Palbociclib (2) – Ibrance®

• Clinical trials
  • To demonstrate the additional benefit of palbociclib in combination with fulvestrant following prior endocrine therapy, the pharmaceutical manufacturer has submitted the final results of the randomised, double-blind Phase III PALOMA-3 trial (A5481023).
  • This multicentre, multinational trial (N=521) included pre-/perimenopausal patients (N=108) and postmenopausal patients (N=413) with HR-positive, HER2-negative metastatic breast cancer who had progressed following prior endocrine therapy. The study compared the combination of palbociclib and fulvestrant (N=347) with placebo and fulvestrant (N=174).

a) Postmenopausal patients who have experienced disease progression following endocrine therapy:

• For postmenopausal patients who have progressed following prior endocrine therapy, the additional benefit of palbociclib in combination with fulvestrant is not proven compared with the appropriate comparator therapy.
• mortality
  • In the PALOMA-3 trial, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death. In PALOMA-3, overall survival was a secondary endpoint.
  • In the primary analysis submitted by the pharmaceutical manufacturer in the dossier, a statistically significant difference in favour of palbociclib plus fulvestrant compared with fulvestrant alone was observed for the patient population of postmenopausal patients from the PALOMA-3 study (HR: 0.76 [95% CI: 0.58; 0.98]; p < 0.034). However, this result is subject to serious uncertainties, which are outlined below.
  • In its assessment of the available analysis results, the G-BA concludes that the statistically significant effect emerging from the primary analysis for postmenopausal patients is subject to serious uncertainties, which is why, on the basis of the available data, it cannot be assumed with the requisite certainty that there is a significant effect of palbociclib in combination with fulvestrant on overall survival compared with fulvestrant alone.
  • For the endpoint category of mortality, an additional benefit for postmenopausal women is therefore not proven on the basis of the available data.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the PALOMA-3 trial and is defined as the time from randomisation to disease progression (determined by the investigator according to the RECIST criteria) or death from any cause.
  • In the palbociclib treatment group, compared with the control group, PFS was statistically significantly prolonged by a median of 5.5 months in postmenopausal patients (9.2 vs. 3.7 months; HR: 0.41 [95% CI: 0.30; 0.56]; p < 0.0001).
  • 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 post-hoc in the dossier for this benefit assessment 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.
• Morbidity – Symptoms of the disease – Time to deterioration (pain)
  • For the endpoint ‘pain’, a statistically significant difference in favour of palbociclib + fulvestrant was observed in postmenopausal patients (HR: 0.63 [95% CI: 0.48; 0.84]; p=0.002).
  • Overall, therefore, the additional benefit of palbociclib in combination with fulvestrant for the endpoint ‘symptoms’ is not proven.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • General health status was assessed using the EQ-5D visual analogue scale. The pharmaceutical manufacturer’s dossier contained responder analyses covering the time to deterioration by a minimum important difference (MID) of 10. These show no statistically significant difference between the treatment arms.
  • An additional benefit of palbociclib in combination with fulvestrant for the health status endpoint (EQ-5D-VAS) is not proven.
• Health-related quality of life
  • No statistically significant difference was observed between the treatment groups for any of the endpoints presented in postmenopausal patients.
  • Additional benefit from palbociclib in combination with fulvestrant in the quality of life endpoint category is not proven.
• Side effects – severe adverse events (CTCAE grade ≥3)
  • With regard to the time to onset of severe adverse events of CTCAE grade 3 or 4 in postmenopausal women, a statistically significant treatment effect was observed to the detriment of palbociclib plus fulvestrant (HR: 4.54 [95% CI: 3.22; 6.41]; p < 0.001).
• Side effects – Specific adverse events (stomatitis)
  • The combination of palbociclib and fulvestrant showed statistically significant disadvantages compared with fulvestrant alone in terms of stomatitis (PT, AEs) (HR: 4.98 [1.53; 16.28]; p = 0.003).
• Overall assessment
  • The PALOMA-3 study provides results for postmenopausal women who have previously received endocrine therapy, enabling an assessment of the additional benefit of palbociclib in combination with fulvestrant compared with fulvestrant alone in terms of mortality (overall survival), morbidity (symptoms and health status), quality of life and side effects.
  • In the mortality endpoint category, the available results for the overall survival endpoint are subject to considerable uncertainty. This is due in particular to the strikingly high proportions of patients without complete survival follow-up, which also vary significantly between the study arms; consequently, the data on patient survival in the study are not known to an extent relevant to the assessment.
  • For the endpoint of overall survival, an additional benefit of palbociclib in combination with fulvestrant is therefore not proven.
  • Based on an overall assessment of the results for the morbidity endpoint category (health status and symptoms), additional benefit is not proven for palbociclib plus fulvestrant compared with fulvestrant alone.
  • With regard to side effects, a statistically significant disadvantage for palbociclib plus fulvestrant compared with fulvestrant for severe adverse events (CTCAE grade 3 or 4), a statistically significant disadvantage was observed for palbociclib plus fulvestrant compared with fulvestrant, particularly with regard to the pronounced myelosuppression caused by palbociclib.
  • Overall, no additional benefit has been demonstrated for palbociclib in combination with fulvestrant for the treatment of postmenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who have previously received endocrine therapy, there is no proof that the appropriate comparator therapy is better than the standard of care.

b2) Pre-/perimenopausal patients who have experienced progression following endocrine therapy:

• For pre-/perimenopausal patients who have progressed following prior endocrine therapy, additional benefit of palbociclib in combination with fulvestrant is not proven compared with the appropriate comparator therapy.
• mortality
  • In the primary analysis for the patient population of pre-/perimenopausal patients from the PALOMA-3 study, as presented by the pharmaceutical manufacturer in the dossier, no statistically significant difference was observed between the treatment arms for the endpoint of overall survival.
  • Based on the available data for pre- and perimenopausal women, 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)
  • For pre- and perimenopausal women, too, a statistically significant treatment effect in favour of palbociclib + fulvestrant was observed with regard to PFS (9.5 vs. 5.6 months; HR: 0.44 [95% CI: 0.23; 0.85]; p = 0.012). This corresponded to a median prolongation of PFS by 3.9 months.
  • The results for the progression-free survival endpoint are not included in this review.
• Morbidity – time to first subsequent chemotherapy
  • The results for the endpoint ‘time to first subsequent chemotherapy’ are not included in this review.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • An additional benefit of palbociclib in combination with fulvestrant for the health status endpoint (EQ-5D-VAS) is not proven.
• Morbidity – Disease symptoms – Time to deterioration
  • In pre- and perimenopausal patients, no statistically significant treatment effect of palbociclib in combination with fulvestrant was observed for any of the endpoints assessed using the EORTC QLQ-C30 and –BR23 questionnaires.
  • Overall, therefore, additional benefit from palbociclib in combination with fulvestrant for the endpoint of symptoms is not proven.
• Health-related quality of life
  • In pre- and perimenopausal patients, too, no statistically significant difference between the treatment groups was observed for any of the endpoints assessed using the EORTC QLQ-C30 and –BR23 questionnaires.
• Side effects – severe adverse events (CTCAE grade ≥3)
  • In pre- and perimenopausal women, there was a statistically significant treatment effect 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: 5.90 [95% CI: 2.91; 11.95]; p < 0.001).
• Side effects – Specific adverse events (skin and subcutaneous tissue disorders)
  • For the combination of palbociclib and fulvestrant in pre- and perimenopausal patients, there are statistically significant disadvantages compared with fulvestrant alone in terms of disorders of the skin and subcutaneous tissue (HR: 4.04 [1.71; 9.57]; p < 0.001).
• Overall assessment
  • For pre- and perimenopausal women who have previously undergone endocrine therapy, results are available from the PALOMA-3 study to assess the additional benefit of palbociclib in combination with fulvestrant compared with fulvestrant alone in terms of mortality (overall survival), morbidity (symptoms and health status), quality of life and side effects from the PALOMA-3 trial.
  • There is no statistically significant difference in overall survival between palbociclib in combination with fulvestrant and fulvestrant alone. In this regard, the serious uncertainties surrounding the results for the endpoint of overall survival must also be taken into account for the present patient population of pre- and perimenopausal patients from the PALOMA-3 study.
  • For the endpoint of overall survival, an additional benefit of palbociclib in combination with fulvestrant is not proven.
  • For endpoints in the categories of morbidity and health-related quality of life, there is no statistically significant treatment effect of palbociclib in combination with fulvestrant.
  • With regard to side effects, a significant statistically significant disadvantage was observed for palbociclib plus fulvestrant compared with fulvestrant alone for the endpoint of severe adverse events (CTCAE grade 3 or 4), a significant statistical disadvantage was observed for palbociclib plus fulvestrant compared with fulvestrant alone, particularly with regard to the pronounced myelosuppression caused by palbociclib.
  • Overall, the G-BA concludes that, for palbociclib in combination with fulvestrant for the treatment of pre- and perimenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who have previously received endocrine therapy, the additional benefit is not proven compared to the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.