Pertuzumab (2) – Perjeta®

• Clinical trials
  • The Phase II NeoSphere trial investigated the efficacy and safety of pertuzumab in the neoadjuvant treatment of adult patients with HER2-positive locally advanced, inflammatory or early-stage breast cancer with a tumour diameter of more than 2 cm.
  • A total of 417 patients were enrolled in the open-label, randomised trial and were treated with either pertuzumab in combination with trastuzumab and docetaxel (Arm A, N = 107), trastuzumab in combination with docetaxel (Arm B, N = 107), pertuzumab in combination with trastuzumab (Arm C, N = 107), or pertuzumab in combination with docetaxel (Arm D, N = 96).

adult patients for the neoadjuvant treatment of HER2-positive, locally advanced, inflammatory breast cancer or early-stage breast cancer with a high risk of recurrence, as part of the treatment of early-stage breast cancer

• For patients with HER2-positive locally advanced, inflammatory or early-stage breast cancer with a high risk of recurrence, an additional benefit is not proven.
• mortality
  • There was no statistically significant difference in overall survival between the relevant study arms (Arm A: pertuzumab in combination with trastuzumab and docetaxel; Arm B: trastuzumab in combination with docetaxel) in the NeoSphere trial, there was no statistically significant difference in overall survival (risk ratio (RR): 1.33; 95% confidence interval (CI): [0.48; 3.71]; p-value = 0.682).
  • No additional benefit of pertuzumab is proven for the endpoint category of mortality.
• Morbidity – Recurrences
  • In this benefit assessment, recurrences were taken into account both in the ‘recurrence rates’ endpoint (13.9% vs. 17.5%) and in the ‘disease-free survival’ endpoint (median 67.2 months vs. not reached).
  • In both analyses, there was no statistically significant difference between the two study arms considered (recurrence rate: RR: 0.79; 95% CI: [0.42; 1.51]; p = 0.532; disease-free survival: hazard ratio (HR): 0.60; 95% CI: [0.28; 1.27]; p = 0.185).
  • With regard to the recurrence rate and disease-free survival, the results of the NeoSphere trial do not provide proof of an additional benefit of pertuzumab over the appropriate comparator therapy.
• Morbidity – 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 (RR: 1.08; 95% CI: [0.67; 1.73]; p = 0.819).
  • An additional benefit is not proven for the endpoint ‘breast-conserving surgery’.
• Morbidity – 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 relevant treatment arms (39.3% vs. 21.5%; RR: 1.83; 95% CI: [1.19; 2.81]; p = 0.0042).
  • Pathological complete remission is regarded as a surrogate endpoint of unclear validity.
  • The results of the validation studies by Cortazar et al. and Minckwitz et al., submitted by the pharmaceutical manufacturer, show that, whilst there is an overall association between pathological complete remission and all-cause mortality at the individual patient level, but at the study level, no evidence of a correlation between the outcomes has been provided.
  • 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, pathological complete remission cannot be used to assess the additional benefit.
  • In addition to the insufficient validation of the surrogate endpoint, it is also unclear, based on current knowledge, to what extent a 17.8% difference in the proportion of patients achieving pathological complete remission between the study arms is relevant.
• (Health-related) quality of life
  • Health-related quality of life was not assessed in the NeoSphere trial.
  • As no data on health-related quality of life are available, an additional benefit of pertuzumab for this endpoint category is not proven.
• Side effects – 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.
• Side effects – severe adverse events (CTCAE ≥ Grade 3)
  • In the intervention arm relevant to the assessment, 72.9% of patients experienced a severe adverse event (CTCAE ≥ Grade 3), compared with 81.3% of patients in the comparator arm.
  • There is no statistically significant difference between the treatment arms (RR: 0.90; 95% CI: [0.77; 1.04]; p = 0.151).
  • An additional benefit of pertuzumab is not proven for this endpoint.
• Side effects – Serious adverse events
  • In the intervention arm relevant to the assessment, 20.6% of patients experienced a serious adverse event, compared with 19.6% of patients in the control arm.
  • The difference between the treatment arms is not statistically significant (RR: 1.05; 95% CI: [0.61; 1.79]; p = 0.922).
  • No additional benefit of pertuzumab has been proven for this endpoint.
• Side effects – discontinuation due to adverse events
  • Therapy discontinuation due to adverse events occurred in 6 patients in the intervention arm. No therapy discontinuations were recorded in the control arm without pertuzumab treatment.
  • The difference between the treatment arms is statistically significant (p = 0.014).
  • Analysis of the 6 therapy discontinuations in the intervention arm showed that, in 4 patients, the adverse event leading to discontinuation was left ventricular dysfunction with a reduction in the ejection fraction to below 50%.
  • Overall, the increased number of therapy discontinuations due to adverse events does not justify downgrading the benefit of pertuzumab, particularly given the small sample size in the NeoSphere trial and the unclear causality.
  • Overall, the statistically significant difference between the treatment arms cannot be attributed to pertuzumab with sufficient certainty; consequently, additional benefit is not proven for this endpoint.
• Conclusion
  • Taking the results on mortality, morbidity and side effects, there is neither additional benefit nor less benefit from 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.
  • With regard to the patient-relevant endpoints considered – overall survival, recurrences, breast-conserving surgery and side effects – the results of the NeoSphere study showed no robust, statistically significant differences between the treatment arms.
  • In light of these considerations, based on the information in the dossier, the results of the benefit assessment and the statements submitted, the G-BA concludes that, on the basis of the data submitted, an additional benefit is not proven for pertuzumab in combination with trastuzumab and chemotherapy compared with trastuzumab in combination with a taxane and, where applicable, an anthracycline.

Courtesy translation only, please refer to the German original.