Brigatinib (2) – Alunbrig®

• Clinical trials
  • ALTA-1L is a multicentre, open-label, randomised controlled trial comparing brigatinib with crizotinib.

a) Adult patients with anaplastic lymphoma kinase (ALK)-positive, advanced, non-small cell lung cancer with brain metastases who have not previously been treated with an ALK inhibitor

• mortality
  • For the endpoint of overall survival, no statistically significant difference was observed between the study arms in the overall study population.
  • However, an effect modification was observed for the characteristic ‘brain metastases at the start of the study’, with a statistically significant benefit in favour of brigatinib compared with crizotinib for patients with brain metastases at the start of the study.
  • For patients with brain metastases at the start of the study, treatment with brigatinib resulted in a prolongation of survival compared with treatment with crizotinib, which is assessed as a significant improvement.
  • In the mortality category, a statistically significant effect in favour of brigatinib was observed, which is assessed as a marked improvement.
• Morbidity – Symptoms
  • For the EORTC QLQ-C30, the pharmaceutical manufacturer submitted responder analyses in the benefit assessment dossier covering the period up to first deterioration (defined as an increase in the score of at least 10 points compared with baseline).
  • For the endpoints of nausea and vomiting, constipation, fatigue and loss of appetite, a statistically significant advantage was observed in favour of brigatinib compared with crizotinib.
  • For the EORTC QLQ-LC13, the pharmaceutical manufacturer submitted responder analyses during the commenting procedure covering the time to first deterioration (defined as an increase in the score of at least 10 points compared with baseline).
  • For the endpoints of pain (arm/shoulder) and peripheral neuropathy, a statistically significant advantage was observed in favour of brigatinib compared with crizotinib in each case.
  • An overall analysis of the results shows a relevant improvement in symptoms—through positive effects on individual endpoints—in patients treated with brigatinib compared with those treated with crizotinib, both for patients with brain metastases at the start of the study and for those without brain metastases at the start of the study.
  • In the morbidity category, there was a major improvement in symptoms (assessed using the EORTC QLQ-C30 and EORTC QLQ-LC13) due to positive effects on individual endpoints with brigatinib compared with crizotinib.
  • These are evident in the patient-reported symptoms of nausea and vomiting, constipation, fatigue and loss of appetite (EORTC QLQ-C30), as well as in pain (arm/shoulder) and peripheral neuropathy (EORTC QLQ-LC13).
• quality of life
  • To assess health-related quality of life, the functional scales of the disease-specific EORTC QLQ-C30 questionnaire were used in the ALTA-1L study.
  • For the endpoints of global health status and emotional functioning, a statistically significant advantage was observed in favour of brigatinib compared with crizotinib.
  • For the social functioning endpoint, a statistically significant advantage was observed in favour of brigatinib.
  • Overall, treatment with brigatinib demonstrates an advantage in terms of health-related quality of life compared with treatment with crizotinib for both patient population a) and patient population b).
  • Treatment with brigatinib also showed positive effects on health-related quality of life, which were observed for the patient-reported endpoints of global health status, emotional functioning and social functioning.
• Side effects
  • In ALTA-1L, an adverse event occurred in almost every patient in both study arms.
  • No statistically significant difference was observed between the study arms in terms of serious adverse events.
  • With regard to severe adverse events of CTCAE grade ≥ 3, there was no statistically significant difference between the study arms.
  • There was no statistically significant difference between the study arms for the endpoint of therapy discontinuation due to an AE.
  • With regard to the specific AEs of eye diseases (SOC), peripheral oedema (PT) and gastrointestinal disorders (SOC), a statistically significant advantage was observed in favour of brigatinib compared with crizotinib.
  • For the specific AE ‘skin and subcutaneous tissue disorders’ (SOC), a statistically significant disadvantage was observed with regard to brigatinib.
  • With regard to specific severe AEs (CTCAE grade ≥ 3) – elevated creatine phosphokinase (PT) and hypertension (PT) – a statistically significant disadvantage was observed compared with crizotinib.
  • Overall, no statistically significant difference was observed between the study arms with regard to side effects, specifically the endpoints of serious adverse events, severe adverse events (CTCAE grade ≥ 3) and discontinuation due to side effects.
  • In the ‘side effects’ endpoint category, there are no advantages or disadvantages for brigatinib.
• Overall assessment
  • In the mortality endpoint category, the available results for the overall survival endpoint in the patient population of patients with brain metastases at the start of the study show a statistically significant prolongation of survival time compared with treatment with crizotinib, which is assessed as a marked improvement.
  • In the morbidity category, there is a relevant improvement in symptoms (assessed using the EORTC QLQ-C30 and EORTC QLQ-LC13) due to positive effects on individual endpoints with brigatinib compared with crizotinib.
  • Treatment with brigatinib also showed positive effects on health-related quality of life, which were observed for the patient-reported endpoints of global health status, emotional functioning and social functioning.
  • Taking the available results as a whole, the G-BA concludes that brigatinib offers considerable added benefit over crizotinib in the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer and brain metastases who have not previously been treated with an ALK inhibitor.

b) Adult patients with anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer without brain metastases who have not previously been treated with an ALK inhibitor

• For brigatinib in the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive, advanced, non-small cell lung cancer who have not previously been treated with an ALK inhibitor and who did not have brain metastases at the start of the study provide a hint of a minor additional benefit.
• Consequently, the G-BA concludes that brigatinib as monotherapy offers a minor additional benefit compared with crizotinib.
• Given the open-label study design and other uncertainties, only a hint of additional benefit can be inferred with regard to the certainty of the findings.
• mortality
  • For the endpoint of overall survival, no statistically significant difference was observed between the study arms in the overall study population.
  • For patients without brain metastases at the start of the study, there was no difference between the study arms.
  • In the mortality category, there was no statistically significant effect in favour of brigatinib.
• Morbidity – Symptoms
  • For the EORTC QLQ-C30, the pharmaceutical manufacturer submitted responder analyses in the benefit assessment dossier for the time to first deterioration (defined as an increase in the score of at least 10 points from baseline).
  • For the endpoints of nausea and vomiting, constipation, fatigue and loss of appetite, a statistically significant advantage was observed in favour of brigatinib compared with crizotinib.
  • For the EORTC QLQ-LC13, the pharmaceutical manufacturer submitted responder analyses during the commenting procedure covering the time to first deterioration (defined as an increase in the score of at least 10 points compared with baseline).
  • For the endpoints of pain (arm/shoulder) and peripheral neuropathy, a statistically significant advantage was observed in favour of brigatinib compared with crizotinib in each case.
  • An overall analysis of the results shows a relevant improvement in symptoms—through positive effects on individual endpoints—in patients treated with brigatinib compared with those treated with crizotinib, both for patients with brain metastases at the start of the study and for those without brain metastases at the start of the study.
  • In the morbidity category, there was a major improvement in symptoms (assessed using the EORTC QLQ-C30 and EORTC QLQ-LC13) due to positive effects on individual endpoints with brigatinib compared with crizotinib.
  • These are evident in the patient-reported symptoms of nausea and vomiting, constipation, fatigue and loss of appetite (EORTC QLQ-C30), as well as in pain (arm/shoulder) and peripheral neuropathy (EORTC QLQ-LC13).
• quality of life
  • To assess health-related quality of life, the functional scales of the disease-specific EORTC QLQ-C30 questionnaire were used in the ALTA-1L study.
  • For the endpoints of global health status and emotional functioning, a statistically significant advantage was observed in favour of brigatinib compared with crizotinib.
  • For the social functioning endpoint, a statistically significant advantage was observed in favour of brigatinib.
  • Overall, treatment with brigatinib demonstrates an advantage in terms of health-related quality of life compared with treatment with crizotinib for both patient population a) and patient population b).
  • Treatment with brigatinib also showed positive effects on health-related quality of life, which were observed for the patient-reported endpoints of global health status, emotional functioning and social functioning.
• Side effects
  • In ALTA-1L, an adverse event occurred in almost every patient in both study arms.
  • No statistically significant difference was observed between the study arms in terms of serious adverse events.
  • With regard to severe adverse events of CTCAE grade ≥ 3, there was no statistically significant difference between the study arms.
  • There was no statistically significant difference between the study arms for the endpoint of therapy discontinuation due to an AE.
  • With regard to the specific AEs of eye diseases (SOC), peripheral oedema (PT) and gastrointestinal disorders (SOC), a statistically significant advantage was observed in favour of brigatinib compared with crizotinib.
  • For the specific AE ‘skin and subcutaneous tissue disorders’ (SOC), a statistically significant disadvantage was observed for brigatinib.
  • With regard to specific severe AEs (CTCAE grade ≥ 3) – elevated creatine phosphokinase (PT) and hypertension (PT) – a statistically significant disadvantage was observed compared with crizotinib.
  • Overall, no statistically significant difference was observed between the study arms with regard to side effects, specifically the endpoints of serious AEs, severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs.
  • In the ‘side effects’ endpoint category, there are no advantages or disadvantages for brigatinib.
• Overall assessment
  • In the mortality endpoint category, the available results for the overall survival endpoint in the patient population of patients without brain metastases at the start of the study show no statistically significant difference in survival time compared with treatment with crizotinib.
  • In the morbidity category, there is a major improvement in symptoms (assessed using the EORTC QLQ-C30 and EORTC QLQ-LC13) due to positive effects on individual endpoints with brigatinib compared with crizotinib.
  • Treatment with brigatinib also showed positive effects on health-related quality of life, which were observed for the patient-reported endpoints of global health status, emotional functioning and social functioning.
  • Taking the available results as a whole, the G-BA concludes that brigatinib offers a modest additional benefit over crizotinib in the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer without brain metastases who have not previously been treated with an ALK inhibitor. There is a minor additional benefit compared to Crizotinib.

Courtesy translation only, please refer to the German original.