Abemaciclib (6) – Verzenios®

• Clinical trials
  • To demonstrate the additional benefit of abemaciclib in combination with anastrozole or letrozole compared with anastrozole or letrozole alone, the pharmaceutical manufacturer has submitted the results of the randomised, double-blind, controlled Phase III MONARCH 3 trial.
  • The MONARCH plus study (Cohort A) is a double-blind, randomised and controlled Phase III trial comparing abemaciclib in combination with anastrozole or letrozole with placebo in combination with anastrozole or letrozole.

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

• In its 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 and other disadvantages relating to disease symptoms.
• For abemaciclib in combination with letrozole or anastrozole for the treatment of postmenopausal patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who have not yet received initial endocrine therapy, a minor additional benefit compared with letrozole or anastrozole is identified on balance.
• The certainty of evidence for the identified additional benefit is classified as ‘hint’.
• mortality
  • In the MONARCH 3 and MONARCH plus trials, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • Overall, the meta-analysis of the studies shows a significant prolongation of overall survival and thus an advantage from treatment with abemaciclib in combination with letrozole or anastrozole compared with letrozole or anastrozole alone.
  • In the MONARCH 3 trial, abemaciclib led to a 12.6-month prolongation of the median overall survival in postmenopausal patients after a prolonged follow-up period.
  • In the MONARCH plus trial, no statistically significant prolongation in overall survival has been observed to date.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival is the primary endpoint in both studies 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.
  • PFS was statistically significantly prolonged in the abemaciclib treatment group compared with the control group.
  • However, the prolonged PFS with abemaciclib was not associated with any advantage in terms of morbidity or quality of life in the meta-analysis of the two studies, MONARCH 3 and MONARCH plus.
  • In summary, the available data do not indicate that the statistically significant prolongation of progression-free survival observed with abemaciclib is associated with an improvement in morbidity or health-related quality of life. The results for the progression-free survival endpoint are therefore not taken into account in this assessment.
• Morbidity – time to first subsequent chemotherapy
  • The endpoint ‘time to first subsequent chemotherapy’ was only assessed in the MONARCH 3 trial and is defined as the period 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.
  • 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, in the present case there are clear uncertainties regarding the validity 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
  • Health-related quality of life was assessed in the MONARCH 3 study using the functional scales and the global health status scale of the cancer-specific EORTC QLQand the breast cancer-specific supplementary module EORTC QLQ-BR23, up to 30 days after the end of treatment.
  • In the analysis of ‘time to first deterioration’ by ≥ 10 points, the meta-analysis revealed a statistically significant difference to the detriment of abemaciclib in combination with letrozole or anastrozole compared with letrozole or anastrozole alone only for the ‘body image’ domain of the breast cancer-specific supplementary module EORTC QLQ-BR23, which was assessed only in the Monarch 3 trial, showed a statistically significant disadvantage for abemaciclib in combination with letrozole or anastrozole compared with letrozole or anastrozole.
  • Overall, based solely on the disadvantage in the ‘body image’ domain of the breast cancer-specific supplementary module EORTC QLQ-BR23, which, moreover, was assessed only in the Monarch 3 trial, no disadvantage can be inferred from the overall analysis of the results for health-related quality of life.
  • There are therefore no relevant differences between the treatment arms with regard to health-related quality of life.
• Side effects – Adverse events (AEs), total
  • In the MONARCH 3 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 94.4% of patients.
  • In the MONARCH plus study, adverse events occurred in 99.5% of patients in the intervention arm and in 89.9% of patients in the control arm.
• Overall assessment
  • With regard to overall survival, the meta-analysis shows an advantage of abemaciclib in combination with letrozole or anastrozole compared with letrozole or anastrozole alone.
  • The assessments of symptoms (measured using the EORTC QLQ-C30 and EORTC QLQ-BR23) used in the benefit assessment for the morbidity endpoint category show, in particular for the domains of fatigue, nausea and vomiting, and loss of appetite, which is why, when considered as a whole, a disadvantage is inferred for symptoms.
  • With regard to health-related quality of life (assessed using the EORTC QLQ-C30 / EORTC QLQ-BR23), there are no differences relevant to the benefit assessment.
  • In the overall analysis of the results on side effects, there are statistically significant and clinically meaningful disadvantages for abemaciclib in combination with anastrozole or letrozole compared with anastrozole or letrozole alone with regard to the endpoints of serious AEs, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
  • In its cost-benefit analysis, the G-BA concludes that, overall, the advantage in terms of overall survival outweighs the significant disadvantages relating to side effects and other disadvantages concerning disease symptoms.

Courtesy translation only, please refer to the German original.