Ribociclib (4) – Kisqali®

• Clinical trials
  • To demonstrate the additional benefit of ribociclib in combination with fulvestrant compared with placebo in combination with fulvestrant, the pharmaceutical manufacturer has submitted the results of the most recent data cut-off from the randomised, double-blind, controlled Phase IIIMONALEESA-3 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

• Indication of a minor additional benefit
• In a decision weighing up the advantage in terms of overall survival against the significant disadvantages in terms of side effects, the G-BA concludes that ribociclib in combination with fulvestrant, in the treatment of postmenopausal patients with HR+ and HER2- advanced or metastatic breast cancer who have not yet received initial endocrine therapy, offers a minor additional benefit compared with fulvestrant.
• The certainty of the evidence for the identified additional benefit is classified as an ‘indication’.
• mortality
  • In the MONALEESA-3 trial, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • With regard to overall survival, the MONALEESA-3 trial showed a statistically significant advantage in favour of ribociclib in combination with fulvestrant compared with fulvestrant alone in patients who had not yet received initial endocrine therapy for locally advanced or metastatic disease.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the MONALEESA-3 study 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 ribociclib treatment group compared with the control group.
  • 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 endpoint ‘time to first subsequent chemotherapy’ was defined as the period from randomisation to the start of the first subsequent chemotherapy or death, regardless of the underlying cause of death.
  • The results for the endpoint ‘time to first subsequent chemotherapy’ are therefore not included in this assessment.
• Health-related quality of life
  • To assess health-related quality of life, the MONALEESA-3 study recorded the global health status and the functional scales of the disease-specific EORTC QLQ-C30 questionnaire. In each case, the time to a permanent deterioration of ≥ 10 points is considered.
  • No statistically significant difference was observed between the treatment groups for any of the five functional scales or for the global health status.
• Side effects – Adverse events
  • In MONALEESA-3, among patients who had not yet received initial endocrine therapy for locally advanced or metastatic disease, an adverse event occurred in 98.9% of patients in the intervention arm, compared with 96.0% of patients in the control arm.
• Overall assessment / Conclusion
  • The MONALEESA-3 study provides results for the patient population a1 regarding the additional benefit of ribociclib in combination with fulvestrant, compared with fulvestrant alone, in terms of mortality (overall survival), morbidity (symptoms, health status and pain), quality of life and side effects.
  • With regard to overall survival, the MONALEESA-3 study demonstrates an advantage of ribociclib in combination with fulvestrant compared with fulvestrant alone.
  • The results for the endpoint categories of morbidity and health-related quality of life show no statistically significant differences between the treatment arms.
  • In the overall analysis of the results on side effects, there were statistically significant and clinically relevant disadvantages for ribociclib in combination with fulvestrant compared with fulvestrant alone with regard to the endpoints of serious AEs, severe AEs (CTCAE grade 3 to 4), therapy discontinuations due to AEs and, in detail, the specific AEs mentioned.
  • In weighing up the advantage in terms of overall survival against the significant disadvantages regarding side effects, the G-BA concludes that, for ribociclib in combination with fulvestrant 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 compared with fulvestrant has been established.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of ribociclib in combination with fulvestrant in patient population a1, the MONALEESA-3 study provides results comparing it with fulvestrant in terms of mortality (overall survival), morbidity (symptoms, health status and pain), quality of life and side effects.
  • With regard to overall survival, the MONALEESA-3 study shows an advantage of ribociclib in combination with fulvestrant compared with fulvestrant alone.
  • The results for the endpoint categories of morbidity and health-related quality of life show no statistically significant differences between the treatment arms.
  • In the overall analysis of the results on side effects, there were statistically significant and clinically relevant disadvantages for ribociclib in combination with fulvestrant compared with fulvestrant alone with regard to the endpoints of serious AEs, severe AEs (CTCAE Grade 3 to 4), therapy discontinuations due to AEs and, in detail, the specific AEs mentioned.
  • In weighing up the advantage in terms of overall survival against the significant disadvantages regarding side effects, the G-BA concludes that ribociclib in combination with fulvestrant, in the treatment of postmenopausal patients with HR+ and HER2- advanced or metastatic breast cancer who have not yet received initial endocrine therapy, offers a minor additional benefit compared with fulvestrant.

b1) Postmenopausal women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who have previously received endocrine therapy

• mortality
  • In the MONALEESAS-3 trial, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • With regard to overall survival, the MONALEESA-3 trial showed no statistically significant difference between the treatment groups for patients with locally advanced or metastatic disease who had previously received endocrine therapy.
  • Given the specific data set presented here and in light of the available robust data on overall survival, the G-BA considers there to be a sufficient basis to exceptionally take into account, for the endpoint of overall survival, the results from the overall population of the MONALEESA-3 to be taken into account, on an exceptional basis, in the overall assessment of additional benefit for the endpoint of overall survival.
  • For the endpoint of overall survival in the overall population, ribociclib in combination with fulvestrant shows an advantage over fulvestrant alone.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the MONALEESA-3 trial 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.
  • In postmenopausal women with advanced or metastatic disease who had previously received endocrine therapy, PFS was also statistically significantly prolonged in the ribociclib treatment group compared with the control group.
  • 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.
• Health-related quality of life
  • To assess health-related quality of life, the MONALEESA-3 study used the global health status and functional scales of the disease-specific EORTC QLQ-C30 questionnaire. For the present assessment, the analysis of the time to a sustained deterioration in quality of life by ≥ 10 points is used.
  • For the emotional functioning symptom scale, a statistically significant advantage was observed in favour of ribociclib in combination with fulvestrant.
  • For the emotional functioning endpoint, a statistically significant effect modification was observed with regard to the characteristic of age (< 65 years, ≥ 65 years). The results indicate a more favourable effect on this endpoint for older patients aged ≥ 65 years.
• Side effects – Adverse events (AEs)
  • In MONALEESA-3, among patients with locally advanced or metastatic disease who had previously received endocrine therapy, an adverse event occurred in 100% of patients in the intervention arm, compared with 94.9% of patients in the control arm.
• Overall assessment / Conclusion
  • The MONALEESA-3 study provides results for the patient population b1 on the assessment of the additional benefit of ribociclib in combination with fulvestrant, compared with fulvestrant alone, in terms of mortality (overall survival), and morbidity (symptoms, pain and health status), quality of life and side effects.
  • With regard to overall survival, the analyses for the patient population b1 show no statistically significant difference between the treatment groups. Taking into account the methodological aspects cited, and in view of the available meaningful data on overall survival, the G-BA considers this specific set of data to provide a sufficient basis for, as an exception, also taking into account the results from the overall population of the MONALEESA-3 to be taken into account in the overall assessment of additional benefit. These show an advantage for ribociclib in combination with fulvestrant over fulvestrant alone for the endpoint of overall survival (overall population).
  • In the morbidity category, there is no statistically significant difference between the treatment groups for either the ‘symptoms’ or ‘health status’ endpoints.
  • For the endpoint ‘emotional functioning’ within the ‘quality of life’ endpoint category, there is an advantage of ribociclib in combination with fulvestrant compared with fulvestrant alone.
  • In the overall review of the results on side effects, there are statistically significant and clinically meaningful disadvantages for ribociclib in combination with fulvestrant compared with fulvestrant alone with regard to the endpoints of severe AEs (CTCAE Grade 3 to 4), therapy discontinuations due to AEs, and, in detail, the specific AEs mentioned.
  • In weighing up the advantage in overall survival from the overall population, the advantage regarding the ‘emotional functioning’ scale within the quality of life endpoint category, and the significant disadvantages in terms of side effects, the G-BA concludes that ribociclib in combination with fulvestrant, in the treatment of postmenopausal patients with HR+ and HER2- advanced or metastatic breast cancer who have previously received endocrine therapy, is found to offer a minor additional benefit compared with fulvestrant.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of ribociclib in combination with fulvestrant in patient population b1, the MONALEESA-3 study provides results comparing it with fulvestrant in terms of mortality (overall survival) and morbidity (symptoms, pain and health status), quality of life and side effects.
  • With regard to overall survival, the analyses for the patient population b1 show no statistically significant difference between the treatment groups. Taking into account the methodological aspects cited, and in view of the available meaningful data on overall survival, the G-BA considers this specific set of data to provide a sufficient basis for, as an exception, also taking into account the results from the overall population of the MONALEESA-3 to be taken into account in the overall assessment of additional benefit. These show an advantage for ribociclib in combination with fulvestrant over fulvestrant alone for the endpoint of overall survival (overall population).
  • In the morbidity category, there is no statistically significant difference between the treatment groups for either the symptomatology or health status endpoints.

Courtesy translation only, please refer to the German original.