Ribociclib (5) – Kisqali®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer has submitted, as part of the dossier, results from the ongoing, open-label, randomised, controlled NATALEE trial, in which ribociclib in combination with anastrozole or letrozole is compared with anastrozole or letrozole alone.

a1) Premenopausal women with early-stage hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)- e breast cancer with a high risk of recurrence; adjuvant treatment

• The additional benefit is not proven.
• mortality
  • For the endpoint of overall survival, following a median follow-up period of approximately 44 months and based on minor event numbers, a statistically significant advantage was observed in favour of ribociclib in combination with an aromatase inhibitor compared with the control arm.
  • The extent of the prolongation in overall survival achieved is assessed as a relevant improvement, though one that does not go beyond a minor extent.
• Morbidity – Recurrences (recurrence rate and invasive disease-free survival (iDFS))
  • 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 achieved by the curative treatment approach in question.
  • Both the event rate and the event time analysis (iDFS) show a statistically significant difference in favour of ribociclib in combination with an aromatase inhibitor compared with the control arm, with a median follow-up of approximately 44 months.
  • The extent of the advantage achieved in terms of recurrence is assessed as a relevant improvement, albeit one that does not go beyond a minor level.
• Morbidity – Symptoms (EORTC QLQ-C30 and EORTC QLQ-BR23)
  • Statistically significant differences between the treatment arms were observed in the QLQ-C30 scales for fatigue, nausea and vomiting, and constipation, as well as in the QLQ-BR23 scales for side effects of systemic therapy, breast symptoms and arm symptoms.
  • However, the 95% confidence interval for the standardised mean difference (SMD) does not lie entirely outside the irrelevance range of −0.2 to 0.2 for any of the scales. It cannot therefore be concluded that the observed effects are clinically relevant.
  • No statistically significant differences were found on the remaining scales; furthermore, for the ‘stress due to hair loss’ scale of the QLQ-BR23, no suitable data are available due to an insufficient proportion of evaluable patients.
• Morbidity – Health Status (EQ-5D VAS)
  • The results show no statistically significant difference between the treatment groups.
• Health-related quality of life – EORTC QLQ-C30 and EORTC QLQ-BR23
  • Statistically significant differences were observed between the treatment arms on the global health status scale and the physical functioning, role functioning and social functioning scales of the QLQ-C30.
  • However, the 95% confidence interval for the standardised mean difference (SMD) does not lie entirely outside the irrelevance range of −0.2 to 0.2 on any scale. It cannot therefore be concluded that the observed effects are clinically relevant.
  • No statistically significant differences were found in the remaining scales of the QLQ-C30 or the QLQ-BR23; furthermore, no suitable data are available for the ‘sexual enjoyment’ scale of the QLQ-BR23 due to an insufficient number of evaluable patients.
• Side effects – Serious adverse events (SAE), severe adverse events (CTCAE grade ≥ 3) and discontinuation due to AEs
  • For the endpoints SAE, severe AEs and discontinuation due to AEs, a statistically significant disadvantage was observed for ribociclib in combination with an aromatase inhibitor compared with the control arm.
• Side effects – Specific adverse events
  • In detail, the specific AEs observed include neutropenia (PT, severe AE), disorders of the skin and subcutaneous tissue (SOC, AE), disorders of the respiratory tract, thoracic cavity and mediastinum (SOC, AE), infections and parasitic diseases (SOC, severe AE), gastrointestinal disorders (SOC, severe AE), general disorders and administration site conditions (SOC, AEs) and hepatobiliary toxicity (SMQ, severe AEs), each showing a statistically significant disadvantage compared to ribociclib in combination with an aromatase inhibitor.
• Overall assessment
  • For the benefit assessment of ribociclib in combination with an aromatase inhibitor for adjuvant treatment in premenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative early-stage breast cancer with a high risk of recurrence, results are available from the open-label, randomised, controlled and currently ongoing NATALEE study regarding the endpoint categories of mortality, morbidity, health-related quality of life and side effects.
  • In a cost-benefit analysis, the G-BA concludes – against the background of the observed effect size on overall survival and recurrence – that the significant disadvantages in terms of side effects call into question the advantages regarding overall survival and recurrence.
  • It is therefore concluded that the additional benefit of ribociclib in combination with an aromatase inhibitor is not proven in patient group a1).

a2) Postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer with a high risk of recurrence; adjuvant treatment

• An additional benefit is not proven.
• mortality
  • For the endpoint of overall survival, no statistically significant difference was observed between the treatment groups over a median follow-up period of approximately 44 months, based on minor event numbers.
• Morbidity – Recurrences (recurrence rate and invasive disease-free survival (iDFS))
  • 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 relapses 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.
  • Both the event rate and the time-to-event analysis show a statistically significant difference in favour of ribociclib in combination with an aromatase inhibitor compared with the control arm, with a median follow-up period of approximately 44 months.
  • The extent of the advantage achieved in terms of recurrence is assessed as a relevant improvement, albeit one that does not go beyond a minor level.
• Morbidity – Symptoms (EORTC QLQ-C30 and EORTC QLQ-BR23)
  • Statistically significant differences between the treatment arms were observed in the nausea and vomiting, pain and constipation subscales of the QLQ-C30, and in the ‘side effects of systemic therapy’ subscale of the QLQ-BR23.
  • However, the 95% confidence interval for the standardised mean difference (SMD) does not lie entirely outside the irrelevance range of −0.2 to 0.2 for any of the scales. It cannot therefore be concluded that the observed effects are clinically relevant.
  • No statistically significant differences were found in the remaining scales; furthermore, for the ‘Stress due to hair loss’ scale of the QLQ-BR23, no suitable data are available due to an insufficient number of evaluable patients.
• Morbidity – Health Status (EQ-5D VAS)
  • The results show no statistically significant difference between the treatment groups.
• Health-related quality of life – EORTC QLQ-C30 and EORTC QLQ-BR23
  • There are no statistically significant differences between the treatment arms on the QLQ-C30 or QLQ-BR23 scales.
  • With regard to the sexual enjoyment subscale of the QLQ-BR23, no suitable data are available due to an insufficient proportion of evaluable female patients.
• Side effects – serious adverse events (SAE), severe adverse events (CTCAE grade ≥ 3) and discontinuation due to AEs
  • For the endpoints SAE, severe AEs and discontinuation due to AEs, a statistically significant disadvantage was observed for ribociclib in combination with an aromatase inhibitor compared with the control arm.
• Side effects – Specific adverse events
  • In detail, the specific AEs included neutropenia (PT, severe AE), gastrointestinal disorders (SOC, AEs), disorders of the skin and subcutaneous tissue (SOC, AEs), disorders of the respiratory tract, thoracic cavity and mediastinum (SOC, AEs), infections and parasitic diseases (SOC, severe AEs), disorders of the nervous system (SOC, severe AEs), fatigue (PT, severe AE), hepatobiliary toxicity (SMQ, severe AE) and renal toxicity (SMQ, severe AE), there was a statistically significant disadvantage for ribociclib in combination with an aromatase inhibitor.
• Overall assessment
  • For the benefit assessment of ribociclib in combination with an aromatase inhibitor for adjuvant treatment in postmenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative early-stage breast cancer with a high risk of recurrence, results are available from the open-label, randomised, controlled and currently ongoing NATALEE study regarding the endpoint categories of mortality, morbidity, health-related quality of life and side effects.
  • In a cost-benefit assessment, the G-BA concludes, in light of the observed effect size regarding recurrences, that the significant disadvantages in terms of side effects call into question the advantage in terms of recurrences.
  • It is therefore concluded that an additional benefit is not proven for ribociclib in combination with an aromatase inhibitor in patient group a2).

a3) Men with early-stage hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)- e breast cancer with a high risk of recurrence; adjuvant treatment

• The pharmaceutical manufacturer has not submitted any data for the assessment of the additional benefit of ribociclib in combination with an aromatase inhibitor in patient group a3). Proof of the additional benefit is therefore provided.
• An additional benefit is not proven.

Courtesy translation only, please refer to the German original.