Ribociclib (2) – Kisqali®

• Clinical trials
  • The pharmaceutical manufacturer has submitted results from the randomised, double-blind Phase III MONALEESA-7 trial to demonstrate the additional benefit of ribociclib in combination with an aromatase inhibitor.
  • This multinational trial (N=672) enrolled pre- and perimenopausal patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer who had not yet received endocrine therapy for the treatment of their advanced or metastatic disease. The study compared the drug combinations ribociclib plus tamoxifen or nsAI (non-steroidal aromatase inhibitor) (N=335) with placebo plus tamoxifen or nsAI (N=337).
• Clinical trials
  • The pharmaceutical manufacturer has submitted results from the randomised, double-blind Phase III MONALEESA-3 trial to demonstrate the additional benefit of ribociclib in combination with fulvestrant.
  • This multinational trial (N=726) enrolled postmenopausal women with locally advanced or metastatic HR-positive, HER2-negative breast cancer who had received no more than one line of endocrine therapy for their locally advanced or metastatic disease. The study compared the combination of ribociclib and fulvestrant (N=484) with placebo and fulvestrant (N=242).

a2) Pre-/perimenopausal women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who had 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, additional benefit from ribociclib in combination with letrozole is not proven compared with letrozole alone.
• In a cost-benefit analysis, the G-BA concludes that additional benefit for ribociclib in combination with letrozole is not proven compared with letrozole alone.
• mortality
  • In the MONALEESA-7 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-7 trial showed no statistically significant difference between the treatment groups for patients who had not yet received initial endocrine therapy at the locally advanced or metastatic stage (HR: 0.78 [95% CI: 0.50; 1.21]; p = 0.268).
  • Based on the available results, the addition of ribociclib to letrozole therapy does not provide any additional benefit for the endpoint category of mortality.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the MONALEESA-7 trial and was 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.
  • Median PFS was statistically significantly prolonged by 8.7 months in the ribociclib treatment group compared with the control group (median 17.9 vs. 9.2 months; HR: 0.59 [95% CI: 0.42; 0.83]; p = 0.002).
  • The results for the progression-free survival endpoint are not included 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 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.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • General health status was assessed using the EQ-5D visual analogue scale.
  • These responder analyses were not pre-specified in the MONALEESA-7 study.
  • They show no statistically significant difference between the treatment arms in terms of time to permanent deterioration.
  • The additional benefit of ribociclib in combination with letrozole for the health status endpoint (EQ-5D-VAS) is not proven.
• Morbidity – Symptoms (pain)
  • For the ‘pain’ endpoint, a statistically significant difference was observed in favour of ribociclib + letrozole (HR: 0.43 [95% CI: 0.23; 0.81]; p=0.007).
• Morbidity – Symptoms (fatigue)
  • A statistically significant advantage was also observed for the ‘fatigue’ endpoint, in favour of ribociclib + letrozole (HR: 0.51 [95% CI: 0.29; 0.90]; p<0.018).
• Health-related quality of life – cognitive functioning
  • For the endpoints ‘cognitive functioning’ and ‘future outlook’, a statistically significant difference was observed in favour of ribociclib + letrozole (HR: 0.61 [95% CI: 0.38; 0.97]; p = 0.040) and (HR: 0.42 [95% CI: 0.23; 0.80]; p = 0.006), respectively.
• Side effects – Serious adverse events (SAEs)
  • No statistically significant difference was observed between the treatment groups with regard to serious adverse events.
• Overall assessment
  • The MONALEESA-7 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.
  • The relevant patient population for the study comprised those patients who experienced a recurrence during or within 12 months of the end of (neo-)adjuvant therapy and who had received prior (neo-)adjuvant treatment with tamoxifen.
  • In the mortality endpoint category, there was no statistically significant difference between the treatment groups for the endpoint of overall survival.
  • Based on the available data, an additional benefit of ribociclib in combination with letrozole for overall survival is not proven.
  • In the morbidity endpoint category, there is an advantage from treatment with ribociclib plus letrozole.
  • With regard to health-related quality of life, there are statistically significant differences in favour of treatment with ribociclib plus letrozole for the endpoints of cognitive functioning and outlook on the future.
  • Thus, advantages of ribociclib in combination with letrozole can be demonstrated for individual endpoints in the questionnaires used; however, the interpretability of these results is limited by the operationalisation used in the MONALEESA-7 study and due to potentially informative censoring resulting from differing median treatment durations across the study arms.
  • In contrast, with regard to side effects, there are significant, statistically significant disadvantages for ribociclib in combination with letrozole in terms of the endpoints of severe adverse events (CTCAE Grade 3 or 4) and, more specifically, for the AEs ‘blood and lymphatic system disorders’ (CTCAE Grade 3 or 4), there are significant, statistically significant disadvantages for ribociclib in combination with letrozole compared with letrozole alone, particularly with regard to the pronounced myelosuppression caused by ribociclib.
  • Overall, the adverse reaction profile of ribociclib differs significantly from that of endocrine therapy.
  • Taking clinical relevance into account, the extent of the disadvantage in terms of side effects does not reach a level that would justify less benefit in the overall assessment.

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 the assessment of the additional benefit for postmenopausal women who have not yet received initial endocrine therapy (patient group a1), reference is made to the previous benefit assessment procedure for ribociclib, as set out in the resolution of 16 March 2018.
• This patient group is not the subject of the present benefit assessment procedure.

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, additional benefit is not proven with ribociclib in combination with an aromatase inhibitor compared with the appropriate comparator therapy.
• For postmenopausal patients who have not yet received initial endocrine therapy, no data have been presented to assess the additional benefit of ribociclib in combination with an aromatase inhibitor compared with the appropriate comparator therapy. The MONALEESA-7 study presented here exclusively investigated pre- and perimenopausal patients.

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 is not proven from ribociclib in combination with an aromatase inhibitor compared with the appropriate comparator therapy.
• For pre- and perimenopausal patients who have previously received endocrine therapy, no data have been presented to assess the additional benefit of ribociclib in combination with an aromatase inhibitor compared with the appropriate comparator therapy. In the submitted MONALEESA-7 study, pre- and perimenopausal patients were studied exclusively as part of initial endocrine therapy for locally advanced or metastatic disease.

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 ribociclib in combination with fulvestrant compared with fulvestrant alone is not proven.
• mortality
  • In the MONALEESA-3 study, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • In the MONALEESA-3 trial, no statistically significant difference in overall survival was observed between the treatment groups for patients who had not yet received initial endocrine therapy for locally advanced or metastatic disease (HR: 0.66 [95% CI: 0.43; 1.02]; p = 0.061).
  • Extrapolating the results from the overall population—which showed a statistically significant difference in favour of ribociclib in combination with fulvestrant—is associated with major uncertainties due to methodological and clinical factors.
• morbidity
  • Progression-free survival (PFS)
  • Median PFS was statistically significantly prolonged by 7.7 months in the ribociclib treatment group compared with the control group (median 20.6 vs. 12.9 months; HR: 0.61 [95% CI: 0.48; 0.77]; p < 0.001).
  • The results for the progression-free survival endpoint are therefore not included in this assessment.
  • Time to first subsequent chemotherapy
  • For patients who are in an early stage of advanced/metastatic breast cancer and who have so far only been treated with endocrine therapy at this stage of the disease, delaying treatment with cytotoxic (intravenous) chemotherapy—which may be associated with known relevant side effects [...]—be of significance.
  • 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.
  • Health status (EQ-5D Visual Analogue Scale)
  • General health status was assessed using the EQ-5D visual analogue scale.
  • These show no statistically significant difference between the treatment arms for the period up to permanent deterioration.
  • No additional benefit of ribociclib in combination with fulvestrant for the health status endpoint (EQ-5D-VAS) is not proven.
  • Symptoms
  • Symptoms were assessed in the MONALEESA-3 study using the symptom scales of the disease-specific EORTC QLQ-C30 questionnaire.
  • No statistically significant difference was observed between the treatment groups for any of the endpoints presented.
  • Pain (BPI-SF)
  • Due to incomplete data on the BPI-SF, this endpoint is not included in the present assessment.
• quality of life
  • To assess health-related quality of life, the functional scales of the disease-specific EORTC QLQ-C30 questionnaire were used in the MONALEESA-3 study.
  • No statistically significant difference was observed between the treatment groups for any of the endpoints presented.
• Side effects
  • Adverse events (AEs)
  • 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.
  • Serious adverse events (SAEs)
  • For serious adverse events, a statistically significant effect was observed to the disadvantage of ribociclib in combination with fulvestrant (HR: 1.61 [95% CI: 1.09; 2.38]; p = 0.015).
  • Severe AEs (CTCAE Grade 3 or 4)
  • A statistically significant treatment effect to the detriment of ribociclib in combination with fulvestrant was observed with regard to the time to onset of severe adverse events of CTCAE grade 3 or 4 (HR: 4.49 [95% CI: 3.39; 5.95]; p < 0.001).
  • Discontinuation due to AEs
  • A statistically significant effect was observed to the detriment of ribociclib in combination with fulvestrant for the median time to therapy discontinuation due to an AE (HR: 2.33 [95% CI: 1.27; 4.26]; p = 0.005).
  • Specific AEs
  • In detail, the combination of ribociclib plus fulvestrant showed a statistically significant disadvantage compared with fulvestrant alone with regard to the endpoint ‘disorders of the blood and lymphatic system’ (CTCAE grade ≥ 3) (HR: 40.72 [95% CI: 13.00; 127.56]; p < 0.001).
  • The adverse reaction profile of ribociclib is qualitatively comparable to that of cytotoxic chemotherapy, particularly with regard to myelosuppression, and differs significantly from the adverse reaction profile of endocrine therapy.
• Overall assessment
  • In the mortality endpoint category, there is no statistically significant difference between the treatment groups for the overall survival endpoint in patient population a1.
  • The results for the endpoint categories of morbidity and health-related quality of life show no statistically significant differences between the treatment arms.
  • With regard to side effects, there were no statistically significant differences between the treatment arms for the endpoints serious adverse events (SAE), severe adverse events (CTCAE grade 3 or 4), therapy discontinuations due to adverse events, and, in more detail, for the specific AE category ‘blood and lymphatic system disorders’ (CTCAE grade 3 or 4), significant, statistically significant disadvantages were observed for ribociclib in combination with fulvestrant compared with fulvestrant alone, particularly with regard to the pronounced myelosuppression caused by ribociclib.
  • In a balanced assessment, the G-BA concludes that, for ribociclib in combination with fulvestrant for the treatment of postmenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who have not yet received initial endocrine therapy at this stage of the disease, an additional benefit is not proven.

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, an additional benefit of ribociclib in combination with fulvestrant is not proven compared with the appropriate comparator therapy.
• For pre-/perimenopausal patients who have not yet received initial endocrine therapy, no data have been provided to assess the additional benefit of ribociclib in combination with fulvestrant compared with the appropriate comparator therapy. The MONALEESA-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, additional benefit from ribociclib in combination with fulvestrant is not proven compared with fulvestrant alone.
• mortality
  • In the MONALEESA-3 trial, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • In the MONALEESA-3 trial, no statistically significant difference in overall survival was observed between the treatment groups for patients with locally advanced or metastatic disease who had received prior endocrine therapy (HR: 0.60 [95% CI: 0.30; 1.23]; p = 0.166).
  • Extrapolating the results from the overall population—which show a statistically significant difference in favour of ribociclib in combination with fulvestrant—is associated with major uncertainties due to methodological and clinical factors.
• morbidity
  • Progression-free survival (PFS)
  • In postmenopausal women with a history of endocrine therapy in the advanced or metastatic stage, PFS was also statistically significantly prolonged by a median of 7.4 months in the ribociclib treatment group compared with the control group (median 18.8 vs. 11.4 months; HR: 0.52 [95% CI: 0.32; 0.86]; p = 0.009).
  • The results for the progression-free survival endpoint are not included in this assessment.
  • For further details on the PFS endpoint, please refer to the section on patient population a1.
  • Time to first subsequent chemotherapy
  • For the endpoint ‘time to first subsequent chemotherapy’, please refer to the discussion under patient population a1.
  • Health status (EQ-5D visual analogue scale)
  • General health status was assessed using the EQ-5D visual analogue scale.
  • These data show no statistically significant difference between the treatment arms for the time to permanent deterioration.
  • Additional benefit from ribociclib in combination with fulvestrant for the health status endpoint (EQ-5D-VAS) is not proven.
  • Symptoms
  • Symptoms were assessed in the MONALEESA-3 study using the symptom scales of the disease-specific EORTC QLQ-C30 questionnaire.
  • No statistically significant difference was observed between the treatment groups for any of the endpoints presented.
  • Pain (BPI-SF)
  • Due to incomplete data on the BPI-SF, this endpoint is not included in the present assessment.
• quality of life
  • To assess health-related quality of life, the functional scales of the disease-specific EORTC QLQ-C30 questionnaire were used in the MONALEESA-3 study.
  • No statistically significant difference was observed between the treatment groups for any of the endpoints presented.
• Side effects
  • Adverse events (AEs)
  • In MONALEESA-3, among patients with a history of endocrine therapy at the locally advanced or metastatic stage, an adverse event occurred in 100% of patients in the intervention arm, compared with 94.7% of patients in the control arm.
  • Serious adverse events (SAEs)
  • No statistically significant difference was observed between the treatment arms with regard to serious adverse events.
  • Severe AEs (CTCAE Grade 3 or 4)
  • A statistically significant treatment effect was observed with regard to the time to onset of severe adverse events of CTCAE grade 3 or 4, to the detriment of ribociclib in combination with fulvestrant (HR: 3.69 [95% CI: 1.95; 7.01]; p < 0.001).
  • 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 ribociclib in combination with fulvestrant (HR: 4.58 [95% CI: 1.08; 19.48]; p = 0.024).
  • Specific AEs
  • In detail, the combination of ribociclib plus fulvestrant showed a statistically significant disadvantage compared with fulvestrant alone with regard to the endpoint ‘disorders of the blood and lymphatic system’ (CTCAE grade ≥ 3) (HR: 10.31 [95% CI: 2.49; 42.69]; p < 0.001).
  • The adverse reaction profile of ribociclib is qualitatively comparable to that of cytotoxic chemotherapy, particularly with regard to myelosuppression, and differs significantly from the adverse reaction profile of endocrine therapy.
• Overall assessment
  • In the mortality endpoint category, there was no statistically significant difference between the treatment groups for the overall survival endpoint in patient population b1.
  • The results for the endpoint categories of morbidity and health-related quality of life show no statistically significant differences between the treatment arms.
  • With regard to side effects, no significant, statistically significant disadvantages were observed for ribociclib in combination with fulvestrant compared with fulvestrant alone in terms of the endpoints of severe adverse events (CTCAE grade 3 or 4), therapy discontinuations due to adverse events, or, in detail, for the specific AE category of disorders of the blood and lymphatic system (CTCAE grade 3 or 4), significant, statistically significant disadvantages were observed for ribociclib in combination with fulvestrant compared with fulvestrant alone, particularly with regard to the pronounced myelosuppression caused by ribociclib.
  • In its decision weighing up the evidence, the G-BA concludes that, for ribociclib in combination with fulvestrant for the treatment of postmenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who have received prior endocrine therapy. An additional benefit for this type of cancer is not proven.

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, an additional benefit of ribociclib in combination with fulvestrant is not proven compared with the appropriate comparator therapy.
• For pre-/perimenopausal patients who have received prior endocrine therapy, no data have been submitted to assess the additional benefit of ribociclib in combination with fulvestrant compared with the appropriate comparator therapy. The submitted MONALEESA-3 study exclusively enrolled postmenopausal patients.

Courtesy translation only, please refer to the German original.