Abemaciclib (2) – Verzenios®

• Clinical trials
  • The pharmaceutical manufacturer has submitted results from the randomised, double-blind Phase III MONARCH-2 trial to demonstrate the additional benefit of abemaciclib in combination with fulvestrant.
  • This multinational trial (N=669) included pre- and perimenopausal and postmenopausal women with locally advanced or metastatic HR-positive, HER2-negative breast cancer who had not yet received endocrine therapy for their locally advanced or metastatic disease or who had already been pre-treated with endocrine therapy. The combination of abemaciclib and fulvestrant (N=446) was compared with placebo and fulvestrant (N=223).

a1) Postmenopausal women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who had not yet received initial endocrine therapy

• For postmenopausal women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who have not yet received initial endocrine therapy, additional benefit is not proven with abemaciclib in combination with fulvestrant compared with the appropriate comparator therapy.
• mortality
  • In the MONARCH-2 trial, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • In the MONARCH-2 trial, no statistically significant difference in overall survival was observed between the treatment arms for postmenopausal patients who had not yet received initial endocrine therapy (HR: 0.76 [95% CI: 0.47; 1.23]; p = 0.279).
  • Based on the available results, the addition of abemaciclib to fulvestrant therapy does not provide any additional benefit for the endpoint category of mortality.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the MONARCH-2 trial and was 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.
  • For this endpoint, the results presented in the pharmaceutical manufacturer’s dossier took the form of pooled analyses for all postmenopausal patients, without distinguishing whether the patients, in the locally advanced or metastatic stage, had previously received endocrine therapy or not. Consequently, no usable data on this endpoint are available for the relevant patient population a1.
• Morbidity – Health status (EQ-5D Visual Analogue Scale) and symptoms
  • In the morbidity endpoint category, health status (EQ-5D VAS) and symptoms (mBPI-SFI, symptom scales of the EORTC QLQ-C30 and –BR23) were assessed.
  • For these endpoints, too, the results were presented in the pharmaceutical manufacturer’s dossier in the form of summarised analyses for all postmenopausal patients, without distinguishing between patients with locally advanced or metastatic disease who had or had not previously received endocrine therapy.
  • Consequently, no usable data are available for the relevant patient population a1.
• quality of life
  • Health-related quality of life was assessed using the functional scales of the EORTC QLQ-C30 and –BR23 questionnaires.
  • Similarly, for the endpoints in this category, there are no usable data available for the relevant patient population due to the summarised analyses described for all postmenopausal patients in the pharmaceutical manufacturer’s dossier and in the documents submitted during the commenting procedure.
• Side effects – Adverse events (AEs)
  • In MONARCH-2, an adverse event occurred in 99.1 % of postmenopausal patients in the intervention arm who had not yet received initial endocrine therapy; in the comparator arm, the figure was 86.8 % of patients.
• Side effects – serious adverse events (SAEs)
  • For serious adverse events, there was a statistically significant disadvantage for abemaciclib in combination with fulvestrant (HR: 3.11 [95% CI: 1.59; 6.09]; p < 0.001).
  • When evaluating the results on serious adverse events, the potential for bias must be taken into account.
• Overall assessment
  • The MONARCH-2 study provides results comparing abemaciclib in combination with fulvestrant against fulvestrant alone regarding mortality (overall survival) and side effects, which can be used to assess the extent of the additional benefit of abemaciclib in combination with fulvestrant.
  • In the mortality endpoint category, the preliminary data for the overall survival endpoint do not allow for a definitive assessment of the effects on overall survival. Based on the available data, there is no statistically significant difference in overall survival between the study arms. Final analyses for the overall survival endpoint are pending. Based on the available data, the additional benefit of abemaciclib in combination with fulvestrant for overall survival is not proven.
  • For the endpoints in the categories of morbidity (symptoms and health status) and quality of life, no usable data are available for the relevant patient population, as the pharmaceutical manufacturer submitted summarised analyses for all postmenopausal patients in the dossier and in the documents provided as part of the commenting procedure, which did not distinguish between whether or not the patients, in the locally advanced or metastatic stage, had already received prior endocrine therapy. Consequently, no usable data are available for the ‘progression-free survival’ endpoint in the patient population under consideration either.
  • With regard to side effects, in terms of the endpoints, serious adverse events (SAEs), severe adverse events (CTCAE Grade 3 or 4) and therapy discontinuations due to adverse events, significant, statistically significant disadvantages were observed for abemaciclib in combination with fulvestrant compared with fulvestrant alone. No analyses were available for the patient population under consideration regarding relevant specific AEs, in particular neutropenia (CTCAE grade 3 or 4). Overall, the adverse event profile of abemaciclib differs significantly from that of endocrine therapy. However, taking clinical relevance into account, the disadvantage in terms of side effects does not reach an extent that would justify less benefit in the overall assessment.
  • In a cost-benefit analysis, the G-BA concludes that, for abemaciclib in combination with fulvestrant for the treatment of postmenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer, who have not yet received initial endocrine therapy at this stage of the disease, an additional benefit over fulvestrant is not proven.

a2) Pre-/perimenopausal women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who have not yet received initial endocrine therapy

• For pre-/perimenopausal patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who have not yet received initial endocrine therapy, the additional benefit of abemaciclib in combination with fulvestrant is not proven compared with the appropriate comparator therapy.
• For pre- and perimenopausal patients who have not yet received initial endocrine therapy, the G-BA has defined ‘tamoxifen in combination with ovarian suppression’ as the appropriate comparator therapy. In MONARCH-2, all pre- and perimenopausal patients in the comparator arm were treated with fulvestrant (and, in addition, a GnRH agonist for ovarian suppression). Fulvestrant has marketing authorisation only for postmenopausal patients. For the treatment of pre- and perimenopausal patients who have not yet received initial endocrine therapy, however, tamoxifen is an authorised treatment option recommended in the guidelines. The appropriate comparator therapy was therefore not adequately implemented for patient population a2.

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

• For postmenopausal women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who have received prior endocrine therapy, additional benefit is not proven with abemaciclib in combination with fulvestrant compared with the appropriate comparator therapy.
• In light of the specific therapeutic and clinical context in this therapeutic indication, and despite remaining uncertainties, fulvestrant or fulvestrant alone, without taking into account other endocrine therapies indicated in accordance with guidelines for this treatment situation, is exceptionally assessed as a sufficiently suitable comparator. No conclusions can be drawn from this regarding the appropriateness of fulvestrant for off-label use in standard care for patients covered by statutory health insurance.
• mortality
  • With regard to overall survival, the MONARCH-2 trial showed no statistically significant difference between the study arms in postmenopausal patients who had previously received endocrine therapy (HR: 1.09 [95% CI: 0.57; 2.09]; p = 0.751).
  • Based on the available results, the addition of abemaciclib to fulvestrant therapy does not provide any additional benefit for the endpoint category of mortality.
• Morbidity – Progression-free survival (PFS)
  • For the endpoint ‘progression-free survival’ , the results in the pharmaceutical manufacturer’s dossier were presented in the form of pooled analyses for all postmenopausal patients, without distinguishing between those who had previously received endocrine therapy and those who had not, in the locally advanced or metastatic stages. Consequently, no usable data are available for this endpoint for the relevant patient population b1.
• Morbidity – Health status (EQ-5D Visual Analogue Scale) and symptoms
  • In the morbidity endpoint category, health status (EQ-5D VAS) and symptoms (mBPI-SFI, symptom scales of the EORTC QLQ-C30 and –BR23) were assessed.
  • For these endpoints, too, the results were presented in the pharmaceutical manufacturer’s dossier in the form of summarised analyses for all postmenopausal patients, without distinguishing whether the patients with locally advanced or metastatic disease had previously received endocrine therapy or not.
  • Consequently, no usable data are available for the relevant patient population b1.
• quality of life
  • Health-related quality of life was assessed using the functional scales of the EORTC QLQ-C30 and –BR23 questionnaires.
  • Similarly, for the endpoints in this category, no usable data are available for the relevant patient population due to the summarised analyses described for all postmenopausal patients in the pharmaceutical manufacturer’s dossier and in the documents submitted during the commenting procedure.
• Side effects – Adverse events (AEs)
  • In MONARCH-2, an adverse event occurred in 97.9 % of postmenopausal patients in the intervention arm who had received prior endocrine therapy; in the control arm, the figure was 89.4 % of patients.
• Side effects – Serious adverse events (SAEs)
  • No statistically significant difference was observed between the study arms with regard to serious adverse events.
  • When evaluating the results on serious adverse events, the potential for bias must be taken into account.
• Side effects – Severe AEs (CTCAE Grade 3 or 4)
  • 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 of CTCAE Grade 3 or 4 (HR: 2.70 [95% CI: 1.64; 4.43]; p < 0.001).
  • As with the SAE endpoint, the results for the severe adverse events endpoint should also be regarded as potentially biased.
• Overall assessment
  • The MONARCH-2 study provides results on mortality (overall survival) and side effects in comparison with fulvestrant alone, which can be used to assess the extent of the additional benefit of abemaciclib in combination with fulvestrant.
  • In the mortality endpoint category, the preliminary data for the overall survival endpoint do not permit a definitive assessment of the effects on overall survival. Based on the available data, there is no statistically significant difference in overall survival between the study arms. Final analyses for the overall survival endpoint are pending. Based on the available data, the additional benefit of abemaciclib in combination with fulvestrant for overall survival is not proven.
  • For the endpoints in the categories of morbidity (symptoms and health status) and quality of life, no usable data are available for the relevant patient population, as the pharmaceutical manufacturer submitted summarised analyses for all postmenopausal patients in the dossier and in the documents provided as part of the commenting procedure, which did not distinguish between whether the patients, in the locally advanced or metastatic stage, had already received prior endocrine therapy or not. Consequently, no usable data are available for the ‘progression-free survival’ endpoint in the patient population under consideration either.
  • With regard to side effects, in terms of the endpoints, severe adverse events (CTCAE Grade 3 or 4) as well as therapy discontinuations due to adverse events, significant, statistically significant disadvantages were observed for abemaciclib in combination with fulvestrant compared with fulvestrant alone. No analyses were available for the patient population under consideration regarding relevant specific AEs, in particular neutropenia (CTCAE Grade 3 or 4). Overall, the adverse event profile of abemaciclib differs significantly from that of endocrine therapy. However, taking clinical relevance into account, the extent of the disadvantage in terms of side effects does not reach a level that would justify less benefit in the overall assessment.
  • In a decision based on a balancing of interests, the G-BA concludes that, for abemaciclib in combination with fulvestrant for the treatment of postmenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who have previously received endocrine therapy at this stage of the disease, an additional benefit is not proven over fulvestrant.

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

• For pre-/perimenopausal patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who have received prior endocrine therapy, an additional benefit of abemaciclib in combination with fulvestrant is not proven compared with the appropriate comparator therapy.
• Given the specific therapeutic and clinical context in this therapeutic indication, and despite remaining uncertainties, fulvestrant or fulvestrant alone, without taking into account other endocrine therapies indicated in accordance with guidelines for this treatment situation, is exceptionally assessed as a sufficiently suitable comparator. No conclusions can be drawn from this regarding the appropriateness of fulvestrant for off-label use in standard care for patients covered by statutory health insurance.
• mortality
  • With regard to overall survival, for pre/perimenopausal patients with a history of endocrine therapy in the MONARCH-2 study, as the pharmaceutical manufacturer did not carry out an analysis for fewer than 10 events in the minor patient population of 46 patients.
• Morbidity – Progression-free survival (PFS)
  • For the endpoint ‘progression-free survival’, the results in the pharmaceutical manufacturer’s dossier were presented in the form of pooled analyses for all pre/perimenopausal patients, without distinguishing whether the patients, in the locally advanced or metastatic stage, had already received prior endocrine therapy or not. Consequently, no usable data are available for this endpoint in the relevant patient population b2.
• Morbidity – Health status (EQ-5D Visual Analogue Scale) and symptoms
  • In the morbidity endpoint category, health status (EQ-5D VAS) and symptoms (mBPI-SFI, symptom scales of the EORTC QLQ-C30 and –BR23) were assessed.
  • For these endpoints, too, the results were presented in the pharmaceutical manufacturer’s dossier in the form of summarised analyses for all postmenopausal patients, without distinguishing whether the patients with locally advanced or metastatic disease had previously received endocrine therapy or not.
  • Consequently, no usable data are available for the relevant patient population b2.
• quality of life
  • Health-related quality of life was assessed using the functional scales of the EORTC QLQ-C30 and –BR23 questionnaires.
  • Similarly, for the endpoints in this category, there are no usable data available for the relevant patient population due to the summarised analyses described for all postmenopausal patients in the pharmaceutical manufacturer’s dossier and in the documents submitted during the commenting procedure.
• Side effects – Adverse events (AEs)
  • In MONARCH-2, an adverse event occurred in 96.2% of pre-/perimenopausal patients in the intervention arm who had received prior endocrine therapy; in the control arm, the figure was 95.0% of patients.
• Side effects – Serious adverse events (SAEs)
  • Due to the small number of events, no data regarding the time-to-event analysis are available for serious adverse events, as the pharmaceutical manufacturer did not carry out an analysis where fewer than 10 events occurred.
• Overall assessment
  • Results from the MONARCH-2 study are available for assessing the extent of the additional benefit of abemaciclib in combination with fulvestrant, compared with fulvestrant alone, in terms of mortality (overall survival) and side effects.
  • In the mortality endpoint category, no data on event-time analysis are available for overall survival in pre- and perimenopausal patients with a history of endocrine therapy, due to the small patient population of 46 patients. Consequently, the preliminary data for this endpoint do not permit a definitive assessment of the effects on overall survival. Final analyses for the endpoint of overall survival are pending. Based on the available data, there is no proof that an additional benefit of abemaciclib in combination with fulvestrant exists for overall survival.
  • No usable data are available for the endpoints in the categories of morbidity (symptoms and health status) and quality of life for the relevant patient population, as the pharmaceutical manufacturer submitted summarised analyses in the dossier and in the documents provided as part of the commenting procedure for all pre/perimenopausal patients, without distinguishing whether the patients had previously received endocrine therapy in the locally advanced or metastatic stage or not. Consequently, no usable data are available for the ‘progression-free survival’ endpoint in the patient population under consideration either.
  • With regard to side effects, a significant, statistically significant disadvantage for abemaciclib in combination with fulvestrant compared with fulvestrant alone was observed for the endpoint of severe adverse events (CTCAE Grade 3 or 4). For serious adverse events and therapy discontinuations due to adverse events, no data are available regarding event-time analyses due to the small number of events. No analyses were available for the patient population under consideration regarding relevant specific AEs, such as, in particular, neutropenia (CTCAE Grade 3 or 4). Overall, the adverse reaction profile of abemaciclib differs markedly from that of endocrine therapy. However, taking clinical relevance into account, the disadvantage associated with the side effects does not reach an extent that would justify less benefit in the overall assessment.
  • In a cost-benefit analysis, the G-BA concludes that, for abemaciclib in combination with fulvestrant for the treatment of pre- and perimenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who have previously undergone endocrine therapy at this stage of the disease, an additional benefit is not proven over fulvestrant.

Courtesy translation only, please refer to the German original.