Osimertinib (4) – Tagrisso®

• Clinical trials
  • The study included adult patients with stage IB–IIIA NSCLC (UICC classification, 7th edition) following complete tumour resection, whose tumours exhibited EGFR mutations in the form of a deletion in exon 19 or a substitution mutation in exon 21 (L858R).

a) Adults with stage IB–IIIA non-small cell lung cancer (NSCLC) with an exon 19 deletion or an exon 21 substitution (L858R) in 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 pharmaceutical manufacturer has not submitted any data to demonstrate additional benefit.
• Consequently, additional benefit is not proven.

b) Adults with stage IB–IIIA non-small cell lung cancer (NSCLC) with an exon 19 deletion or an exon 21 substitution (L858R) in 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 not suitable for such treatment.

• mortality
  • In the ADAURA trial, overall survival was defined as the time from randomisation to death from any cause.
  • No statistically significant difference was observed between the study arms for the endpoint of overall survival.
  • Overall, the number of events was minor.
• Morbidity – Recurrences
  • These endpoints are represented by the recurrence rate and disease-free survival, and comprise 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.
  • For both endpoints (recurrence rates and disease-free survival), there is a statistically significant advantage in favour of osimertinib.
  • The extent of the effect is an indication of a clinically significant improvement compared with ‘watchful waiting’.
  • The median follow-up period achieved (22.5 months in the intervention arm, 18.7 months in the control arm) is not considered by the G-BA to be sufficiently long to adequately reflect the high-risk period for the occurrence of a recurrence following the primary diagnosis.
• Health-related quality of life – SF-36v2 – physical and mental total scores
  • Quality of life was assessed using the SF-36v2.
  • For the physical total score of the SF-36v2, the responder analysis over the period up to confirmed deterioration revealed a statistically significant disadvantage compared with ‘watchful waiting’ for osimertinib.
  • For the mental health summary score of the SF-36v2, based on the responder analysis over the time to confirmed deterioration, there was no statistically significant difference between the study arms.
  • Overall, the results indicate that osimertinib is associated with a disadvantage compared with ‘watchful waiting’ in terms of health-related quality of life.
• Side effects
  • In its dossier, the pharmaceutical manufacturer presents analyses of the endpoints relating to side effects from the time of the first dose of the study treatment up to 28 days after the last dose.
  • Total adverse events (AEs): In the ADAURA trial, AEs occurred in almost all patients enrolled in both study arms.
  • Serious AEs (SAEs): For the SAE endpoint, there was no statistically significant difference between the study arms.
  • Severe AEs (CTCAE grade ≥ 3), therapy discontinuations due to AEs: For the endpoints ‘severe AEs’ and ‘therapy discontinuation due to AEs’, a statistically significant disadvantage was observed in each case compared with ‘watchful waiting’ for osimertinib.
  • Skin and subcutaneous tissue disorders (AEs): For the endpoint ‘skin and subcutaneous tissue disorders’ (AEs), there was a statistically significant disadvantage for osimertinib compared with ‘watchful waiting’.
  • For the specific AEs involving the gastrointestinal tract (AEs) (including the AEs diarrhoea, mouth ulceration and stomatitis), gastrointestinal disorders (severe AEs), paronychia (AE) and loss of appetite (AE), a statistically significant difference in favor of osimertinib was observed in each case compared with ‘watchful waiting’.
• 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 a deletion in exon 19 or a substitution mutation in exon 21 (L858R), results from the ADAURA study are available for the endpoint categories of mortality, morbidity, health-related quality of life and side effects, compared with ‘watchful waiting’.
  • For the endpoint of overall survival, the available results show no statistically significant difference. Overall, the number of events is minor.
  • Preventing recurrence is an essential treatment goal in this curative treatment setting. For the two endpoints ‘recurrence rate’ and ‘disease-free survival’, a statistically significant advantage in favour of osimertinib is evident. The extent of the effect indicates a clinically significant improvement compared with ‘watchful waiting’. However, the results for this endpoint are not considered sufficient to reliably quantify the extent of the improvement, particularly in light of the uncertainties described regarding the ADAURA trial and given the median follow-up period (22.5 months in the intervention arm, 18.7 months in the control arm), are not considered sufficient to allow for a reliable quantification of the extent of the improvement.
  • With regard to health-related quality of life assessed using the SF-36v2, there is a statistically major difference to the disadvantage of osimertinib compared with ‘watchful waiting’ for the physical total score and no statistically significant difference was found between the study arms for the mental health total score. Thus, when the results regarding health-related quality of life are considered as a whole, osimertinib is at a disadvantage compared with ‘watchful waiting’.
  • 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’.
  • Overall, the positive effect on recurrence is offset by relevant disadvantages in terms of health-related quality of life and side effects. The disadvantages in the categories of side effects and health-related quality of life are weighed against the aim of curative treatment and do not, on the whole, call into question the positive effect on recurrence. The extent of the effect on recurrence indicates a clinically significant improvement compared with ‘watchful waiting’; however, given the uncertainties described, this cannot be quantified with certainty.

Courtesy translation only, please refer to the German original.