Pertuzumab / Trastuzumab (2) – Phesgo®

• Clinical trials
  • The NeoSphere trial cited here is a multicentre, open-label, randomised controlled Phase II trial in which adults (N=417) with HER2-positive locally advanced, inflammatory or early-stage invasive breast cancer, with a primary tumour diameter of > 2 cm and an Eastern Cooperative Oncology Group performance status of ≤ 1.

Adults with HER2-positive locally advanced, inflammatory or early-stage breast cancer with a high risk of recurrence for neoadjuvant treatment

• Additional benefit is not proven for neoadjuvant treatment in adults with HER2-positive locally advanced, inflammatory or early-stage breast cancer at high risk of recurrence.
• When the results on mortality, morbidity and side effects, there is no additional benefit compared with the appropriate comparator therapy, nor is there any less benefit from pertuzumab in the neoadjuvant treatment of HER2-positive locally advanced, inflammatory or early-stage breast cancer with a high risk of recurrence.
• The G-BA therefore concludes that the additional benefit is not proven for the subcutaneous fixed-dose combination of pertuzumab and trastuzumab, in combination with chemotherapy, compared with trastuzumab in combination with a taxane and, where appropriate, an anthracycline.
• mortality
  • For the endpoint of overall survival, no statistically significant difference was observed between the study arms relevant to the assessment (Arm A: pertuzumab + trastuzumab + docetaxel, Arm B: trastuzumab + docetaxel).
  • No additional benefit is therefore identified for the endpoint of overall survival.
• morbidity
  • Recurrences (recurrence rate and disease-free survival)
  • In both analyses, there is no statistically significant difference between the two study arms considered.
  • With regard to the recurrence rate and disease-free survival, the additional benefit of pertuzumab + trastuzumab over the appropriate comparator therapy is not proven.
  • Breast-conserving surgery
  • The proportion of patients who, in the opinion of the study doctor, were able to undergo breast-conserving surgery following neoadjuvant therapy did not differ statistically significantly between the treatment arms.
  • An additional benefit is not proven for the endpoint of breast-conserving surgery.
  • Pathological complete remission
  • The primary endpoint of the NeoSphere trial was pathological complete remission, for which there was a statistically significant difference between the two treatment arms relevant to the analysis.
  • Pathological complete remission (pCR) is regarded as a surrogate endpoint of unclear validity.
  • Overall, sufficient validation of a surrogate endpoint generally requires evidence of a correlation at both the patient level and the study level. As this is not the case for the endpoint in question, pCR cannot be used to assess additional benefit.
  • The NeoSphere trial failed to demonstrate that the difference in the proportion of patients achieving pCR translates into a statistically significant difference in the proportion of patients experiencing recurrence. Nor is there any difference in overall survival between the two patient groups.
• quality of life
  • Data on health-related quality of life were not collected in the NeoSphere study.
• Side effects
  • The data from the NeoSphere study relate exclusively to side effects of the intravenous combination of pertuzumab and trastuzumab. Adverse events directly attributable to the subcutaneous administration of the fixed-dose combination could not be recorded within the scope of this study.
  • Adverse events
  • With the exception of two patients in the pertuzumab arm, an adverse event was documented in all patients in the study arms under consideration.
  • Severe adverse events (CTCAE ≥ Grade 3)
  • There is no statistically significant difference between the treatment arms.
  • Serious adverse events
  • There is no statistically significant difference between the treatment arms.
  • Discontinuation due to adverse events
  • Six patients in the intervention arm discontinued therapy due to adverse events. No therapy discontinuations were recorded in the control arm. The difference between the treatment arms is statistically significant to the detriment of pertuzumab + trastuzumab.
  • Overall, the increased number of therapy discontinuations is not reflected in the overall rates of SUEs and severe AEs (CTCAE ≥ Grade 3). Furthermore, the NeoSphere study involved minor numbers of cases and the causality is unclear. Overall, the statistically significant difference between the treatment arms cannot therefore be attributed to pertuzumab with sufficient certainty; consequently, additional benefit is not proven for the endpoint of side effects.
• Overall assessment / Conclusion
  • For the endpoints of overall survival, recurrence, breast-conserving surgery and side effects, the results of the NeoSphere trial showed no robust, statistically significant differences between the treatment arms. Data on health-related quality of life were not collected in the NeoSphere trial.
  • In the overall assessment of the results on mortality, morbidity and side effects, there is neither an additional benefit nor less benefit of pertuzumab compared with the appropriate comparator therapy in the neoadjuvant treatment of HER2-positive locally advanced, inflammatory or early-stage breast cancer with a high risk of recurrence. The G-BA therefore concludes that an additional benefit is not proven for the subcutaneous fixed-dose combination of pertuzumab and trastuzumab, in combination with chemotherapy, compared with trastuzumab in combination with a taxane and, where appropriate, an anthracycline.

Courtesy translation only, please refer to the German original.