Aflibercept (Zaltrap, 1) – Zaltrap®

• Clinical trials
  • The VELOUR trial was a randomised, double-blind, parallel-group trial in which aflibercept was compared with placebo, as an adjunct to combination chemotherapy consisting of irinotecan/5-fluorouracil/folinic acid (FOLFIRI).

Patients with metastatic colorectal cancer who have been pre-treated with an oxaliplatin-containing regimen

• For adult patients with metastatic colorectal cancer (MCRC) that has progressed during or following an oxaliplatin-containing regimen, there is an indication for a minor additional benefit compared with the appropriate comparator therapy.
• The G-BA classifies the extent of the additional benefit of aflibercept as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a moderate and not merely minor improvement in therapy-relevant benefit that has not previously been achieved.
• The certainty of the finding (probability of the additional benefit) is therefore classified in the ‘indication’ category.
• mortality
  • Treatment with aflibercept in combination with FOLFIRI showed a statistically significant prolongation of overall survival compared with treatment with the FOLFIRI combination chemotherapy alone (hazard ratio: 0.82, p-value: 0.003).
  • The median overall survival was 13.5 months for patients in the aflibercept+FOLFIRI group and 12.1 months in the FOLFIRI group, resulting in a median survival benefit of 1.4 months.
  • Given that median survival in second-line treatment for metastatic colorectal cancer is approximately 10 to 13 months, this is considered relevant for the assessment of additional benefit.
• morbidity
  • There are no evaluable endpoints available for assessing the additional benefit with regard to morbidity.
• quality of life
  • Quality of life was not assessed in the VELOUR study.
  • Consequently, no data are available for assessing the additional benefit in terms of quality of life.
• Side effects
  • In the VELOUR study, almost every patient experienced at least one adverse event, both in the aflibercept+FOLFIRI group (99.2%) and in the FOLFIRI treatment group (97.9%).
  • Due to the very high proportion in both groups, no conclusions regarding the assessment of additional benefit can be drawn from a comparative analysis based on the endpoint ‘total adverse events’.
  • Patients treated with aflibercept plus FOLFIRI were significantly more likely to experience severe adverse events (SAEs) of CTCAE grades 3 and 4 than patients treated with FOLFIRI alone.
  • Furthermore, serious adverse events (SAEs) also occurred significantly more frequently when Aflibercept was administered in addition to FOLFIRI.
  • A subgroup analysis by age (< 65 years; ≥ 65 years) revealed an effect modification, whereby older patients (≥ 65 years) were more frequently affected by additional serious adverse events than younger patients (< 65 years).
  • Adverse events occurring during treatment led to discontinuation of therapy in 26.8% of patients treated with aflibercept plus FOLFIRI and in 12.1% of patients treated with FOLFIRI alone.
  • The increased number of therapy discontinuations indicates that the adverse events associated with aflibercept treatment cannot be managed to such an extent that treatment can be continued as a matter of routine.
  • An overall analysis of the side effect endpoints reveals greater harm associated with aflibercept plus FOLFIRI compared with the appropriate comparator therapy, FOLFIRI.
  • The differences in the extent of serious adverse events (SAE) for patients aged ≥ 65 years and patients aged < 65 years – taking into account the other endpoints relating to side effects – are not considered significant enough to warrant a distinction being made by age group in the overall assessment of side effects.
• Overall assessment
  • Overall, there is an additional benefit for aflibercept in combination with FOLFIRI compared with the appropriate comparator therapy, FOLFIRI, with regard to the endpoint of overall survival.
  • Given the findings on side effects, the greater harm associated with treating patients with aflibercept in addition to FOLFIRI must be taken into account in the overall assessment.
  • For other patient-relevant endpoints in this indication, such as health-related quality of life or indication-specific symptoms, there is no evidence of additional benefit.
  • No data on health-related quality of life or morbidity are available and cannot be included.
  • Statements regarding quality of life are considered particularly important in palliative care settings.
  • In the overall assessment, the effect of aflibercept on overall survival of 1.4 months is evaluated in light of the potential for harm associated with aflibercept and taking into account the severity of the disease.
  • Overall, a moderate improvement in treatment-related benefit and thus a minor additional benefit is identified.

Courtesy translation only, please refer to the German original.