Ramucirumab (2) – Cyramza®

• Clinical trials
  • In this double-blind, controlled, multicentre Phase III trial, a total of 1,072 patients were randomised in a 1:1 ratio. The study investigated the therapeutic effect of ramucirumab in combination with FOLFIRI (536 patients) compared with FOLFIRI alone (536 patients) in the treatment of patients with metastatic colorectal cancer.

a) Adult patients with metastatic colorectal cancer (mCRC) who had experienced tumour progression during or following prior treatment with bevacizumab, oxaliplatin and a fluoropyrimidine

• mortality
  • overall survival
  • The results of the RAISE study showed a statistically significant prolongation of overall survival for treatment with ramucirumab in combination with FOLFIRI compared with FOLFIRI in combination with placebo (hazard ratio (HR) 0.84; 95% confidence interval (CI) [0.73; 0.98]; p = 0.022). The median survival time in the treatment arm (13.3 months) was 1.6 months longer than in the control arm (11.7 months).
  • For the endpoint of overall survival, there is proof of an effect modification by the characteristic ‘sex’ (interaction test p = 0.049). Accordingly, men in the active treatment arm showed no statistically significant difference in median survival time (13.8 months) compared with 12.4 months in the control arm. In contrast, women in the ramucirumab group achieved a statistically significant median prolongation of survival time of 12.7 months (HR 0.74; 96% CI [0.59; 0.91]; p = 0.005) of 2.0 months compared with the control group (10.7 months).
• morbidity
  • Progression-free survival (PFS)
  • PFS was assessed as a secondary endpoint in the RAISE trial and was defined as the time from randomisation to disease progression or death from any cause.
  • The treatment arm (5.7 months) showed a statistically significant prolongation of median progression-free survival (HR 0.79; 95% CI [0.70; 0.90]; p < 0.001) of 1.2 months.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of the endpoint was assessed in the RAISE study as a standalone endpoint via the primary endpoint ‘overall survival’. The ‘disease progression’ component of the morbidity endpoint was not assessed on the basis of symptoms, but exclusively by means of imaging procedures. Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
  • Symptoms (EORTC QLQ-C30)
  • The available analyses show, based on the relevant symptom scales, a statistically significant disadvantage of the ramucirumab-FOLFIRI combination compared with the placebo-FOLFIRI combination in terms of the median time to deterioration for the endpoints of fatigue (0.6-month disadvantage; HR 1.28; 95% CI [1.11; 1.48]; p = 0.001), loss of appetite (2.3-month disadvantage; HR 1.43; 95% CI [1.22; 1.68]; p < 0.001) and constipation (2.8-month disadvantage; HR 1.22; 95% CI [1.02; 1.46]; p = 0.031).
  • For the endpoints loss of appetite (interaction test p < 0.001) and constipation (interaction test p = 0.008), there is proof of an effect modification by the characteristic ‘gender’. Women in the intervention arm did not experience a significant effect on these symptoms. In contrast, for men, there is evidence for the endpoints of loss of appetite (3.9-month disadvantage; HR 1.90; 95% CI [1.54; 2.35]; p < 0.001) and constipation (4.1-month disadvantage; HR 1.47; 95% CI [1.16; 1.86]; p = 0.002). Hints of a negative effect of the Ramucirumab-FOLFIR combination compared to the control
• Health-related quality of life
  • EORTC QLQ-C30
  • The median time to deterioration was found to be longer for the endpoints of global health status (1.5-month disadvantage; HR 1.32; 95% CI [1.13; 1.55]; p = 0.001), physical functioning (1.4-month disadvantage; HR 1.29; 95% CI [1.09; 1.52]; p = 0.003), role functioning (1.1-month disadvantage; HR 1.38; 95% CI [1.18; 1.61]; p < 0.001) and emotional functioning (2.3-month disadvantage; HR 1.24; 95% CI [1.03; 1.50]; p = 0.026).
  • For the endpoints of global health status, physical functioning and emotional functioning, there is an indication of effect modification by the characteristic ‘gender’; for the endpoint of role functioning, there is proof of such an effect. In women, the ramucirumab-FOLFIRI combination had no significant effect on the aforementioned endpoints. In contrast, for men, treatment with the ramucirumab-FOLFIRI combination showed negative, statistically significant effects compared with the placebo-FOLFIRI combination for the endpoints of global health status (2.3-month disadvantage; HR 1.40; 95% CI [1.13; 1.72]; p = 0.002), physical functioning (1.8-month disadvantage; HR 1.42; 95% CI [1.14; 1.77]; p = 0.001), role functioning (1.8-month disadvantage; HR 1.57; 95% CI [1.28; 1.92]; p < 0.001) and emotional functioning (1.8-month disadvantage; HR 1.41; 95% CI [1.11; 1.80]; p = 0.005).
• Side effects
  • Serious adverse events (SAEs)
  • No statistically significant difference was observed between the treatment groups for the SAE endpoint.
  • Severe AEs (CTCAE grade ≥ 3)
  • For the endpoint of severe AEs (CTCAE grade ≥ 3), a statistically significant difference was observed to the detriment of the ramucirumab-FOLFIRI combination compared with the placebo-FOLFIRI combination (1.7-month disadvantage; HR 1.55; 95% CI [1.34; 1.80]; p < 0.001). The overall rate of adverse events (AEs) of CTCAE grade ≥ 3 was significantly higher in the treatment arm (79%) than in the control arm (62%). The most common AEs included neutropenia (21.7% versus 11.2%), a reduced neutrophil count (17.4% versus 12.1%) and hypertension (10.8% versus 2.8%) were among the most common AEs with a CTCAE grade of ≥ 3.
  • Therapy discontinuation due to AEs
  • For the endpoint of therapy discontinuation due to AEs, a statistically significant difference was observed to the disadvantage of the ramucirumab-FOLFIRI combination compared with the placebo-FOLFIRI combination (HR 2.38; 95% CI [1.79; 3.16]; p < 0.001). In the treatment arm, 29.1% of patients discontinued treatment, whilst in the control arm, 13.3% of patients discontinued treatment.
  • Specific AE
  • For the endpoints ‘bleeding/haemorrhage’ and ‘bleeding/haemorrhage: gastrointestinal bleeding’, there was a statistically significant difference to the detriment of the ramucirumab-FOLFIRI combination (HR 2.15; 95% CI [1.73; 2.69]; p < 0.001; HR 1.77; 95% CI [1.17; 2.65]; p = 0.006). Statistically significant differences to the detriment of the active treatment arm were also observed for the adverse events of peripheral oedema (relative risk (RR) 2.25; 95% CI [1.63; 3.09]; p < 0.001), hand-foot syndrome (RR 2.34; 95% CI [1.54; 3.55]; p < 0.001) and headache (RR 1.90; 95% CI [1.33; 2.72]; p < 0.001).

Courtesy translation only, please refer to the German original.