Osimertinib (6) – Tagrisso®

• Clinical trials
  • The study included adult patients with non-squamous, unresectable stage IIIB, IIIC and IV, whose tumours harboured EGFR mutations in the form of a deletion in exon 19 or a substitution mutation in exon 21 (L858R) and who had not received prior treatment.

Adults with advanced NSCLC whose tumours harbour EGFR mutations in the form of a deletion in exon 19 or a substitution mutation in exon 21 (L858R); first-line treatment

• An additional benefit is not proven
• mortality
  • In the FLAURA-2 trial, overall survival was defined as the time from randomisation to death from any cause.
  • No statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
  • Data from the third data cut-off point indicate a positive effect of osimertinib in combination with pemetrexed and platinum-based chemotherapy compared with osimertinib alone.
• Morbidity – Progression-free survival (PFS)
  • In the FLAURA-2 trial, progression-free survival was defined as the time from randomisation or from the first dose of the trial treatment for the safety run-in period until objective disease progression or death from any cause.
  • For the PFS endpoint, there is a statistically significant advantage for osimertinib in combination with pemetrexed and platinum-based chemotherapy compared with osimertinib alone.
  • The results for the PFS endpoint are not included in this assessment.
• Morbidity – CNS metastases
  • The proportion of patients with CNS metastases in the FLAURA-2 trial was 41%.
• Morbidity – Symptoms (EORTC QLQ-C30, EORTC QLQ-LC13 and PGIS)
  • For the endpoints of pain, dyspnoea, insomnia and diarrhoea, the analyses show no statistically significant difference between the treatment arms in each case. (EORTC QLQ-C30)
  • For the endpoints of fatigue, nausea and vomiting, loss of appetite and constipation, a statistically significant difference was observed; however, the relevance of this difference cannot be confirmed by examining the standardised mean difference. (EORTC QLQ-C30)
  • For the endpoint of cough, a statistically significant difference was observed, but its clinical relevance could not be confirmed by examining the standardised mean difference. However, for patients with CNS metastases at baseline, there was a hint of an advantage from treatment with osimertinib in combination with pemetrexed and platinum-based chemotherapy compared with osimertinib alone. (EORTC QLQ-LC13)
  • For the endpoints of haemoptysis, dysphagia, pain (arm/shoulder), pain (other parts of the body), pain (chest), dyspnoea, peripheral neuropathy and alopecia, the analyses based on the mean difference showed no statistically significant difference between the treatment arms in any case. (EORTC QLQ-LC13)
  • For the endpoint ‘pain (other parts of the body)’, there is an effect modification by the characteristic of age. For patients aged < 65 years, there is a hint of a disadvantage associated with the treatment regimen of osimertinib in combination with pemetrexed and platinum-based chemotherapy compared with osimertinib alone. (EORTC QLQ-LC13)
  • For the endpoint ‘mouth ulcers’, a statistically significant difference is observed, although its clinical relevance cannot be confirmed by examining the standardised mean difference. (EORTC QLQ-LC13)
  • For the endpoints haemoptysis, dysphagia, pain (arm/shoulder), pain (other parts of the body), pain (chest), dyspnoea, peripheral neuropathy and alopecia, the analyses based on the mean difference show no statistically significant difference between the treatment arms in each case. (PGIS)
• Morbidity – Health status (assessed using the EQ-5D VAS)
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • No statistically significant difference was observed between the treatment arms.
• Quality of life – EORTC-QLQ-30
  • For the endpoints of role functioning and emotional functioning, no significant difference was observed between the treatment arms.
  • For the endpoints physical functioning, cognitive functioning, social functioning and overall health status, a statistically significant difference was observed; however, the relevance of this difference cannot be confirmed by examining the standardised mean difference.
  • Overall, the results on health-related quality of life show no advantages of osimertinib in combination with pemetrexed and platinum-based chemotherapy compared with osimertinib as monotherapy.
• Side effects – serious adverse events
  • For the SAE endpoint, a statistically significant disadvantage was observed for osimertinib in combination with pemetrexed and platinum-based chemotherapy in patients aged < 65 years. In patients aged ≥ 65 years, no significant difference was observed between the treatment arms.
• Side effects – Severe adverse events (CTCAE grade ≥ 3)
  • For the endpoint of severe adverse events (CTCAE grade ≥ 3), there was a statistically significant difference in favor of osimertinib + pemetrexed + platinum-based chemotherapy compared with osimertinib alone, which has a disadvantage.
• Side effects – Therapy discontinuation due to adverse events
  • For the endpoint of discontinuation due to adverse events, there was a statistically significant difference in favor of osimertinib in combination with pemetrexed and platinum-based chemotherapy compared with osimertinib alone, which has a disadvantage.
• Overall assessment
  • For the assessment of the additional benefit of osimertinib in combination with pemetrexed and platinum-based chemotherapy for adults with advanced NSCLC whose tumours harbour an EGFR mutation in the form of an exon 19 deletion or an exon 21 substitution, results on mortality, morbidity, health-related quality of life and side effects are available from the randomised, controlled, multicentre FLAURA-2 trial.
  • In a decision based on a balancing of interests, taking into account the positive effect on overall survival observed in the third data cut-off, the G-BA has concluded that for osimertinib in combination with pemetrexed and platinum-based chemotherapy for the treatment of adults with advanced NSCLC whose tumours harbour an EGFR mutation in the form of a deletion in exon 19 or a substitution mutation in exon 21, an additional benefit is not proven compared with monotherapy with osimertinib.

Courtesy translation only, please refer to the German original.