Pertuzumab (1) – Perjeta®

• Clinical trials
  • The CLEOPATRA trial was a randomised, controlled, double-blind Phase III trial in which pertuzumab was compared with placebo as an additional treatment to trastuzumab in combination with docetaxel.

a) HER2-positive metastatic breast cancer – patients with visceral metastases

• For adult patients with HER2-positive metastatic breast cancer with visceral metastases, there is a hint of considerable additional benefit compared with the appropriate comparator therapy.
• The G-BA classifies the extent of the additional benefit of pertuzumab as considerable, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• Compared with the appropriate comparator therapy, this represents a considerable improvement in treatment-related benefit in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, as a moderate prolongation of survival is achieved.
• Mortality – Overall survival
  • For patients with visceral metastases, the result for the overall population is confirmed, and a statistically significant advantage is observed for treatment with pertuzumab compared with the comparator therapy (hazard ratio: 0.57; 95% CI: 0.44–0.74).
  • For patients with visceral metastases, pertuzumab in combination with trastuzumab and docetaxel achieves a moderate prolongation of survival; consequently, at the endpoint level, a considerable additional benefit compared with the comparator therapy is observed for this patient group.
• Morbidity – Progression-free survival
  • The endpoint ‘progression-free survival (PFS)’ shows a statistically significant prolongation of progression-free survival in favour of pertuzumab for patients with visceral metastases.
  • This endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The morbidity component ‘time to first objective disease progression’ was not assessed on the basis of symptoms but exclusively by means of imaging procedures and cytological examinations, which is insufficient for classification as a patient-relevant endpoint.
  • Given the consistent direction of effect for the patient-relevant endpoint ‘overall survival’ and the endpoint ‘progression-free survival’, the PFS endpoint—which is not directly patient-relevant in this case—supports the conclusion regarding additional benefit, although this does not alter the conclusion.
• quality of life
  • No usable data were available for the health-related quality of life endpoints, as these endpoints were based, on the one hand, on a non-validated version of the FACT-B (Functional Assessment of Cancer Therapy – Breast Cancer) and, on the other hand, were partly defined post-hoc.
• Side effects
  • In the CLEOPATRA trial, almost every patient experienced at least one adverse event, both in the pertuzumab+trastuzumab+docetaxel group (100 per cent) and in the trastuzumab+docetaxel group (98.7 per cent).
  • A similarly high proportion of patients in both treatment groups experienced a severe adverse event (CTCAE grade ≥ 3). No significant difference in the overall rate was observed between the treatment groups.
  • The most common severe adverse events (> 3 %) were leucopenia, neutropenia, febrile neutropenia and diarrhoea. Febrile neutropenia (13.7% vs. 7.6%) and severe diarrhoea (9.1% vs. 5.1%) occurred significantly more frequently in the pertuzumab arm than in the comparator arm.
  • Furthermore, a significantly higher proportion of patients in the pertuzumab group experienced serious adverse events (36.3% vs. 29.0%), with the most common serious adverse events including neutropenia, febrile neutropenia and diarrhoea.
  • Therapy discontinuations due to adverse events occurred with comparable frequency in both treatment groups and were predominantly due to the discontinuation of docetaxel.
  • The available data, based on the naive proportions (proportion of patients with at least one event), indicate overall greater harm when pertuzumab is administered in addition to trastuzumab and docetaxel, as evidenced in particular by an increase in serious adverse events.
  • The assessment takes into account that, due to the significantly longer average follow-up period in the pertuzumab arm of the study, a bias against pertuzumab is to be expected.
  • In the event of a statistically significant disadvantage for pertuzumab in combination with trastuzumab and docetaxel, greater harm compared with the appropriate comparator therapy cannot be entirely ruled out, despite the bias against pertuzumab.
  • Taking the above aspects into account, and in particular against the background of the severity of the disease, the findings regarding side effects are not, on the whole, classified as so severe as to justify a downgrading of the extent of the additional benefit in the overall assessment.
• Overall assessment
  • For patients with visceral metastases, an overall assessment of the results on mortality and side effects indicates an additional benefit for the endpoint of overall survival, demonstrating a moderate prolongation of survival.
  • No evaluable data are available for other patient-relevant endpoints in this indication, such as health-related quality of life or indication-specific symptoms.
  • Statements regarding quality of life are considered particularly important in palliative care settings.
• Conclusion
  • The G-BA classifies the extent of the additional benefit of pertuzumab in combination with trastuzumab and docetaxel for patients with HER2-positive metastatic breast cancer and visceral metastases as ‘considerable’ on the basis of the criteria set out in Section 5(7) of the AM-NutzenV.
  • Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a significant improvement in treatment-related benefit in terms of the endpoint of all-cause mortality that has not previously been achieved.
  • However, classification as a major additional benefit is not justified.

b) HER2-positive metastatic breast cancer – patients with non-visceral metastases

• For adult patients with HER2-positive metastatic breast cancer with non-visceral metastases, additional benefit is not proven.
• No additional benefit is demonstrated for any endpoint compared with the appropriate comparator therapy. No increased harm is identified. Therefore, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, an additional benefit is not proven.
• Mortality – overall survival
  • However, in patients with non-visceral metastases, no difference in overall survival was observed between the treatment groups (hazard ratio: 1.42; 95% CI: 0.71; 2.84).
  • Consequently, for patients with non-visceral metastases, an additional benefit for the endpoint of overall survival is not proven.
• quality of life
  • No usable data were available for the health-related quality of life endpoints, as these endpoints were based, on the one hand, on a non-validated version of the FACT-B (Functional Assessment of Cancer Therapy – Breast Cancer) and, on the other hand, were partly defined post-hoc.
• Side effects
  • The available data, based on the naive proportions (proportion of patients with at least one event), indicate overall greater harm when pertuzumab is administered in addition to trastuzumab and docetaxel, manifested in particular by an increase in serious adverse events.
  • The assessment takes into account that, due to the significantly longer average follow-up period in the pertuzumab arm of the study, a bias against pertuzumab is to be expected.
• Conclusion
  • For patients with non-visceral metastases, in view of the results on mortality and side effects, there is no additional benefit for any endpoint.
  • Overall, it is therefore concluded that pertuzumab in combination with trastuzumab and docetaxel does not demonstrate additional benefit compared with the appropriate comparator therapy for this patient group.

c) Patients with HER2-positive locally recurrent, inoperable breast cancer

• For patients with HER2-positive locally recurrent, inoperable breast cancer, there are no data in the pharmaceutical manufacturer’s dossier comparing pertuzumab in combination with trastuzumab and docetaxel with radiotherapy.
• Consequently, additional benefit compared with the appropriate comparator therapy is deemed not proven.

Courtesy translation only, please refer to the German original.