse events (AEs) occurred at least once in almost every patient in both study arms.
  • For the endpoint ‘serious adverse events (SAEs)’, there are no statistically significant differences between the treatment arms.
  • However, there are statistically significant differences between the treatment arms in favour of osimertinib for severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
  • For the endpoint of severe AEs (CTCAE grade ≥ 3), there was a statistically significant effect modification by the characteristic of sex in favour of men, whereas no statistically significant difference between the treatment arms was observed for women.
  • Statistically significant differences in favour of osimertinib compared with the control arm are also evident for certain specific adverse events: For the endpoints ‘elevated alanine aminotransferase (CTCAE grade ≥ 3)’, ‘skin and subcutaneous tissue disorders (CTCAE grade ≥ 3)’ and ‘acneiform dermatitis’.
  • Overall, therefore, in the endpoint category of side effects, there are exclusively statistically significant advantages in favour of osimertinib.
• Overall assessment
  • Compared with erlotinib and gefitinib, osimertinib leads to a significant prolongation of overall survival.
  • Advantages of osimertinib over erlotinib and gefitinib can also be observed in terms of morbidity for the endpoint of alopecia.
  • No relevant differences were observed for the endpoint categories of morbidity and health-related quality of life on any other subscale of the measurement instruments used.
  • Compared with erlotinib and gefitinib, osimertinib leads to a significant reduction in severe AEs (CTCAE grade ≥ 3). Further statistically significant differences in favour of osimertinib were also observed in terms of treatment discontinuations due to AEs, as well as for certain specific AEs (‘elevated alanine aminotransferase (CTCAE grade ≥ 3)’, ‘Skin and subcutaneous tissue disorders (CTCAE grade ≥ 3)’ and ‘acneiform dermatitis’).

b) Adult patients with locally advanced or metastatic NSCLC with EGFR activating mutations other than L858R or del 19 (excluding de novo T790M)

• The additional benefit is not proven.
• In its application dossier, the pharmaceutical manufacturer does not provide any data for this patient group. Therefore, additional benefit is not proven for this patient group.
• As the FLAURA study only included patients with the EGFR mutations L858R or del 19, no data are available for patients with other activating EGFR mutations.

Courtesy translation only, please refer to the German original.