Abemaciclib (3) – Verzenios®

• Clinical trials
  • To demonstrate the additional benefit of abemaciclib in combination with fulvestrant compared with placebo in combination with fulvestrant, the pharmaceutical manufacturer has submitted the results of the most recent data cut-off from the randomised, double-blind, controlled Phase IIIMONARCH-2 trial, which is already known from the previous benefit assessment of abemaciclib in the current therapeutic indication.
  • The MONARCH plus study is a double-blind RCT in which abemaciclib in combination with fulvestrant is directly compared with fulvestrant (+placebo).

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

• An additional benefit is not proven
• The lack of analyses for the MONARCH plus study differentiated by patient populations a1 and b1 results in significant uncertainty in the assessment of the available results in patient population a1.
• mortality
  • In the MONARCH-2 trial, no statistically significant difference in overall survival was observed between the study arms for postmenopausal patients who had not yet received initial endocrine therapy.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • In the responder analyses, a statistically significant difference in favour of abemaciclib in combination with fulvestrant compared with fulvestrant alone was observed for the health status endpoint, both at a MID of 7 points and at a MID of 10 points.
  • There is therefore an advantage in terms of health status.
• Morbidity – Symptoms
  • For the endpoints of nausea/vomiting, constipation, arm symptoms and breast symptoms, a statistically significant advantage was observed in each case for abemaciclib + fulvestrant.
  • For the endpoint of diarrhoea, a statistically significant difference was observed to the disadvantage of abemaciclib plus fulvestrant.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the MONARCH-2 trial and is defined as the time from randomisation to disease progression (determined by the investigator according to RECIST criteria version 1.1) or death, regardless of the underlying cause of death.
  • The results for the progression-free survival endpoint are not included in this assessment.
• Morbidity – Time to first subsequent chemotherapy
  • Notwithstanding the fundamental question of whether the endpoint ‘time to first subsequent chemotherapy’ should also be reflected in other relevant endpoints in order to be considered patient-relevant, there are significant uncertainties in the present case regarding the interpretability of the results for this endpoint, which mean that no conclusions regarding additional benefit can be drawn from the available data.
• Health-related quality of life
  • For the endpoint ‘social functioning’, there is a statistically significant advantage in favour of abemaciclib in combination with fulvestrant.
  • Taking all the results on health-related quality of life into account, it is not possible to conclude that treatment with abemaciclib in combination with fulvestrant offers either an advantage or a disadvantage compared with fulvestrant alone.
• Side effects – Adverse events (AEs)
  • In MONARCH-2, 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.
• Side effects – Serious adverse events
  • For serious adverse events, there was a statistically significant disadvantage for abemaciclib in combination with fulvestrant.
• Side effects – Severe AEs (CTCAE grade ≥ 3)
  • A statistically significant treatment effect to the detriment of abemaciclib in combination with fulvestrant was observed with regard to the time to onset of severe adverse events with a CTCAE grade of ≥ 3.
• Side effects – Discontinuation due to AEs
  • A statistically significant effect was observed to the detriment of abemaciclib in combination with fulvestrant in terms of the median time to therapy discontinuation due to an AE.
• Side effects – Specific AEs
  • For the specific AEs of neutropenia and diarrhoea, both of CTCAE grade ≥ 3, the proportion of patients in the abemaciclib plus fulvestrant treatment group was significantly higher in each case compared with the proportion of patients in the fulvestrant plus placebo control group.
• Overall assessment
  • In the overall assessment of the available results on symptoms and health status, abemaciclib in combination with fulvestrant shows an advantage in the morbidity endpoint category.
  • In weighing up the advantage in the morbidity endpoint category against the significant disadvantages in terms of side effects, the G-BA concludes that for abemaciclib in combination with fulvestrant for the treatment of postmenopausal women with HR+ and HER2- advanced or metastatic breast cancer who have received initial endocrine therapy, an additional benefit is not proven.

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

• Hint for a minor additional benefit
• Particularly due to uncertainties relevant to the assessment, arising from the lack of corresponding analyses for patient population b1 from the MONARCH plus trial, the certainty of the evidence for the observed additional benefit is classified as ‘hint’.
• mortality
  • With regard to overall survival, a statistically significant advantage was observed in favour of abemaciclib in combination with fulvestrant compared with fulvestrant alone in patients with locally advanced or metastatic breast cancer who had previously received endocrine therapy.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • In the responder analyses, no statistically significant difference in favour of abemaciclib in combination with fulvestrant compared with fulvestrant alone was observed for the health status endpoint, either at a MID of 7 points or at a MID of 10 points.
  • There is therefore no advantage in terms of health status.
• Morbidity – Symptoms
  • For the endpoints of nausea/vomiting and pain, a statistically significant advantage was observed in favour of abemaciclib + fulvestrant in each case.
  • For the endpoint of insomnia, there was no statistically significant difference between the treatment groups. However, there was an effect modification by the characteristic of age. For patients aged ≥ 65 years, there is a statistically significant advantage with regard to abemaciclib plus fulvestrant compared with fulvestrant alone. For patients aged < 65 years, there is no statistically significant difference between the treatment groups.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the MONARCH-2 trial and is defined as the time from randomisation to disease progression (determined by the investigator according to RECIST criteria version 1.1) or death, regardless of the underlying cause of death.
  • The results for the progression-free survival endpoint are not included in this assessment.
• Morbidity – Time to first subsequent chemotherapy
  • Notwithstanding the fundamental question of whether the endpoint ‘time to first subsequent chemotherapy’ should also be reflected in other relevant endpoints in order to be considered patient-relevant, there are significant uncertainties in the present case regarding the interpretability of the results for this endpoint, which mean that no conclusions regarding additional benefit can be drawn from the available data.
• Health-related quality of life
  • The time to deterioration in overall health status and to deterioration in physical functioning and emotional functioning was statistically significantly prolonged in the abemaciclib treatment group compared with the control group.
• Side effects – Adverse events (AEs)
  • In MONARCH-2, an adverse event occurred in 97.9% of postmenopausal patients in the intervention arm who had not yet received initial endocrine therapy; in the control arm, the figure was 89.4% of patients.
• Side effects – Serious adverse events
  • No statistically significant difference was observed between the study arms with regard to serious adverse events.
• Side effects – Severe AEs (CTCAE grade ≥ 3)
  • A statistically significant treatment effect was observed to the detriment of abemaciclib in combination with fulvestrant with regard to the time to onset of severe adverse events with a CTCAE grade of ≥ 3.
• Side effects – Discontinuation due to AEs
  • A statistically significant effect was observed to the detriment of abemaciclib in combination with fulvestrant in terms of the median time to therapy discontinuation due to an AE.
• Side effects – Specific AEs
  • For the specific AEs of neutropenia and diarrhoea, each of CTCAE grade ≥ 3, the proportion of patients in the abemaciclib plus fulvestrant treatment group was significantly higher than that in the fulvestrant plus placebo control group.
• Overall assessment
  • With regard to overall survival, the MONARCH-2 trial demonstrated an advantage of abemaciclib in combination with fulvestrant compared with fulvestrant alone.
  • In the morbidity endpoint category, an advantage of abemaciclib plus fulvestrant compared with fulvestrant alone was observed.
  • For the quality of life endpoint category, a significant overall advantage is inferred.
  • In its cost-benefit analysis, the G-BA concludes that, due to the advantage in overall survival—supported by the positive effects in the morbidity and quality of life outcome categories—the improvement in treatment-related benefit overall outweighs the significant disadvantages associated with 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.

b2) Pre-/perimenopausal women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who have received prior endocrine therapy

• An additional benefit is not proven.
• mortality
  • In the MONARCH-2 trial, no statistically significant difference in overall survival was observed between the study arms for pre- and perimenopausal patients who had previously received endocrine therapy.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • In the responder analyses, no statistically significant difference in favour of abemaciclib in combination with fulvestrant compared with fulvestrant alone was observed for the health status endpoint, either at a MID of 7 points or at a MID of 10 points.
  • There is therefore no advantage with regard to health status.
• Morbidity – Symptoms
  • For the endpoints of constipation and side effects of systemic treatment, a statistically significant difference in favour of abemaciclib + fulvestrant was observed in each case.
  • However, the extent of the effect is minor in each case, and the overall number of events is low; consequently, no advantage can be inferred from this alone when considering the results for symptoms as a whole.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the MONARCH-2 study and is defined as the time from randomisation to disease progression (determined by the investigator according to RECIST criteria version 1.1) or death, regardless of the underlying cause of death.
  • The results for the endpoint of progression-free survival are not included in this assessment.
• Morbidity – Time to first subsequent chemotherapy
  • Notwithstanding the fundamental question of whether the endpoint ‘time to first subsequent chemotherapy’ should also be reflected in other relevant endpoints in order to be considered patient-relevant, there are significant uncertainties in the present case regarding the interpretability of the results for this endpoint, which mean that no conclusions regarding additional benefit can be drawn from the available data.
• Health-related quality of life
  • For all endpoints presented, no statistically significant difference was observed between the treatment groups.
• Side effects – Adverse events (AEs)
  • In MONARCH-2, an adverse event occurred in 96.2 % of postmenopausal patients in the intervention arm who had not yet received initial endocrine therapy; in the control arm, the figure was 95.0 % of patients.
• Side effects – serious adverse events
  • No statistically significant difference was observed between the study arms with regard to serious adverse events.
• Side effects – Severe AEs (CTCAE grade ≥ 3)
  • A statistically significant treatment effect was observed to the detriment of abemaciclib in combination with fulvestrant with regard to the time to onset of severe adverse events with a CTCAE grade of ≥ 3.
• Side effects – Discontinuation due to AEs
  • No statistically significant difference was observed between the treatment groups for the endpoint of discontinuation due to AEs.
• Side effects – Specific AEs
  • For the specific AEs of neutropenia and diarrhoea, both at CTCAE grade ≥ 3, the proportion of patients in the abemaciclib plus fulvestrant treatment group was significantly higher than that in the fulvestrant plus placebo control group.
• Overall assessment
  • In the mortality endpoint category, no statistically significant difference was observed between the treatment groups for the overall survival endpoint.
  • For the endpoint category of morbidity and for health-related quality of life, no overall advantages or disadvantages can be identified for treatment with abemaciclib in combination with fulvestrant compared with fulvestrant alone.
  • In a balanced assessment, the G-BA concludes that for abemaciclib in combination with fulvestrant for the treatment of pre/perimenopausal women with HR+ and HER2- advanced or metastatic breast cancer who have previously received endocrine therapy, an additional benefit over fulvestrant is not proven.

Courtesy translation only, please refer to the German original.