Pertuzumab / Trastuzumab (3) – Phesgo®

• Clinical trials
  • APHINITY is a multicentre, double-blind, randomised trial comparing pertuzumab + trastuzumab + chemotherapy with a placebo + trastuzumab + chemotherapy regimen.

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

• mortality
  • No statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
  • There is therefore no proof of additional benefit for the endpoint of overall survival.
  • The final analysis of overall survival from the currently ongoing study is still pending.
• Morbidity – Recurrences (event rate and disease-free survival)
  • A statistically significant advantage was observed in the recurrence rate, favouring pertuzumab + trastuzumab + chemotherapy compared with placebo + trastuzumab + chemotherapy.
  • The time-to-event analysis shows a statistically significant positive effect for pertuzumab + trastuzumab + chemotherapy.
  • When considering both endpoints, a positive effect – albeit of a minor quantitative extent – is observed for pertuzumab + trastuzumab + chemotherapy in terms of preventing recurrence.
• Health-related quality of life
  • For the endpoint ‘emotional functioning’, a statistically significant advantage in favour of pertuzumab + trastuzumab + chemotherapy was observed at the 36-month follow-up. The extent of the effect is minor.
  • No statistically significant difference was observed for the other endpoints.
  • Overall, no advantage or disadvantage of treatment with pertuzumab + trastuzumab + chemotherapy compared with trastuzumab + chemotherapy was observed in terms of health-related quality of life.
• Side effects
  • Almost every participant in the APHINITY trial experienced at least one AE at least once, both whilst receiving pertuzumab + trastuzumab + chemotherapy and whilst receiving trastuzumab + chemotherapy.
  • For serious adverse events, there was a statistically significant disadvantage associated with pertuzumab + trastuzumab + chemotherapy.
  • With regard to severe adverse events with a CTCAE grade of ≥ 3, there was a statistically significant disadvantage of pertuzumab + trastuzumab + chemotherapy compared with trastuzumab + chemotherapy.
  • No statistically significant difference was observed between the study arms for the endpoint of therapy discontinuation due to an AE.
  • Pertuzumab + trastuzumab + chemotherapy showed a statistically significant advantage over trastuzumab + chemotherapy with regard to the specific severe AE (CTCAE grade 3 or 4) skeletal muscle, connective tissue and bone disorders (SOC).
  • In contrast, pertuzumab plus trastuzumab plus chemotherapy showed a statistically significant disadvantage with regard to the specific AEs diarrhoea (PT), pruritus (PT), heart failure (PT), as well as for specific severe AEs (CTCAE Grade 3 or 4) such as anaemia (PT), diarrhoea (PT), stomatitis (PT), fatigue (PT), low white blood cell count (PT) and metabolic and nutritional disorders (SOC).
  • With regard to the number of serious cases of heart failure in the APHINITY trial, this was a rare event in both treatment groups. The extent of the difference in absolute terms is minor.
• Overall assessment / Conclusion
  • This benefit assessment evaluates the subcutaneous (s.c.) fixed-dose combination of pertuzumab and trastuzumab. As part of the marketing authorisation process for the subcutaneous fixed-dose combination, bioequivalence and therapeutic equivalence were demonstrated in comparison with the separate intravenous combination of pertuzumab and trastuzumab. This assessment is therefore based on the data for the separate combination from the APHINITY trial.
  • In the mortality endpoint category, the available results for the overall survival endpoint show no statistically significant difference between the study arms. Median survival has not yet been reached due to the minor number of events; final analyses for the overall survival endpoint are pending. An additional benefit is not proven for the endpoint of overall survival.
  • With regard to the recurrences that occurred, presented as the recurrence rate and DFS, there were statistically significantly fewer recurrences for pertuzumab + trastuzumab + chemotherapy compared with trastuzumab + chemotherapy. The extent of this effect is assessed as a relevant, but no more than a moderate, improvement. The prevention of relapses represents an essential therapeutic goal in the present curative treatment setting.
  • With regard to the symptoms recorded in the study, no overall advantage or disadvantage can be identified from treatment with pertuzumab + trastuzumab + chemotherapy.
  • With regard to patient-reported health-related quality of life, a moderate advantage was observed for the ‘emotional functioning’ endpoint. This finding on health-related quality of life supports the overall assessment.
  • With regard to side effects, no statistically significant difference was observed between the study arms for the endpoint ‘discontinuation due to AEs’. With regard to serious adverse events (SAEs) and severe adverse events (CTCAE grade ≥ 3), treatment with pertuzumab + trastuzumab + chemotherapy resulted in a disadvantage. In detail, among the cardiac side effects relevant to the therapeutic indication, there was a statistically significant increase in serious heart failure. However, in absolute terms, this disadvantage affects only a minor proportion of patients. When side effects are considered as a whole, a significant disadvantage is identified for pertuzumab + trastuzumab + chemotherapy.
  • On balance, the positive effect—which is particularly relevant in the present adjuvant therapy setting in terms of preventing recurrence, albeit to only a moderate extent—is offset by the significant disadvantages associated with side effects, particularly serious side effects. The significant disadvantages in terms of side effects are weighed against the aim of curative treatment in this context.
  • The G-BA has therefore concluded, following a balancing assessment, that the advantage outweighs the disadvantages. It is thus concluded that there is a minor additional benefit for pertuzumab/trastuzumab in combination with chemotherapy compared with trastuzumab plus chemotherapy in the adjuvant treatment of adults with HER2-positive early-stage breast cancer at high risk of recurrence.

Courtesy translation only, please refer to the German original.