Osimertinib (5) – Tagrisso®

a) Adults with stage IB–IIIA non-small cell lung cancer (NSCLC) with an exon 19 deletion or an exon 21 substitution (L858R) of the epidermal growth factor receptor (Epidermal Growth Factor Receptor, EGFR) for adjuvant treatment following complete tumour resection, who are suitable for adjuvant platinum-based chemotherapy

• The additional benefit is not proven.
• No data are available to enable an assessment of the additional benefit. In its dossier, the pharmaceutical manufacturer does not take patient population a) into account and, accordingly, does not provide any data for the assessment of the additional benefit.

b) adults with stage IB–IIIA NSCLC with an exon 19 deletion or exon 21 substitution (L858R) of the epidermal growth factor receptor (Epidermal Growth Factor Receptor, EGFR) for adjuvant treatment following complete tumour resection after prior adjuvant platinum-based chemotherapy, or who are unsuitable for such treatment

• mortality
  • In the ADAURA trial, overall survival was defined as the time from randomisation to death from any cause or the end of the trial.
  • For the endpoint of overall survival, a statistically significant advantage was observed in favour of osimertinib compared with watchful waiting.
  • The median survival time had not been reached in either treatment group at the time of the current data cut-off (final analysis of overall survival), which must be considered in the context of the early stage of treatment in the course of the disease.
  • When interpreting the effect, it should be borne in mind that, for a significant proportion of patients with recurrence in the control arm of the ADAURA study, it is likely that follow-up treatment with an EGFR tyrosine kinase inhibitor was inadequate.
  • Given the magnitude of the effect, the advantage of osimertinib in terms of the overall survival endpoint is not in doubt; however, its extent is non-quantifiable.
• Morbidity – Recurrences
  • These endpoints are represented by the recurrence rate and disease-free survival, and include the events of local/regional recurrence, distant recurrence including CNS recurrences, and death from any cause.
  • The recurrence rate is defined as the proportion of patients who, following complete tumour resection, experience a recurrence or die by the current data cut-off date.
  • Disease-free survival is defined as the time from randomisation to disease recurrence or death (from any cause in the absence of recurrence).
  • For both endpoints (recurrence rates and disease-free survival), there is a statistically significant advantage in favour of osimertinib, whose extent is assessed as a very large improvement.
• Side effects
  • Serious AEs (SAEs)
  • For the SAE endpoint, there was no statistically significant difference between the treatment arms.
  • Severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs
  • For the endpoints of severe AEs and discontinuation due to AEs, a statistically significant difference was observed in each case to the disadvantage of osimertinib compared with watchful waiting.
  • Skin and subcutaneous tissue disorders (SOC, AEs)
  • For the endpoint ‘skin and subcutaneous tissue disorders’ (SOC, AEs), there was a statistically significant difference in favor of osimertinib compared with watchful waiting that is associated with a disadvantage.
  • ILD and pneumonitis (PTs, SUEs) and cardiac events (severe AEs)
  • For the endpoints interstitial lung disease (ILD) and pneumonitis (PTs, SUEs) and cardiac events (severe AEs), no statistically significant difference was observed between the treatment arms.
  • Other specific AEs
  • For the specific AEs gastrointestinal disorders (SOC, AEs, including: diarrhoea [PT, AEs], mouth ulceration [PT, AEs], stomatitis [PT, AEs]), paronychia (PT, AEs), decreased appetite (PT, AEs), gastrointestinal disorders (SOC, severe AEs) and investigations (SOC, severe AEs), a statistically significant difference was observed in each case, to the disadvantage of osimertinib compared with a ‘wait-and-see’ approach.
  • In summary, based on several adverse effects in the form of severe AEs (CTCAE grade ≥ 3), therapy discontinuations due to AEs, and, in detail, specific AEs, a disadvantage for treatment with osimertinib can be identified.
• Overall assessment / Conclusion
  • For the benefit assessment of osimertinib as monotherapy for adjuvant treatment following complete tumour resection in adult patients with stage IB–IIIA non-small cell lung cancer (NSCLC), whose tumours harbour mutations in the epidermal growth factor receptor (Epidermal Growth Factor Receptor, EGFR) in the form of an exon 19 deletion or an exon 21 substitution mutation (L858R). The results of the ADAURA study on the endpoint categories of mortality, morbidity, health-related quality of life and side effects compared with watchful waiting.
  • For the endpoint of overall survival, there is a statistically significant advantage in favour of osimertinib compared with a watch-and-wait approach. The median survival time had not yet been reached in either treatment group at the time of the current data cut-off (final analysis of overall survival), which must be considered in the context of the early stage of treatment in the disease course. When interpreting the effect, it should be borne in mind that, for a significant proportion of patients with recurrence in the control arm of the ADAURA study, it is likely that follow-up treatment with an EGFR tyrosine kinase inhibitor was inadequate. Given the magnitude of the effect, the advantage of osimertinib in terms of the overall survival endpoint is not called into question; however, its extent is non-quantifiable.
  • Preventing recurrence is an essential therapeutic goal in the present curative treatment setting. For both endpoints – recurrence rate and disease-free survival – there is a statistically significant advantage in favour of osimertinib, which is regarded as a very large improvement.
  • For the health-related quality of life endpoints, there were no statistically significant differences between the treatment arms.
  • With regard to side effects, there was no statistically significant difference between the study arms for the endpoint of serious AEs. For the endpoints of severe AEs (CTCAE grade ≥ 3), therapy discontinuations due to AEs, and, in detail, specific AEs, there were negative effects of osimertinib compared with watchful waiting; consequently, a net disadvantage for treatment with osimertinib is observed.
  • On balance, the positive effects observed for the endpoints of recurrence and overall survival are offset by the negative effects observed for the endpoints relating to side effects. The disadvantage regarding side effects is weighed against the aim of curative treatment and does not call into question the extent of the improvement in the overall assessment.

Courtesy translation only, please refer to the German original.