Ribociclib (3) – Kisqali®

• Clinical trials
  • To demonstrate the additional benefit of ribociclib in combination with letrozole compared with placebo in combination with letrozole, the pharmaceutical manufacturer has submitted the results of the most recent data cut-off from the randomised, double-blind, controlled Phase IIIMONALEESA-2 trial, which is already known from the previous benefit assessment of ribociclib in the current therapeutic indication.

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

• Overall, there is a hint of a minor additional benefit for ribociclib plus letrozole compared with letrozole alone in the treatment of postmenopausal women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who have not yet received initial endocrine therapy.
• Given the decisive importance of the overall survival result for the trade-off decision outlined above in the overall assessment of additional benefit, the certainty of the evidence for the established additional benefit is therefore classified as ‘hint’.
• mortality
  • For the endpoint of overall survival, there is a statistically significant difference in favour of ribociclib in combination with letrozole compared with letrozole alone.
• Morbidity – Progression-free survival (PFS)
  • For progression-free survival, a statistically significant difference was observed between the treatment groups in favour of ribociclib.
  • In summary, the available data do not indicate that the statistically significant prolongation of progression-free survival observed with ribociclib 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 results for the endpoint ‘time to first subsequent chemotherapy’ are therefore not taken into account in this assessment.
• Morbidity – Symptoms
  • For the dyspnoea symptom scale of the EORTC QLQ-C30, an effect modification by the characteristic of age is observed. For patients aged ≥ 65 years, there is a statistically significant disadvantage of ribociclib plus letrozole compared with letrozole alone. For patients aged < 65 years, there is no statistically significant difference between the treatment groups.
  • No usable data are available for the endpoint ‘burden of hair loss’. For all other endpoints presented, no statistically significant difference was observed between the treatment groups.
• Morbidity – Health status
  • The differences in mean scores show no statistically significant difference in favour of ribociclib in combination with letrozole.
  • In the responder analyses, no statistically significant difference was observed between the two treatment arms for the health status endpoint, neither at a MID of 7 points nor at a MID of 10 points.
• Health-related quality of life
  • For the endpoint ‘future prospects’, a statistically significant difference was observed in favour of ribociclib + letrozole. No valid analyses are available for the endpoint ‘sexual enjoyment’. For all other endpoints presented, no statistically significant difference was observed between the treatment groups.
  • In the health-related quality of life endpoint category, a moderate advantage was observed in only one domain.
• Side effects – Serious adverse events (SAEs)
  • For serious adverse events, a statistically significant difference was observed to the disadvantage of ribociclib + letrozole compared with placebo + letrozole.
• Side effects – Severe AEs (CTCAE Grade 3 or 4)
  • For the endpoint of severe adverse events (CTCAE Grade 3 or 4), a statistically significant difference was observed to the disadvantage of ribociclib + letrozole compared with placebo + letrozole.
• Side effects – discontinuation due to AEs
  • A statistically significant effect was observed for this endpoint, to the detriment of ribociclib plus letrozole compared with letrozole alone. In the intervention arm, 19.8% of patients discontinued the study medication completely or partially, compared with 4.5% in the control arm.
• Side effects – Specific AEs
  • In detail, with regard to specific adverse events, the combination of ribociclib plus letrozole showed statistically significant disadvantages compared with letrozole alone for the endpoints ‘Blood and lymphatic system disorders’ (CTCAE Grade 3 or 4), ‘Gastrointestinal disorders’ (CTCAE Grade 3 or 4), ‘Infections and infestations’ (CTCAE Grade 3 or 4) and ‘Investigations’ (CTCAE Grade 3 or 4). Neutropenia (CTCAE Grade 3 or 4), which is included in the endpoint ‘Blood and lymphatic system disorders’, is the defining event here.
• Overall assessment / Conclusion
  • The MONALEESA-2 study provides results for assessing the additional benefit of ribociclib in combination with letrozole, compared with letrozole alone, in terms of mortality (overall survival), morbidity (symptoms and health status), quality of life and side effects.
  • With regard to overall survival, the MONALEESA-2 study shows an advantage of ribociclib plus letrozole over letrozole alone. In the morbidity category, there is no statistically significant difference between the treatment arms for either the endpoints of symptoms or health status. With regard to health-related quality of life, overall, neither advantages nor disadvantages can be inferred for treatment with ribociclib in combination with letrozole compared with letrozole alone.
  • In the overall analysis of the results on side effects, there are statistically significant and clinically meaningful disadvantages for ribociclib in combination with letrozole compared with letrozole alone with regard to the endpoints of serious AEs, severe AEs (CTCAE grades 3 to 4), therapy discontinuations due to AEs, and, in detail, the specific AEs mentioned.
  • In its cost-benefit analysis, the G-BA concludes that, for ribociclib in combination with letrozole in the treatment of postmenopausal patients with HR+ and HER2- advanced or metastatic breast cancer who have not yet received initial endocrine therapy, a minor additional benefit has been identified compared with letrozole monotherapy, due to the prolongation of survival.

Courtesy translation only, please refer to the German original.