Abemaciclib (7) – 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.

a) Verzenios in combination with endocrine therapy for the adjuvant treatment of premenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, nodal-positive early-stage breast cancer with a high risk of recurrence

• Hint for a minor additional benefit
• Taking the available results as a whole, the relevant—but no more than minor—improvement in overall survival and the relevant—but no more than minor—advantage in terms of preventing recurrence are offset by significant disadvantages in terms of side effects. In a balanced assessment, the G-BA concludes that there is a moderate – and not merely minor – improvement in treatment-related benefit and thus a minor additional benefit for abemaciclib in combination with endocrine therapy compared with endocrine therapy alone.
• mortality
  • Overall survival was defined in the MONARCH-E trial as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant advantage was observed in favour of abemaciclib in combination with endocrine therapy compared with the control arm.
  • The extent of the prolongation in overall survival achieved is assessed as a relevant improvement, but no more than a minor one.
• Morbidity – Recurrences (recurrence rate and disease-free survival (DFS))
  • Patients in this therapeutic indication are treated with a curative therapeutic approach. The failure of a curative therapeutic approach is, in principle, clinically relevant to the patient. In this regard, the interpretability of endpoints relating to relapses depends on the extent to which the selected individual components are suitable for adequately reflecting the failure of the potential cure through the curative treatment approach in question.
  • In this benefit assessment, both the recurrence rate and the DFS measure are considered in relation to recurrence. Both measures encompass the following events: local breast cancer recurrence, regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, secondary primary carcinoma (not breast cancer), and death from any cause.
  • This operationalisation is considered appropriate for reflecting a failure of the potential cure achieved through the curative therapeutic approach.
  • For the ‘recurrence’ endpoint, there is a statistically significant advantage with regard to abemaciclib in combination with endocrine therapy compared with endocrine therapy alone for each of the endpoint components: recurrence rate and disease-free survival.
  • Overall, when considering both endpoint components, a relevant but minor advantage is observed for abemaciclib in combination with endocrine therapy in terms of preventing recurrence.
• Morbidity – Symptoms (FACIT-Fatigue)
  • In the MONARCH-E study, the endpoint ‘symptoms’ was assessed using the validated FACIT-Fatigue questionnaire.
  • The results show a statistically significant disadvantage for abemaciclib in combination with endocrine therapy for the ‘symptoms’ endpoint. However, as the 95% CI of the standardised mean difference does not lie entirely outside the non-significant range of –0.2 to 0.2, it cannot be concluded that the observed effect is clinically relevant.
• Quality of life – Functional Assessment of Cancer Therapy – Breast (FACT-B)
  • Health-related quality of life is also assessed in the study using 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. However, as the 95% CI of the standardised mean difference does not lie entirely outside the irrelevance range of –0.2 to 0.2, it cannot be concluded that the observed effect is clinically relevant.
• Side effects – serious adverse events (SAEs), severe adverse events (CTCAE grade ≥ 3) and discontinuation due to AEs
  • For the endpoints SAE, severe AEs and discontinuation due to AEs, there is a statistically significant disadvantage for abemaciclib in combination with endocrine therapy compared with the control arm in each case.
• Overall assessment
  • For the endpoint of overall survival, there is a statistically significant advantage of abemaciclib in combination with endocrine therapy, which is assessed overall as a relevant but minor improvement.
  • In the morbidity category, there is a relevant, but no more than a minor, advantage of abemaciclib in combination with endocrine therapy in terms of preventing recurrence. In the current curative treatment setting, the prevention of recurrence represents a particularly relevant treatment objective. With regard to symptoms (FACIT-Fatigue), there is a statistically significant disadvantage compared to abemaciclib in combination with endocrine therapy. However, it cannot be concluded that the observed effect is relevant. For the health status endpoint (EQ-5D VAS), there is neither an advantage nor a disadvantage. Overall, an advantage is inferred for abemaciclib in combination with endocrine therapy.
  • With regard to health-related quality of life (FACT-B), there is a statistically significant disadvantage compared to abemaciclib in combination with endocrine therapy. However, it cannot be concluded that the observed effect is clinically relevant. Consequently, neither a benefit nor a disadvantage can be identified for health-related quality of life.
  • With regard to side effects, a significant disadvantage is identified for abemaciclib in combination with endocrine therapy, based on the disadvantages observed in the endpoints of serious adverse events, severe adverse events and discontinuation due to AEs, and, in detail, also for the specific adverse events.
  • Taking the available results as a whole, the relevant—but no more than minor—improvement in overall survival and the relevant—but no more than minor—advantage in terms of preventing recurrence are offset by significant disadvantages in terms of side effects. In a balanced assessment, the G-BA concludes that, taken as a whole, there is a moderate – and not merely minor – improvement in treatment-related benefit and thus a minor additional benefit for abemaciclib in combination with endocrine therapy compared with endocrine therapy alone.

a) Verzenios in combination with endocrine therapy for the adjuvant treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, nodal-positive early-stage breast cancer with a high risk of recurrence

• An additional benefit is not proven.
• On balance, the relevant but no more than minor advantage in terms of recurrence is offset by significant disadvantages in terms of side effects. No statistically significant difference is observed in terms of overall survival. In a cost-benefit analysis, the G-BA concludes – against the background of the absolute difference in recurrence rates between the treatment groups – that the significant disadvantages in terms of side effects call into question the relevant, but no more than minor, advantage regarding the recurrence endpoint. In this assessment, account is taken of the fact that the interpretability of the available results on recurrence is limited, as censoring occurred at an early stage and then continuously throughout the entire course of the study, and to a significant extent. It is therefore concluded that the additional benefit of abemaciclib in combination with endocrine therapy compared with endocrine therapy alone is not proven.
• mortality
  • Overall survival was defined in the MONARCH-E study as the time from randomisation to death from any cause.
  • There is no statistically significant difference between the two treatment groups for the endpoint of overall survival.
• Morbidity – Recurrences (recurrence rate and disease-free survival (DFS))
  • Patients in this therapeutic indication are treated with a curative therapeutic approach. The failure of a curative therapeutic approach is, in principle, clinically relevant to patients. In this regard, the interpretability of endpoints relating to recurrence depends on the extent to which the selected individual components are suitable for adequately reflecting the failure of the potential cure achieved by the curative treatment approach in question.
  • In this benefit assessment, both the recurrence rate and the analysis of DFS are considered in relation to recurrence. Both measures encompass the following events: local breast cancer recurrence, regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, secondary primary carcinoma (not breast cancer), and death from any cause.
  • This operationalisation is considered appropriate for capturing a failure of the potential cure achieved through the curative treatment approach.
  • For the ‘recurrence’ endpoint, there is a statistically significant advantage with regard to abemaciclib in combination with endocrine therapy compared with endocrine therapy alone for each of the endpoint components: recurrence rate and disease-free survival.
  • Overall, when considering both endpoint components, a relevant but no more than a minor advantage is observed for abemaciclib in combination with endocrine therapy in terms of preventing recurrence.
• Morbidity – Symptoms (FACIT-Fatigue)
  • In the MONARCH-E study, the endpoint ‘symptoms’ was assessed using the validated FACIT-Fatigue questionnaire.
  • For the symptom endpoint, there is a statistically significant difference in favor of abemaciclib in combination with endocrine therapy that is associated with a disadvantage. However, as the 95% CI of the standardised mean difference does not lie entirely outside the irrelevance range of –0.2 to 0.2, it cannot be concluded that the observed effect is clinically relevant.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • Health status was assessed using the EQ-5D Visual Analogue Scale.
  • The results show a statistically significant difference for the health status endpoint in favor of abemaciclib in combination with endocrine therapy, which has a disadvantage compared to other treatments. However, as the 95% CI of the standardised mean difference does not lie entirely outside the irrelevance range of -0.2 to 0.2, it cannot be concluded that the observed effect is clinically relevant.
• Quality of life – Functional Assessment of Cancer Therapy – Breast (FACT-B)
  • Health-related quality of life is also assessed in the study using the disease-specific FACT-B questionnaire.
  • For the health-related quality of life endpoint, there is a statistically significant disadvantage associated with abemaciclib in combination with endocrine therapy. However, as the 95% CI of the standardised mean difference does not lie entirely outside the irrelevance range of -0.2 to 0.2, it cannot be concluded that the observed effect is clinically relevant.
• Side effects – Serious adverse events (SAEs), severe adverse events (CTCAE grade ≥ 3) and discontinuation due to AEs
  • For the endpoints SAE, severe AEs and discontinuation due to AEs, there is a statistically significant disadvantage for abemaciclib in combination with endocrine therapy compared with the control arm.
• Overall assessment
  • For the endpoint of overall survival, there is no statistically significant difference between the treatment groups.
  • In the morbidity category, there is a relevant, albeit minor, advantage of abemaciclib in combination with endocrine therapy in terms of preventing recurrence. In the present curative treatment setting, preventing recurrence is a particularly relevant treatment objective. With regard to symptoms (FACIT-Fatigue) and health status (EQ-5D VAS), statistically significant disadvantages of abemaciclib in combination with endocrine therapy were observed. However, it cannot be concluded that the observed effects are clinically relevant. Overall, an advantage is inferred for abemaciclib in combination with endocrine therapy.
  • With regard to side effects, a significant disadvantage is observed for abemaciclib in combination with endocrine therapy, based on the disadvantages in the endpoints ‘serious adverse events’, ‘severe adverse events’ and ‘discontinuation due to AEs’, and, in detail, also for the specific adverse events as a whole.

Courtesy translation only, please refer to the German original.