Osimertinib (2) – Tagrisso®

• Clinical trials
  • The pharmaceutical manufacturer has submitted the results of the AURA3 study to demonstrate the additional benefit of osimertinib in the treatment of patients who have been pre-treated with an EGFR tyrosine kinase inhibitor (EGFR-TKI) and for whom cytotoxic chemotherapy is an option. (D5160C00003).
  • The AURA3 trial (N=419) is a randomised, open-label Phase III trial comparing osimertinib (N=279) with platinum-based chemotherapy (cisplatin plus pemetrexed or carboplatin plus pemetrexed; N=140).

a) Patients who have previously been treated with an EGFR tyrosine kinase inhibitor and for whom cytotoxic chemotherapy is an option

• For patients who have previously been treated with an EGFR tyrosine kinase inhibitor and for whom cytotoxic chemotherapy is an option, there is a hint of a considerable additional benefit of osimertinib compared with cisplatin plus pemetrexed or carboplatin plus pemetrexed.
• The certainty of the evidence for the defined additional benefit is classified as ‘hint’.
• mortality
  • In the AURA3 trial, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • No statistically significant difference in overall survival was observed between the study arms (hazard ratio (HR): 0.74 [95% confidence interval (CI): 0.50; 1.10]; p-value = 0.130).
  • Median survival has not yet been reached due to the small number of events; the final analyses for the overall survival endpoint are pending.
  • The results for overall survival are potentially highly biased due to the high proportion of patients who switched from the control arm to the intervention arm following confirmed tumour progression (67.1% in the overall population at the second data cut-off).
  • For the endpoint category of mortality, the available results show no additional benefit of osimertinib compared with cisplatin plus pemetrexed or carboplatin plus pemetrexed.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the AURA3 trial and is defined as the time from randomisation to disease progression (determined by the investigator using the RECIST criteria) or death from any cause.
  • PFS is a composite endpoint comprising endpoints from different endpoint categories (mortality and morbidity).
  • This does not affect the overall conclusion regarding the extent of the additional benefit.
• quality of life
  • To assess health-related quality of life, the AURA3 study utilised the functional scales of the disease-specific EORTC QLQ-C30 questionnaire.
  • For the present assessment, the analysis of the mean change in scores at week 24 compared with the start of the study is used.
  • Statistically significant differences in favour of osimertinib were observed for all endpoints.
  • Of these, the effects for the endpoints of global health status, physical functioning, role functioning, cognitive functioning and social functioning can be classified as relevant effects (Hedges’ g confidence interval entirely outside the irrelevance range).
  • For the endpoint ‘emotional functioning’, however, the effect cannot be interpreted as relevant due to the position of the confidence interval for Hedges’ g.
  • For the quality of life endpoint, too, a high potential for bias in the results must be taken into account due to the open-label study design, the change in treatment, and differences in response rates between the treatment arms.
  • In the overall assessment of the results from the EORTC QLQ-C30 functional scales, there are exclusively positive effects of osimertinib compared with cisplatin plus pemetrexed or carboplatin plus pemetrexed in terms of health-related quality of life.
• Side effects – Adverse events (AEs)
  • In AURA3, an adverse event occurred in 97.8% of patients in the intervention arm, compared with 99.3% of patients in the control arm.
  • The results are presented here for supplementary information only.
• Overall assessment
  • The AURA3 study provides results for assessing the additional benefit of osimertinib compared with cisplatin plus pemetrexed or carboplatin plus pemetrexed in terms of mortality (overall survival), morbidity (symptoms and health status), quality of life and side effects.
  • In the mortality endpoint category, the preliminary data for the overall survival endpoint do not allow for a definitive assessment of the effects, as the median overall survival has not yet been reached due to the low number of events.
  • The assessment takes into account that, at the time of analysis, 67% of patients had switched from the control arm to treatment with osimertinib (cross-over), meaning that the result for overall survival is subject to potentially significant bias.
  • Based on the available data, the additional benefit of osimertinib over cisplatin plus pemetrexed or carboplatin plus pemetrexed for overall survival is not proven.
  • The results for the morbidity endpoint category show predominantly positive effects on symptoms following treatment with osimertinib compared with treatment with cisplatin plus pemetrexed or carboplatin plus pemetrexed.
  • Treatment with osimertinib showed an advantage with regard to the patient-reported symptoms of fatigue, nausea and vomiting, dyspnoea, alopecia and pain (chest), whilst a disadvantage was observed for the symptom of diarrhoea.
  • With regard to health-related quality of life, treatment with osimertinib showed exclusively beneficial effects; advantages of osimertinib were observed for the patient-reported endpoints of global health status, physical functioning, role functioning, cognitive functioning and social functioning.
  • However, the available results for the endpoint categories of morbidity and health-related quality of life have minor certainty due to the lack of blinding in the study and the high proportion of patients who switched treatments.
  • Compared with cisplatin plus pemetrexed or carboplatin plus pemetrexed, osimertinib leads to a significant reduction in serious adverse events (SAEs) and severe adverse events (CTCAE grade ≥ 3).
  • Consequently, osimertinib is found to provide a considerable additional benefit has been established compared with cisplatin plus pemetrexed or carboplatin plus pemetrexed.

Courtesy translation only, please refer to the German original.