Ramucirumab (5) – Cyramza®

• Clinical trials
  • Both studies are randomised, placebo-controlled, double-blind, multicentre trials, in each of which treatment with ramucirumab + best standard care (BSC) was compared with treatment with placebo + BSC.
  • This benefit assessment included a patient population from the REACH study and the entire REACH-2 study in the form of a meta-analysis.

Adult patients with advanced or inoperable hepatocellular carcinoma who are not being treated with the intention of a cure and for whom locoregional therapy is not an option, who have a serum alpha-fetoprotein (AFP) of ≥ 400 ng/ml and who had previously been treated with sorafenib

• Overall, there is proof of a minor additional benefit for ramucirumab + BSC compared with placebo + BSC in the treatment of patients with advanced or inoperable hepatocellular carcinoma who have a serum alpha-fetoprotein (AFP) of ≥ 400 ng/ml and who have previously been treated with sorafenib.
• Consequently, the certainty of the proof for the observed additional benefit is classified as ‘Proof’.
• mortality
  • A statistically significant difference in favour of ramucirumab + BSC compared with placebo + BSC was observed for overall survival (hazard ratio (HR): 0.69 [95% confidence interval (CI): 0.57; 0.84]; p-value <0.001).
  • The median overall survival in the intervention arm was 3.05 months longer than in the control arm (median 8.08 vs. 5.03 months). This is assessed as a minor prolongation of overall survival.
  • Consequently, this endpoint shows an additional benefit, the extent of which is considered to be minor.
• Morbidity – Progression-free survival (PFS)
  • The time-to-event analysis for PFS in the pooled patient population (patients in the AFP ≥ 400 ng/ml subpopulation from the REACH study and all patients from the REACH-2 study) revealed a statistically significant difference in favour of ramucirumab + BSC compared with placebo + BSC (stratified HR: 0.572; [95% CI: 0.472; 0.694]; p-value < 0.0001).
  • The median PFS was prolonged by 1.3 months for patients in the ramucirumab + BSC arm (2.8 months) compared with patients in the placebo + BSC arm (1.5 months).
  • The PFS endpoint is a composite endpoint comprising endpoints from the mortality and morbidity categories.
  • The overall conclusion regarding the extent of the additional benefit remains unaffected.
• Morbidity – Health status (assessed using the EQ-5D VAS)
  • In the REACH and REACH-2 studies, health status was assessed using the EQ-5D via the visual analogue scale (VAS).
  • The responder analyses of the pooled data show, based on a MID of 7 mm, a statistically significant but minor difference between the treatment arms in favour of ramucirumab + BSC compared with placebo + BSC; based on a MID of 10 mm, no statistically significant difference was observed.
  • These results are considered insufficient to demonstrate, with the necessary certainty, an advantage in terms of the health status endpoint.
• Morbidity – Symptoms (assessed using the FHSI-8)
  • For the benefit assessment, the pharmaceutical manufacturer submitted responder analyses using different response criteria: a deterioration of ≥ 3 points (sensitivity analyses for ≥ 2 and ≥ 4 points), as well as a responder analysis submitted during the commenting procedure with a response criterion of ≥ 5 points.
  • For the response criterion of ≥ 5 points, there is a statistically significant difference in favour of ramucirumab + BSC compared with placebo + BSC.
• quality of life
  • Data on health-related quality of life were not collected using appropriate instruments in the REACH and REACH-2 studies.
• Side effects – Total adverse events (AEs)
  • The overall rate of side effects is presented only as supplementary information, as the operationalisation of side effects also includes events that are not relevant to patients.
• Side effects – Serious AEs, severe AEs (CTCAE grade ≥ 3), discontinuation due to adverse events
  • Event-time analyses are available for the endpoints of serious AEs, severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs for the benefit assessment.
  • For the specified endpoints, the meta-analysis shows no statistically significant difference between the treatment groups in each case.
  • In each case, there is no hint that ramucirumab + BSC causes greater or minor harm compared with placebo + BSC.
  • An additional benefit is therefore not proven.
• Side effects – Specific adverse events
  • With regard to specific AEs, the respective event rates and Kaplan-Meier curves for the specific AEs ‘gastrointestinal disorders’, ‘hyperbilirubinaemia’ and ‘investigations’ show that these adverse events occur less frequently and at a later stage in the ramucirumab + BSC arm than in the placebo + BSC arm.
  • In each case, there is an indication of a minor risk of harm with ramucirumab + BSC compared with placebo + BSC.
  • By contrast, the specific AEs ‘peripheral oedema’, ‘headache’ and ‘hypertension’ occur more frequently and earlier in the ramucirumab + BSC arm than in the placebo + BSC arm.
  • This provides an indication, in each case, that Ramucirumab + BSC is associated with greater harm compared with placebo + BSC.
• Overall assessment
  • With regard to overall survival, the meta-analysis shows an advantage of ramucirumab + BSC over placebo + BSC, whose extent is classified as minor.
  • In the morbidity category, a statistically significant effect in favour of ramucirumab + BSC, assessed as clinically relevant, was observed for the endpoint of symptoms (measured using the FHSI-8).
  • No suitable data on health-related quality of life are available from the REACH and REACH-2 studies.
  • In the overall analysis of the results on side effects, there are statistically significant differences in specific adverse events. These show both positive and negative effects of ramucirumab + BSC compared with placebo + BSC.
  • In the overall assessment of all endpoints, neither an advantage nor a disadvantage of ramucirumab + BSC compared with placebo + BSC is identified in the category of side effects.
  • In its overall assessment, the G-BA concludes that for ramucirumab + BSC in the treatment of patients with advanced or inoperable hepatocellular carcinoma who have a serum alpha-fetoprotein (AFP) of ≥ 400 ng/ml and who have previously been treated with sorafenib, there is a minor additional benefit compared with placebo + BSC.

Courtesy translation only, please refer to the German original.