Pertuzumab / Trastuzumab (4) – Phesgo®

• Clinical trials
  • The APHINITY trial 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

• Consequently, the G-BA has determined that pertuzumab/trastuzumab in combination with chemotherapy offers a minor additional benefit in the adjuvant treatment of adults with HER2-positive early-stage breast cancer and a high risk of recurrence, compared with trastuzumab plus chemotherapy.
• Consequently, the certainty of the evidence for the established additional benefit is classified as ‘indication’.
• mortality
  • overall survival
  • In the APHINITY trial, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • For this endpoint, there is a statistically significant difference between the treatment arms in favour of pertuzumab + trastuzumab + chemotherapy.
  • Given the minor extent and questionable validity of the observed effect in the mortality endpoint category, and in light of the study’s uncertainties regarding follow-up therapies and thus its generalisability to the German healthcare context, nonor a disadvantage of pertuzumab + trastuzumab + chemotherapy in the mortality endpoint category.
• Morbidity – Recurrences (recurrence rate and disease-free survival)
  • In this benefit assessment, recurrences are considered in terms of both the recurrence rate and disease-free survival as endpoints.
  • At the time of this data cut-off, the median time to recurrence had not yet been reached in either treatment group. For the recurrence rate, the absolute difference is 4.9% (140 events out of 1,811 (7.7%) vs. 175 events out of 1,823 (9.6%) patients).
  • When both endpoints are considered, a considerable overall advantage is observed for pertuzumab + trastuzumab + chemotherapy compared with trastuzumab + chemotherapy in terms of preventing recurrence.
• Morbidity – Symptoms
  • Symptoms were assessed in the APHINITY study using the symptom scales of the cancer-specific EORTC QLQ-C30 questionnaire and the breast cancer-specific supplementary module QLQ-BR23.
  • The proportion of patients with a deterioration of ≥ 10 points is used for the assessment.
  • For the endpoints of fatigue and breast-related symptoms, statistically significant disadvantages were observed only at the end of anti-HER2 therapy.
  • For the endpoint ‘diarrhoea’, a statistically significant disadvantage is initially observed at the end of anti-HER2 therapy. At the 36-month follow-up, however, a statistically significant advantage is observed.
  • In summary, with regard to the symptom-related endpoints, statistically significant disadvantages are observed only at the end of anti-HER2 therapy in individual endpoints. These disadvantages are no longer evident at the 36-month follow-up; for the endpoint of diarrhoea, there is even a statistically significant advantage. In summary, neither an advantage nor a disadvantage for pertuzumab + trastuzumab + chemotherapy can be identified with regard to symptoms.
• Health-related quality of life
  • Health-related quality of life was assessed in the APHINITY study using the functional scales of the EORTC QLQ-C30 and EORTC-QLQ-BR23.
  • For the endpoint ‘emotional functioning’, a statistically significant advantage in favour of pertuzumab + trastuzumab + chemotherapy was observed at the 36-month follow-up.
  • In summary, in the quality of life category, there were no advantages or disadvantages of pertuzumab + trastuzumab + chemotherapy compared with trastuzumab + chemotherapy.
• Side effects – Serious adverse events (SAEs)
  • With regard to serious adverse events, there is a statistically significant disadvantage associated with pertuzumab + trastuzumab + chemotherapy.
• Side effects – Severe AEs (CTCAE Grade 3 or 4)
  • With regard to severe adverse events with a CTCAE grade of ≥ 3, there is a statistically significant disadvantage of pertuzumab + trastuzumab + chemotherapy compared with trastuzumab + chemotherapy.
  • In the subgroup analysis by region (patient populations: USA/Canada, Asia/Pacific, Western Europe, Latin America, others), statistically significant differences were observed only for the USA/Canada and Asia/Pacific regions, but not for the Western Europe region.
• Side effects – Specific AEs
  • For pertuzumab + trastuzumab + chemotherapy, there is a statistically significant advantage over trastuzumab + chemotherapy with regard to the severe AE ‘musculoskeletal, connective tissue and bone disorders’ (SOC).
  • A statistically significant disadvantage is observed for pertuzumab + trastuzumab + chemotherapy with regard to the specific AEs diarrhoea (PT), pruritus (PT), heart failure (PT), anaemia (PT), stomatitis (PT), fatigue (PT), low white blood cell count (PT) and metabolic and nutritional disorders (SOC).
• Side effects – heart failure (serious)
  • Serious heart failure is a serious adverse event for patients. However, serious heart failure occurred only rarely in both treatment groups. The extent of the difference in absolute terms is minor.
• In the ‘Side effects’ category, an overall relevant disadvantage is identified for pertuzumab + trastuzumab + chemotherapy.
• Overall assessment
  • On balance, no advantage or disadvantage relevant to the benefit assessment can be identified with regard to overall survival. The benefit in terms of preventing recurrence is offset by significant side effects. In weighing up the evidence, the G-BA concludes that the advantages outweigh the disadvantages.

Courtesy translation only, please refer to the German original.