Abemaciclib (4) – Verzenios®

• Clinical trials
  • To demonstrate the additional benefit of abemaciclib in combination with fulvestrant compared with fulvestrant alone, the pharmaceutical manufacturer has submitted the results of the randomised, double-blind, controlled Phase III MONARCH 2 trial.
  • The MONARCH plus study (Cohort B) is a double-blind, randomised and controlled Phase III trial comparing abemaciclib in combination with fulvestrant with fulvestrant alone.

a) postmenopausal women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who have not yet received initial endocrine therapy

• The additional benefit is not proven
• mortality
  • For the endpoint of overall survival, the meta-analysis of the studies shows no statistically significant difference between the treatment groups.
• Morbidity – Progression-free survival
  • Progression-free survival was the primary endpoint in both studies and was defined as the time from randomisation to disease progression (assessed by the investigator according to RECIST criteria version 1.1) or death, regardless of the underlying cause of death.
  • PFS was statistically significantly prolonged in the abemaciclib treatment group compared with the control group.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The results for the progression-free survival endpoint are not included in this assessment.
• Morbidity – time to first subsequent chemotherapy
  • The endpoint ‘time to first subsequent chemotherapy’ was only assessed in the MONARCH 2 trial and is defined as the time from randomisation to the start of the first subsequent chemotherapy or death, regardless of the underlying cause of death.
  • The pharmaceutical manufacturer’s dossier lacks detailed information on post-progression therapies; furthermore, the pharmaceutical manufacturer does not provide essential information regarding the circumstances surrounding the decision to treat with or without chemotherapy.
• Morbidity – Pain
  • For the endpoint ‘pain’ (assessed using the mBPI-SF and based on analgesic use), time-to-event analyses are available for the period from randomisation to the first worsening of pain.
  • For the endpoint of pain (most severe pain in the last 24 hours and increase in analgesic use), the studies show no statistically significant difference between the treatment groups, either for the combined endpoint or for its individual components.
• Morbidity – Symptoms
  • Symptoms were assessed in both the MONARCH 2 and MONARCH plus studies using the cancer-specific questionnaire EORTC QLQ-C30 and the breast cancer-specific supplementary module EORTC QLQ-BR23, respectively, up to the end of treatment.
  • The results for the ‘symptoms’ endpoint cannot therefore be meaningfully interpreted and cannot be used for the benefit assessment.
• Morbidity – Health status (EQ-5D visual analogue scale)
  • Health status is assessed in the MONARCH 2 study using the EQ-5D visual analogue scale (VAS) up to 30 days after the end of treatment.
  • The results for the health status endpoint cannot therefore be meaningfully interpreted and cannot thus be used for the benefit assessment.
• quality of life
  • Health-related quality of life was assessed in both studies using the functional scales and the global health status scale of the cancer-specific EORTC QLQ-C30 and the breast cancer-specific supplementary module EORTC QLQ-BR23 until disease progression occurred.
  • The results on quality of life cannot therefore be meaningfully interpreted and cannot thus be used for benefit assessment.
• Side effects – Adverse events (AEs), total
  • In the MONARCH 2 trial, an adverse event occurred in 98.8% of postmenopausal patients in the intervention arm who had not yet received initial endocrine therapy; in the control arm, the figure was 91.4% of patients.
  • In the MONARCH plus study, adverse events occurred in 100% of patients in the intervention arm and in 85.0% of patients in the control arm.
• Side effects – Serious adverse events (SAEs), severe adverse events (CTCAE grade ≥ 3), discontinuation due to AEs
  • For the endpoints, serious adverse events (CTCAE grade ≥ 3), severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs, the meta-analysis showed a statistically significant disadvantage in each case for abemaciclib compared to fulvestrant.
• Side effects – Specific adverse events
  • For the specific adverse events neutropenia (CTCAE grade ≥ 3), diarrhoea (CTCAE grade ≥ 3), anaemia (CTCAE grade ≥ 3), eye diseases (adverse events), gastrointestinal disorders (AEs), disorders of the skin and subcutaneous tissue (AEs) and disorders of the kidneys and urinary tract (AEs), the meta-analysis reveals a statistically significant disadvantage for abemaciclib and fulvestrant in each case.
• Overall assessment
  • For the assessment of the additional benefit of abemaciclib in combination with fulvestrant for the treatment of hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer in postmenopausal patients who have not yet received initial endocrine therapy (patient population a1), a meta-analysis provides results for the endpoint categories of mortality, morbidity, health-related quality of life and side effects compared with fulvestrant.
  • In a cost-benefit analysis, the G-BA concludes that, for abemaciclib in combination with fulvestrant for the treatment of postmenopausal patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer who have received initial endocrine therapy does not have an additional benefit compared to Fulvestrant.

b1) postmenopausal women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who have previously received endocrine therapy

• Indication of a minor additional benefit
• The certainty of evidence for the observed additional benefit is classified as ‘indication’.
• mortality
  • In the MONARCH 2 and MONARCH plus trials, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • For the endpoint of overall survival, the meta-analysis of studies in postmenopausal patients who had previously received endocrine therapy shows a statistically significant advantage in favour of abemaciclib in combination with fulvestrant compared with fulvestrant alone.
  • There is an effect modification by the characteristic ‘type of disease’ for overall survival.
  • In the overall assessment of the available results from the MONARCH 2 and MONARCH plus studies, the effect modification observed for the endpoint of overall survival based on the characteristic ‘type of disease’ is not considered sufficient to allow separate conclusions regarding additional benefit to be drawn in the overall assessment.
• Morbidity – Progression-free survival
  • Progression-free survival was the primary endpoint in both studies and was defined as the time from randomisation to disease progression (determined by the investigator using the RECIST criteria version 1.1) or death, regardless of the underlying cause of death.
  • PFS was statistically significantly prolonged in the abemaciclib treatment group compared with the control group.
  • The results for the progression-free survival endpoint are not included in this assessment.
• Morbidity – time to first subsequent chemotherapy
  • The endpoint ‘time to first subsequent chemotherapy’ was only assessed in the MONARCH 2 trial and is defined as the time from randomisation to the start of the first subsequent chemotherapy or death, regardless of the underlying cause of death.
• Morbidity – Pain
  • For the endpoint ‘pain’ (assessed using the mBPI-SF and based on analgesic use), event time analyses are available for the period from randomisation to the first worsening of pain.
  • For the endpoint ‘pain’ (severe pain in the last 24 hours and increased use of painkillers), the studies show no statistically significant difference between the treatment groups, either for the combined endpoint or for its individual components.
  • Furthermore, for the endpoint ‘worst pain in the last 24 hours’, an effect modification by the characteristic of age is evident.
  • The validity of the available subgroup results is considered insufficient for the overall assessment of additional benefit.
• Morbidity – Symptoms
  • Symptoms were assessed in both the MONARCH 2 and MONARCH plus studies using the cancer-specific questionnaire EORTC QLQ-C30 and the breast cancer-specific supplementary module EORTC QLQ-BR23, respectively, up to the end of treatment.
  • The results for the endpoint ‘symptoms’ cannot therefore be meaningfully interpreted and cannot be used for the benefit assessment.
• Morbidity – Health status (EQ-5D visual analogue scale)
  • Health status is assessed in the MONARCH 2 study using the EQ-5D visual analogue scale (VAS) up to 30 days after the end of treatment.
  • The results for the health status endpoint cannot therefore be meaningfully interpreted and cannot thus be used for the benefit assessment.
• quality of life
  • Health-related quality of life was assessed in both studies using the functional scales and the global health status scale of the cancer-specific EORTC QLQ-C30 and the breast cancer-specific supplementary module EORTC QLQ-BR23 until disease progression occurred.
  • The results on quality of life cannot therefore be meaningfully interpreted and cannot thus be used for the benefit assessment.
• Side effects – Adverse events (AEs)
  • In the MONARCH 2 trial, an adverse event occurred in 97.9 % of postmenopausal patients in the intervention arm who had previously received endocrine therapy; in the control arm, the figure was 89.4 % of patients.
  • In the MONARCH plus study, adverse events occurred in 100% of patients in the intervention arm and in 69.2% of patients in the control arm.
• Side effects – Serious adverse events (SAEs)
  • No statistically significant difference was observed between the study arms with regard to serious adverse events.
• Side effects – Severe AEs (CTCAE grade ≥ 3), discontinuation due to AEs
  • For the endpoints of severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs, the meta-analysis revealed a statistically significant disadvantage in each case for abemaciclib in combination with fulvestrant.
• Side effects – Specific AEs
  • For the specific AEs neutropenia (severe AE) and diarrhoea (severe AE), the MONARCH 2 study showed, in detail, a statistically significant disadvantage in each case for abemaciclib in combination with fulvestrant compared with fulvestrant alone.
  • Furthermore, for the endpoints ‘gastrointestinal disorders’ (AE) and ‘skin and subcutaneous tissue disorders’ (AE), the meta-analysis revealed, in detail, a statistically significant disadvantage compared with fulvestrant for abemaciclib + fulvestrant.
• Overall assessment
  • Data are available for the assessment of the additional benefit of abemaciclib in combination with fulvestrant for the treatment of hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer in postmenopausal patients who have previously received endocrine therapy (patient population b1), a meta-analysis provides results for the endpoint categories of mortality, morbidity, health-related quality of life and side effects compared with fulvestrant.
  • In a cost-benefit analysis, the G-BA concludes that, due to the advantage in overall survival, the improvement in treatment-related benefit outweighs the significant disadvantages in terms of side effects.
  • For abemaciclib in combination with fulvestrant for the treatment of postmenopausal patients with HR+ and HER2- advanced or metastatic breast cancer who have received prior endocrine therapy, a minor additional benefit compared with fulvestrant is identified on balance.

Courtesy translation only, please refer to the German original.