Abemaciclib (1) – Verzenios®

• Clinical trials
  • To demonstrate the additional benefit of abemaciclib in combination with an aromatase inhibitor as initial therapy in postmenopausal patients, the pharmaceutical manufacturer has submitted the results of the randomised, double-blind Phase III MONARCH-3 trial.
  • This multinational trial (N=493) enrolled postmenopausal patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer. The drug combinations abemaciclib plus anastrozole or letrozole (N=328) were compared with placebo plus anastrozole or letrozole (N=165).

a1) Postmenopausal women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who have 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 from abemaciclib in combination with anastrozole or letrozole is not proven compared with anastrozole or letrozole alone.
• mortality
  • With regard to overall survival, no statistically significant difference was observed between the study arms in MONARCH-3 (HR: 1.07 [95% CI: 0.69; 1.66]; p = 0.757).
  • Based on the available results, the addition of abemaciclib to treatment with anastrozole or letrozole does not provide any additional benefit for the endpoint category of mortality.
• Morbidity – diarrhoea
  • For the endpoint ‘diarrhoea’, a statistically significant difference was observed to the detriment of abemaciclib plus anastrozole or letrozole (HR: 2.23 [95% CI: 1.44; 3.45]; p<0.001).
  • In the morbidity endpoint category, treatment with abemaciclib plus anastrozole or letrozole was associated with a disadvantage regarding the symptom of diarrhoea.
• Morbidity – time to first subsequent chemotherapy
  • The endpoint ‘time to first subsequent chemotherapy’ was defined post-hoc in the dossier for this benefit assessment as the period from randomisation to the start of the first subsequent chemotherapy or death, regardless of the underlying cause of death.
  • 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 significant 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.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • These show no statistically significant difference between the treatment arms for the time to permanent deterioration.
  • An additional benefit of abemaciclib in combination with anastrozole or letrozole for the health status endpoint (EQ-5D-VAS) is not proven.
• Health-related quality of life – body image
  • For the ‘body image’ endpoint, a statistically significant difference was observed to the detriment of abemaciclib + anastrozole or letrozole (HR: 1.55 [95% CI: 1.00; 2.40]; p=0.047).
  • In the health-related quality of life category, treatment with abemaciclib plus anastrozole or letrozole resulted in a disadvantage in terms of the ‘body image’ endpoint.
• Side effects – Adverse events (AEs)
  • In MONARCH-3, an adverse event occurred in 98.8% of patients in the intervention arm, compared with 94.4% of patients in the control arm.
• Side effects – Serious adverse events (SAEs)
  • For serious adverse events, there was a statistically significant disadvantage for abemaciclib in combination with anastrozole or letrozole (HR: 1.90 [95% CI: 1.24; 2.90]; p = 0.003).
  • Consequently, for women aged ≥ 65 years, there was a statistically significant effect to the detriment of abemaciclib plus anastrozole or letrozole (HR: 3.33 [95% CI: 1.80; 6.17]; p < 0.001).
• Side effects – severe AEs (CTCAE grade 3 or 4)
  • A statistically significant treatment effect was observed, to the detriment of abemaciclib in combination with anastrozole or letrozole, with regard to the time to onset of severe adverse events of CTCAE grade 3 or 4 (HR: 3.14 [95% CI: 2.25; 4.39]; p < 0.001).
  • For women aged ≥ 65 years, a statistically significant effect was observed to be disadvantageous for abemaciclib plus anastrozole or letrozole (HR: 5.77 [95% CI: 3.54; 9.41]; p < 0.001).
  • A statistically significant disadvantage of abemaciclib plus anastrozole or letrozole was also observed in women aged < 65 years (HR: 1.94 [95% CI: 1.23; 3.07]; p = 0.004).
• Side effects – discontinuation due to AEs
  • For the median time to therapy discontinuation due to an AE, there was a statistically significant effect to the detriment of abemaciclib in combination with anastrozole or letrozole (HR: 6.25 [95% CI: 2.73; 14.34]; p < 0.001).
• Side effects – neutropenia (CTCAE grade ≥ 3)
  • The combination of abemaciclib plus anastrozole or letrozole showed a statistically significant disadvantage compared with anastrozole or letrozole alone in terms of neutropenia (CTCAE grade ≥ 3) (RR: 19.20 [4.78; 77.16]; p < 0.001).
• Overall assessment
  • 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.
  • The results for the morbidity endpoint category show a disadvantage of treatment with abemaciclib plus anastrozole or letrozole compared with treatment with anastrozole or letrozole alone with regard to the symptom of diarrhoea.
  • With regard to health-related quality of life, treatment with abemaciclib plus anastrozole or letrozole shows a disadvantage in terms of the ‘body image’ endpoint.
  • With regard to side effects, no statistically significant disadvantages were observed for abemaciclib in combination with anastrozole or letrozole compared with anastrozole or letrozole alone for the endpoints of serious adverse events (SAEs), severe adverse events (CTCAE Grade 3 or 4), therapy discontinuations due to adverse events, or, specifically for the specific adverse event neutropenia (CTCAE grade 3 or 4), significant, statistically significant disadvantages were observed for abemaciclib in combination with anastrozole or letrozole compared with anastrozole or letrozole alone, particularly with regard to the pronounced myelosuppression caused by abemaciclib.
  • 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 decision based on a balancing of interests, the G-BA concludes that, for abemaciclib in combination with anastrozole or letrozole for the treatment of postmenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer does not have an additional benefit compared to anastrozole or letrozol.

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 an aromatase inhibitor is not proven compared with the appropriate comparator therapy.
• For pre- and perimenopausal patients who have not yet received initial endocrine therapy, no data have been presented to assess the additional benefit of abemaciclib in combination with an aromatase inhibitor compared with the appropriate comparator therapy. The MONARCH-3 study presented here exclusively involved postmenopausal patients.

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, an additional benefit of abemaciclib in combination with an aromatase inhibitor compared with the appropriate comparator therapy is not proven.
• For postmenopausal patients who have previously received endocrine therapy, no data have been submitted to assess the additional benefit of abemaciclib in combination with an aromatase inhibitor compared with the appropriate comparator therapy. In the submitted MONARCH-3 study, postmenopausal patients were studied exclusively as part of initial endocrine therapy for locally advanced or metastatic disease.

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, additional benefit from abemaciclib in combination with an aromatase inhibitor compared with the appropriate comparator therapy is not proven.
• For pre- and perimenopausal patients who have previously received endocrine therapy, no data have been submitted to assess the additional benefit of abemaciclib in combination with an aromatase inhibitor compared with the appropriate comparator therapy. The MONARCH-3 study, which was submitted to support the combination therapy of abemaciclib with an aromatase inhibitor, exclusively enrolled postmenopausal patients.

Courtesy translation only, please refer to the German original.