Palbociclib (1) – Ibrance®

• Clinical trials
  • The PALOMA-2 trial (N=666) is a randomised, double-blind Phase III trial comparing the combination of palbociclib and letrozole (N=444) with placebo and letrozole (N=222).
  • The PALOMA-1 trial consists of a single-arm, non-randomised Phase I sub-study and a randomised Phase II sub-study, which enrolled a patient population comparable to that of PALOMA-2 who had not previously received endocrine therapy.

a1) Postmenopausal patients receiving first-line treatment

• For postmenopausal patients receiving first-line treatment, an additional benefit over letrozole is not proven.
• Consequently, the G-BA concludes that additional benefit is not proven for palbociclib in combination with letrozole over letrozole alone for the treatment of postmenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer.
• mortality
  • Median survival has not yet been reached due to the minor number of events; final analyses for the overall survival endpoint are pending.
  • For the mortality endpoint category, the available results indicate that there is no additional benefit from adding palbociclib to letrozole therapy.
• Morbidity – Progression-free survival (PFS)
  • PFS was statistically significantly prolonged by a median of 10.3 months in the palbociclib treatment group compared with the control group (median 24.8 vs. 14.5 months; HR: 0.58 [95% CI: 0.46; 0.72]; p < 0.0001).
  • In summary, the available data do not indicate that the statistically significant prolongation of progression-free survival observed with palbociclib – defined as radiologically confirmed disease progression according to RECIST criteria — is associated with an improvement in morbidity or health-related quality of life.
  • The results for the progression-free survival endpoint are therefore not included in this assessment.
• Morbidity – time to first subsequent (intravenous) chemotherapy
  • With regard to the PALOMA-2 trial, there are serious uncertainties concerning the interpretability of the results for the endpoint ‘time to first subsequent chemotherapy’.
  • Firstly, mortality was not taken into account in the relevant analysis.
  • Consequently, when deaths are taken into account, there is no statistically significant difference between the treatment arms in the event rates for the time to first subsequent intravenous chemotherapy.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • The mean values for the change measured between the start of the study and the end of treatment did not differ statistically significantly between the study arms.
  • For the health status endpoint (EQ-5D-VAS), therefore, the additional benefit of palbociclib in combination with letrozole is not proven.
• Quality of life – time to deterioration in quality of life (FACT-B)
  • There was no statistically significant difference between the treatment arms, either for the overall FACT-B scale or for the other (sub)scales considered.
  • An additional benefit is not proven for palbociclib in combination with letrozole in the quality of life endpoint category.
• Side effects – Adverse events (AEs)
  • An adverse event was recorded for almost all patients in both arms of the PALOMA-2 trial (intervention arm: 98.9 per cent, control arm: 95.5 per cent).
• Side effects – Serious adverse events (SAEs)
  • For serious adverse events, there is a statistically significant treatment effect to the detriment of palbociclib (PALOMA-2: HR: 1.63 [95% CI: 1.06; 2.49]; p = 0.023).
• Side effects – Severe AEs (CTCAE Grade 3/4)
  • With regard to the time to onset of severe adverse events of CTCAE grade 3 or 4, there is a significant treatment effect to the detriment of palbociclib plus letrozole (PALOMA-2: HR: 5.50 [95% CI: 4.14; 7.31]; p < 0.001).
• Side effects – discontinuation due to AEs
  • In the PALOMA-2 trial, the median time to therapy discontinuation due to an adverse event did not differ statistically significantly between the treatment arms.
• Overall assessment
  • In the overall analysis of the endpoints relating to side effects, no advantages were observed; however, there were significant disadvantages due to an increase in serious AEs and severe AEs (CTCAE grade 3 or 4) with treatment using palbociclib and letrozole compared with treatment using the appropriate comparator therapy, letrozole.
  • In its cost-benefit analysis, the G-BA concludes that, for palbociclib in combination with 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 Letrozol.

a2) Pre-/perimenopausal patients in first-line treatment

• For pre-/perimenopausal patients in first-line treatment, the additional benefit of palbociclib over the appropriate comparator therapy is not proven.
• No data were submitted for the assessment of the additional benefit of palbociclib compared with the appropriate comparator therapy in pre-/perimenopausal patients receiving first-line treatment.

b1) Postmenopausal patients with disease progression following prior endocrine therapy

• For postmenopausal and pre-/perimenopausal patients with disease progression following prior endocrine therapy, additional benefit is not proven compared with the appropriate comparator therapy.
• In its overall assessment, the G-BA concludes that, for palbociclib in combination with fulvestrant for the treatment of postmenopausal and pre-/perimenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who have previously received endocrine therapy, additional benefit is not proven compared with fulvestrant.
• mortality
  • In PALOMA-3, there was no statistically significant difference in the overall study population between treatment with palbociclib plus fulvestrant and fulvestrant alone (HR: 1.02 [95% CI: 0.46; 2.25]; p-value = 0.970).
  • Median survival has not yet been reached due to the small number of events; final analyses for the overall survival endpoint are pending.
  • Based on the available results, the combination therapy of palbociclib and fulvestrant shows no additional benefit compared with fulvestrant alone for the endpoint category of mortality.
• Morbidity – Progression-free survival (PFS)
  • PFS was statistically significantly prolonged by a median of 5.4 months in the palbociclib treatment group compared with the control group (9.2 vs. 3.8 months; HR: 0.42 [95% CI: 0.32; 0.56]; p < 0.001).
  • In summary, the available data do not indicate that the statistically significant prolongation of progression-free survival observed with palbociclib – radiologically confirmed disease progression according to RECIST criteria — is associated with an improvement in morbidity or health-related quality of life.
  • The results for the progression-free survival endpoint are not included in this assessment.
• Morbidity – time to first subsequent (intravenous) chemotherapy
  • Firstly, mortality or death was not taken into account in the relevant analysis.
  • In this benefit assessment, there are therefore serious uncertainties regarding the interpretation of the results for the endpoint ‘time to first subsequent (intravenous) chemotherapy’.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • General health status was assessed using the EQ-5D visual analogue scale. The mean values of the change observed between the start of the study and the end of treatment did not differ statistically significantly between the study arms.
  • An additional benefit of palbociclib 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 palbociclib (HR: 0.63 [95% CI: 0.48; 0.84]; p=0.002).
• Morbidity – Symptoms (burden of hair loss)
  • For the endpoint ‘burden of hair loss’, however, there was a statistically significant difference to the detriment of palbociclib (HR: 2.43 [95% CI: 1.17; 5.07]; p=0.014).
• Quality of life – time to deterioration in quality of life (emotional functioning)
  • A statistically significant difference in favour of palbociclib plus fulvestrant was observed for the endpoint ‘emotional functioning’ (HR: 0.66 [95% CI: 0.48; 0.91]; p=0.011).
• Quality of life – time to deterioration in quality of life (sexual enjoyment)
  • For the endpoint ‘Sexual Enjoyment’, however, there was a statistically significant treatment effect to the detriment of palbociclib plus fulvestrant (HR: 1.78 [95% CI: 0.99; 3.21]; p=0.0496).
• Side effects – Adverse events (AEs)
  • In PALOMA-3, an adverse event occurred in 98.9% of patients in the intervention arm, compared with 95.5% of patients in the control arm.
• Side effects – Serious adverse events (SAEs)
  • There was no statistically significant treatment effect between palbociclib plus fulvestrant and fulvestrant alone with regard to serious adverse events.
• Side effects – Severe AEs (CTCAE Grade 3/4)
  • A statistically significant treatment effect was observed to the detriment of palbociclib plus fulvestrant with regard to the time to onset of severe adverse events of CTCAE grade 3 or 4 (HR: 6.19 [95% CI: 4.25; 9.02]; p < 0.001).
• Side effects – discontinuation due to AEs
  • There was no statistically significant difference between the treatment arms in the median time to therapy discontinuation due to an adverse event.
• Overall assessment
  • Overall, the G-BA concludes that, for palbociclib in combination with fulvestrant for the treatment of postmenopausal and pre-/perimenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who have previously received endocrine therapy, additional benefit is not proven compared to fulvestrant.
  • With regard to side effects, no significant disadvantage was identified for palbociclib plus fulvestrant compared with fulvestrant alone in terms of the endpoint of severe adverse events (CTCAE grade 3 or 4), a significant disadvantage was identified for palbociclib plus fulvestrant compared with fulvestrant alone, particularly with regard to the pronounced myelosuppression caused by palbociclib.

b2) Pre-/perimenopausal patients with disease progression following prior endocrine therapy

• For postmenopausal and pre-/perimenopausal patients with disease progression following prior endocrine therapy, an additional benefit over the appropriate comparator therapy is not proven.
• Overall, the G-BA concludes that, for palbociclib in combination with fulvestrant for the treatment of postmenopausal and pre-/perimenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who have previously received endocrine therapy, additional benefit compared with fulvestrant is not proven.
• Overall assessment
  • In its overall assessment, the G-BA concludes that, for palbociclib in combination with fulvestrant for the treatment of postmenopausal and pre-/perimenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who have previously received endocrine therapy, additional benefit is not proven compared with fulvestrant.

Courtesy translation only, please refer to the German original.