Pertuzumab (3) – Perjeta®

• Clinical trials
  • This was a two-arm, randomised, double-blind, controlled phase 3 trial comparing pertuzumab + trastuzumab + chemotherapy with trastuzumab + chemotherapy.

Adult patients with HER2-positive early-stage breast cancer at high risk of recurrence, for adjuvant treatment

• There is a hint of a minor additional benefit for pertuzumab in combination with trastuzumab and chemotherapy for the adjuvant treatment of adult patients with HER2-positive early-stage breast cancer at high risk of recurrence.
• Pertuzumab in combination with trastuzumab and chemotherapy is therefore found to provide a minor additional benefit compared with trastuzumab in combination with chemotherapy in the adjuvant treatment of adult patients with HER2-positive early-stage breast cancer at high risk of recurrence.
• mortality
  • overall survival
  • For the endpoint of overall survival, there is no statistically significant difference between the treatment groups (hazard ratio: 0.89, confidence interval: 0.65–1.23, p-value: 0.486).
  • At the time of data analysis, the median survival time had not yet been reached in either treatment group, with a minor overall number of events: 4.0% vs. 4.4% deaths in the relevant patient population of the study.
  • There is therefore no proof of an additional benefit of pertuzumab in combination with trastuzumab and chemotherapy in terms of overall survival.
• Morbidity – Recurrences / Disease-free survival (DFS)
  • Patients in this therapeutic indication are treated with a curative approach: adjuvant therapy following complete resection of the primary tumours and, where applicable, affected lymph nodes.
  • Disease-free survival (DFS)
  • The time-to-event analysis shows a statistically significant positive effect for pertuzumab + trastuzumab + chemotherapy compared with trastuzumab + chemotherapy (hazard ratio: HR: 0.78 [0.64; 0.96], p-value 0.019).
  • Recurrences (event rate)
  • For the endpoint ‘recurrences (event rate)’ too, a statistically significant positive effect of a comparable magnitude was observed for pertuzumab + trastuzumab + chemotherapy compared with trastuzumab + chemotherapy: 166 patients (9.2%) vs. 211 patients (11.6%) with a recurrence event (risk ratio: 0.79 [0.65; 0.96], p-value: 0.018). The absolute difference is minor: minus 2.4 per cent.
  • When both endpoints are considered, a positive effect of pertuzumab + trastuzumab + chemotherapy compared with trastuzumab + chemotherapy is observed in terms of preventing recurrence, although the quantitative extent of this effect is minor.
  • With regard to the disease recurrences observed in the study (operationalised in the endpoints DFS and recurrence rate), the extent of the statistically significant but only moderately positive effect of pertuzumab in combination with trastuzumab and chemotherapy was observed compared with trastuzumab in combination with chemotherapy.
• Health-related quality of life
  • For the endpoint ‘emotional functioning’, a statistically significant advantage was observed in the treatment group receiving pertuzumab + trastuzumab + chemotherapy at the 36-month follow-up. The extent of the effect is minor.
  • For the other endpoints – ‘Global Health Status’, ‘Physical Functioning’, ‘Role Functioning’, ‘Cognitive Functioning’, ‘Body Image’, ‘Sexual Activity’ and ‘Enjoyment of Sex’ – there is no statistically significant difference.
  • With regard to health-related quality of life, overall, neither an advantage nor a disadvantage of treatment with pertuzumab + trastuzumab + chemotherapy compared with trastuzumab + chemotherapy was observed.
  • In terms of patient-reported health-related quality of life, a moderate advantage was observed in the ‘emotional functioning’ endpoint.
• Side effects
  • Serious AEs
  • In the treatment group receiving pertuzumab + trastuzumab + chemotherapy, a statistically significant higher number of patients were affected by serious adverse events (SAEs).
  • Severe AEs (CTCAE grade ≥ 3)
  • Adverse events classified as ‘severe adverse events’ according to the CTCAE classification (CTCAE grade ≥ 3) occurred with statistically significant greater frequency during treatment with pertuzumab + trastuzumab + chemotherapy.
  • Therapy discontinuation due to AEs
  • There was no statistically significant difference between the treatment groups in the number of therapy discontinuations due to AEs.
  • Heart failure (serious)
  • Serious heart failure occurred at a statistically significantly higher rate in the treatment group receiving pertuzumab + trastuzumab + chemotherapy compared with the treatment group receiving trastuzumab + chemotherapy.
  • Diarrhoea (serious and non-serious)
  • In the treatment group receiving pertuzumab + trastuzumab + chemotherapy, both serious and non-serious diarrhoea occurred at a statistically significantly higher rate compared with the treatment group receiving trastuzumab + chemotherapy.
  • Metabolic and nutritional disorders (serious)
  • In the treatment group receiving pertuzumab + trastuzumab + chemotherapy, serious metabolic and nutritional disorders occurred at a statistically significant higher rate compared with the treatment group receiving trastuzumab + chemotherapy.
  • When the endpoints relating to adverse events are considered as a whole, a disadvantage is observed when pertuzumab is administered in addition to trastuzumab plus chemotherapy.
  • For the endpoint category of side effects, less benefit was observed for treatment with pertuzumab + trastuzumab + chemotherapy compared with trastuzumab + chemotherapy.
• Overall assessment
  • In the overall assessment of the results from the APHINITY trial across all patient-relevant endpoints, the positive effect—which is particularly relevant in the current adjuvant therapy setting—in terms of preventing recurrence is, albeit to a moderate extent, offset by significant disadvantages regarding side effects, particularly serious side effects.
  • After weighing up the evidence, the G-BA has concluded that the advantages outweigh the disadvantages.

Courtesy translation only, please refer to the German original.