Amivantamab (2) – Rybrevant®

• Clinical trials
  • The MARIPOSA trial is an ongoing, multicentre, partially blinded, randomised, controlled, three-arm Phase III trial comparing amivantamab plus lazertinib (Arm A) with osimertinib (Arm B) and lazertinib (Arm C) as monotherapies.
  • For the purposes of this benefit assessment, the study arms Amivantamab + Lazertinib and Osimertinib are relevant.

Adults with advanced NSCLC and EGFR exon 19 deletions or exon 21 L858R substitution mutations; first-line treatment

• mortality
  • In the MARIPOSA trial, overall survival was defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, the overall population showed a statistically significant survival benefit in favour of amivantamab in combination with lazertinib compared with osimertinib, with the extent of the benefit assessed as a marked improvement.
  • An effect modification was observed for the characteristic ‘age’. In the subgroup analysis, a statistically significant advantage in favour of amivantamab in combination with lazertinib was observed for individuals aged < 65 years. In contrast, no statistically significant advantage was observed for individuals aged ≥ 65 years. These subgroup results are considered a relevant finding of the present benefit assessment. They indicate that older patients benefit less from the treatment. However, they are not considered sufficient to derive separate conclusions regarding additional benefit in the overall assessment. Furthermore, no effect modification is observed for other patient-relevant endpoints.
• Morbidity – Symptoms (EORTC QLQ-C30)
  • Symptoms of the disease were assessed in the MARIPOSA study using the EORTC QLQ-C30 questionnaire. The analysis of event rates presented in the dossier was not suitable for the benefit assessment. The pharmaceutical manufacturer submitted event duration analyses for confirmed deterioration with its response; these form the basis of the present assessment.
  • For the endpoints of diarrhoea and loss of appetite, there are statistically significant advantages in favour of amivantamab in combination with lazertinib.
  • No differences were observed for the other symptoms: fatigue, nausea and vomiting, pain, dyspnoea, constipation and insomnia.
• Health-related quality of life (EORTC QLQ-C30)
  • Disease-related symptoms were assessed in the MARIPOSA study using the EORTC QLQ-C30 questionnaire. The analysis of event rates presented in the dossier was not suitable for the benefit assessment. The pharmaceutical manufacturer submitted event time analyses for confirmed deterioration as part of its response, which form the basis of this assessment.
  • For the endpoints of physical functioning and role functioning, a statistically significant difference was observed in each case to the disadvantage of amivantamab in combination with lazertinib.
  • No differences were observed for the endpoints of global health status, emotional functioning, cognitive functioning and social functioning.
  • For the endpoints of physical functioning and role functioning, the overall picture indicates disadvantages. With regard to health-related quality of life, a disadvantage is therefore inferred for amivantamab in combination with lazertinib.
• Side effects – Total adverse events (AEs)
  • In the MARIPOSA trial, an AE occurred in almost all patients in both the control and intervention arms. The results are presented here for supplementary information only.
• Overall assessment
  • Results from the MARIPOSA study are available for the assessment of the additional benefit of amivantamab in combination with lazertinib as first-line treatment for adult patients with advanced non-small cell lung cancer with EGFR exon 19 deletions or exon-21-L858R substitution mutations, results on mortality, morbidity, health-related quality of life and side effects are available from the MARIPOSA study. In this RCT, amivantamab in combination with lazertinib was compared with osimertinib.
  • The results for the overall survival endpoint show a statistically significant difference, with a clear advantage for amivantamab in combination with lazertinib. An effect modification by the characteristic ‘age’ is evident. In the subgroup analysis, a statistically significant advantage in favour of amivantamab in combination with lazertinib was observed for individuals aged < 65 years. In contrast, no statistically significant advantage was observed for individuals aged ≥ 65 years. These subgroup results are considered a relevant finding in the present benefit assessment. They indicate that older patients benefit less from the treatment. However, they are not considered sufficient to derive separate conclusions regarding additional benefit in the overall assessment. Furthermore, this effect modification is not observed for other patient-relevant endpoints.
  • In the morbidity endpoint category, symptoms (EORTC QLQ-C30, NSCLC-SAQ, PGIS) and health status (EORTC QLQ-C30, EQ-5D VAS) were assessed, with positive effects observed for the endpoints of diarrhoea and loss of appetite. Overall, an advantage is inferred for amivantamab in combination with lazertinib.
  • With regard to health-related quality of life (EORTC QLQ-C30), an overall disadvantage can be observed due to negative effects on the endpoints of physical functioning and role functioning.
  • In terms of side effects, disadvantages for amivantamab in combination with lazertinib are observed for the endpoints SAE, severe AE and therapy discontinuations due to AE, as well as, in detail, for the specific UE ‘venous thromboembolic event’ and other specific UEs. Overall, significant disadvantages can therefore be identified in the side effect category.
  • In the overall assessment of the available results for patient-relevant endpoints, the clear advantage in overall survival is offset by significant disadvantages in terms of side effects. Further advantages are evident in the morbidity endpoint category, whilst further disadvantages are observed in health-related quality of life. In a balanced assessment, the G-BA concludes that there is a minor additional benefit for amivantamab in combination with lazertinib as first-line treatment for adult patients with advanced non-small cell lung cancer with EGFR exon-19 deletions or exon-21 L858R substitution mutations.

Courtesy translation only, please refer to the German original.