Abemaciclib (5) – Verzenios®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer has submitted in the dossier the results of the ongoing, open-label, randomised, controlled MONARCH-E trial, in which abemaciclib in combination with standard endocrine therapy is compared with standard endocrine therapy alone.

a1) Premenopausal women with early-stage, hormone receptor-positive, HER2-negative breast cancer at high risk of recurrence

• Overall, therefore, there is a hint of a minor additional benefit of abemaciclib in combination with endocrine therapy compared with endocrine therapy alone.
• Consequently, the certainty of the evidence for the observed additional benefit is classified overall as ‘hint’.
• mortality
  • In the MONARCH-E trial, overall survival was defined as the time from randomisation to death from any cause.
  • No statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
• Morbidity – Recurrences (recurrence rate and disease-free survival)
  • Patients in this therapeutic indication are treated with a curative therapeutic approach: adjuvant therapy following complete resection of the primary tumours and, where applicable, affected lymph nodes. Any remaining tumour cells may cause a recurrence later on. A recurrence means that the attempt at a cure through the curative therapeutic approach was unsuccessful. The occurrence of a recurrence is clinically relevant to the patient.
  • The composite endpoint of relapses comprises the following individual components: local breast cancer recurrence, regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, secondary primary carcinoma (not breast cancer), death from any cause without a preceding recurrence.
  • For the present evaluation, the results of the operationalisations for the ‘recurrence’ endpoint—expressed as the proportion of patients with recurrence (recurrence rate) and as disease-free survival—are used.
  • For the endpoint ‘recurrence’, a statistically significant advantage in favour of abemaciclib in combination with endocrine therapy compared with endocrine therapy alone is observed for both the ‘recurrence rate’ component and the ‘disease-free survival’ component of the endpoint.
  • When considering both endpoint components together, a considerable overall advantage was observed for abemaciclib in combination with endocrine therapy in terms of preventing recurrence.
• Morbidity – Symptoms (FACIT-Fatigue)
  • In the MONARCH-E study, the endpoint of fatigue was assessed using the validated FACIT-Fatigue questionnaire.
  • The results show a statistically significant disadvantage for abemaciclib in combination with endocrine therapy for the symptom-related endpoint, as assessed by FACIT-Fatigue. However, the 95% CI of the standardised mean difference does not lie entirely outside the non-significant range of −0.2 to 0.2 in either case. It cannot therefore be concluded that the observed effect is clinically significant.
• Health-related quality of life – Functional Assessment of Cancer Therapy – Breast (FACT-B)
  • Health-related quality of life is assessed in the study using, amongst other measures, the disease-specific FACT-B questionnaire.
  • The results show a statistically significant disadvantage for abemaciclib in combination with endocrine therapy compared to the health-related quality of life endpoint, as assessed using the FACT-B. However, the 95% CI of the standardised mean difference does not lie entirely outside the irrelevance range of −0.2 to 0.2. It cannot therefore be concluded that the observed effect is clinically relevant.
• Side effects – Adverse events (AEs)
  • In the MONARCH-E trial, an adverse event occurred in 98.2% of premenopausal patients in the intervention arm and in 86.9% in the control arm. The results are presented here for supplementary information only.
• Overall assessment
  • For the benefit assessment of abemaciclib in combination with endocrine therapy for the treatment of hormone receptor-positive, HER2-negative early-stage breast cancer with a high risk of recurrence in premenopausal patients, results are available from the ongoing, open-label, randomised, controlled MONARCH-E study on the endpoint categories of mortality, morbidity, health-related quality of life and side effects.
  • In the mortality endpoint category, the available results for the overall survival endpoint show no statistically significant difference between the study arms. Only minor numbers of events have been recorded for the overall survival endpoint.
  • In the morbidity category, for the endpoint of recurrence – expressed as the recurrence rate and disease-free survival – there were statistically significantly fewer recurrences in patients treated with abemaciclib in combination with endocrine therapy. In the present adjuvant treatment setting, the prevention of recurrence is a particularly relevant treatment objective.
  • With regard to symptoms, there is a statistically significant difference to the disadvantage of abemaciclib in combination with endocrine therapy. However, it cannot be concluded that the observed effect is clinically relevant. In terms of health status, there is neither an advantage nor a disadvantage associated with abemaciclib in combination with endocrine therapy.
  • In the quality of life category, there is a statistically significant disadvantage for abemaciclib in combination with endocrine therapy. However, it cannot be concluded that the observed effect is clinically relevant.
  • With regard to side effects, statistically significant disadvantages were observed for the endpoints of serious adverse events (SAEs), severe adverse events (AEs) and discontinuation due to AEs for treatment with abemaciclib in combination with endocrine therapy, and, in detail, also for the specific AEs.
  • On balance, the relevant advantage in terms of preventing recurrences is offset by significant disadvantages in terms of side effects. The disadvantages relating to side effects are weighed against the fact that preventing recurrences is an essential therapeutic goal in the present curative treatment context.
  • In its decision based on a balancing of interests, the G-BA concludes that the advantage in terms of preventing recurrence outweighs the disadvantages associated with side effects and that, overall, there is a moderate—and not merely minor—improvement in the treatment-related benefit. Abemaciclib in combination with endocrine therapy is therefore found to offer a minor additional benefit compared with endocrine therapy alone in the adjuvant treatment of premenopausal patients with HER2-positive early-stage breast cancer and a high risk of recurrence.

a2) Postmenopausal women with early-stage, hormone receptor-positive, HER2-negative breast cancer at high risk of recurrence

• Overall, it is therefore concluded that additional benefit from abemaciclib in combination with endocrine therapy compared with endocrine therapy alone is not proven.
• mortality
  • In the MONARCH-E trial, overall survival was defined as the time from randomisation to death from any cause.
  • No statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
• Morbidity – Recurrences (recurrence rate and disease-free survival)
  • Patients in this therapeutic indication are treated with a curative therapeutic approach: adjuvant therapy following complete resection of the primary tumours and, where applicable, affected lymph nodes. Any remaining tumour cells may cause a recurrence later on. A recurrence means that the attempt to achieve a cure through the curative therapeutic approach was unsuccessful. The occurrence of a recurrence is clinically relevant to the patient.
  • The composite endpoint of recurrence comprises the following individual components: local breast cancer recurrence, regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, secondary primary carcinoma (not breast cancer), death from any cause without a preceding recurrence.
  • For the present evaluation, the results of the operationalisations for the ‘recurrence’ endpoint—expressed as the proportion of patients with recurrence (recurrence rate) and as disease-free survival—are used.
  • For the endpoint ‘recurrence’, a statistically significant advantage in favour of abemaciclib in combination with endocrine therapy compared with endocrine therapy alone is observed for both the ‘recurrence rate’ component and the ‘disease-free survival’ component of the endpoint.
  • When both endpoint components are considered together, an overall advantage in terms of preventing recurrence is observed for abemaciclib in combination with endocrine therapy.
• Morbidity – Symptoms (FACIT-Fatigue)
  • In the MONARCH-E study, the endpoint ‘fatigue’ was assessed using the validated FACIT-Fatigue questionnaire.
  • The results show a statistically significant disadvantage for abemaciclib in combination with endocrine therapy compared to the symptom-related endpoint assessed by the FACIT-Fatigue. However, the 95% CI for the standardised mean difference does not lie entirely outside the non-significant range of −0.2 to 0.2 in either case. It cannot therefore be concluded that the observed effect is clinically significant.
• Health-related quality of life – Functional Assessment of Cancer Therapy – Breast (FACT-B)
  • Health-related quality of life is assessed in the study using, amongst other measures, the disease-specific FACT-B questionnaire.
  • The results show a statistically significant disadvantage for abemaciclib in combination with endocrine therapy compared to the health-related quality of life endpoint assessed using the FACT-B. However, the 95% CI of the standardised mean difference does not lie entirely outside the irrelevance range of −0.2 to 0.2. It cannot therefore be concluded that the observed effect is clinically relevant.
• Side effects – Adverse events (AEs)
  • In the MONARCH-E trial, an adverse event occurred in 98.2% of postmenopausal patients in the intervention arm and in 88.5% in the control arm. The results are presented here for supplementary information only.
• Overall assessment
  • For the benefit assessment of abemaciclib in combination with endocrine therapy for the treatment of hormone receptor-positive, HER2-negative early-stage breast cancer with a high risk of recurrence in postmenopausal patients, results are available from the ongoing, open-label, randomised, controlled MONARCH-E study on the endpoint categories of mortality, morbidity, health-related quality of life and side effects.
  • In the mortality endpoint category, the available results for the overall survival endpoint show no statistically significant difference between the study arms. Only minor numbers of events have been recorded for the overall survival endpoint.
  • In the morbidity category, for the endpoint of recurrence – expressed as the recurrence rate and disease-free survival – there were statistically significantly fewer recurrences in patients treated with abemaciclib in combination with endocrine therapy. In the current adjuvant treatment setting, the prevention of recurrence is a particularly relevant treatment objective.
  • With regard to symptoms and health status, statistically significant disadvantages were observed in relation to abemaciclib in combination with endocrine therapy. However, it cannot be concluded that the observed effects are clinically relevant.
  • In the quality of life category, there is a statistically significant disadvantage for abemaciclib in combination with endocrine therapy. However, it cannot be concluded that the observed effect is clinically relevant.
  • With regard to side effects, statistically significant disadvantages were observed for the endpoints of serious adverse events (SAEs), severe adverse events (AEs) and discontinuation due to AEs for treatment with abemaciclib in combination with endocrine therapy; in detail, this was also predominantly the case for the specific AEs.
  • On balance, the advantage in terms of preventing recurrences is offset by significant disadvantages relating to side effects. The disadvantages relating to side effects are weighed against the fact that preventing recurrences is an essential therapeutic goal in the present curative treatment context.
  • In a balanced assessment, and against the background of the observed effect size for the endpoint of recurrence, the G-BA concludes that the significant disadvantages in terms of side effects call into question the advantage regarding the endpoint of recurrence. It was taken into account that the statistical power of the available results for the endpoint of recurrence in the present treatment context is limited, as the median follow-up period in the study is only approximately 28 months.
  • It is therefore concluded overall that an additional benefit is not proven for abemaciclib in combination with endocrine therapy compared with endocrine therapy alone in the adjuvant treatment of postmenopausal patients with HER2-positive early-stage breast cancer and a high risk of recurrence.

a3) Men with early-stage, hormone receptor-positive, HER2-negative breast cancer and a high risk of recurrence

• An additional benefit is not proven.
• No interpretable data are available for the assessment of the additional benefit of abemaciclib in combination with endocrine therapy compared with the appropriate comparator therapy in men with hormone receptor-positive, HER2-negative early-stage breast cancer with a high risk of recurrence.
• The pharmaceutical manufacturer has submitted results for a total of 19 patients, of whom 10 were treated with abemaciclib in combination with endocrine therapy and 9 with endocrine therapy alone. Consequently, there is insufficient data to assess the additional benefit.

Courtesy translation only, please refer to the German original.