Ramucirumab (3) – Cyramza®

• Clinical trials
  • In this randomised, double-blind, controlled, multicentre Phase III trial, a total of 1,253 patients were randomised in a 1:1 ratio to receive treatment with ramucirumab in combination with docetaxel (628 patients) or docetaxel in combination with placebo (625 patients).

adult patients with locally advanced or metastatic non-small cell lung cancer who had experienced tumour progression following platinum-based chemotherapy

• The conclusion is that an additional benefit is not proven for ramucirumab in combination with docetaxel for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer who have experienced tumour progression following platinum-based chemotherapy.
• mortality
  • Overall survival was assessed as the primary endpoint in the REVEL trial and was defined as the time from randomisation to death, regardless of the cause of death.
  • Treatment with ramucirumab in combination with docetaxel showed a statistically significant prolongation of overall survival compared with docetaxel in combination with placebo (hazard ratio (HR) 0.86; 95% confidence interval (CI) [0.75; 0.98]; p = 0.023). The median survival time in the treatment arm (10.51 months) was 1.38 months longer than the median survival time in the control arm (9.13 months).
  • For the endpoint of overall survival, there is proof of an effect modification by the characteristic ‘age’ (interaction test: p = 0.004). In patients aged ≥ 65 years, ramucirumab had no significant effect on survival (HR 1.10; 95% CI [0.89; 1.36], p = 0.393); positive effects (HR 0.74; 95% CI [0.62; 0.87], p < 0.001) were observed only in younger patients (< 65 years).
• Morbidity – Progression-free survival
  • Progression-free survival was assessed as a secondary endpoint in the REVEL trial and was defined as the time from randomisation to disease progression or death from any cause.
  • The median progression-free survival (PFS) was 4.50 months for the ramucirumab-docetaxel combination compared with 3.02 months in the control group (absolute difference: 1.48 months). The difference is statistically significant (HR 0.76; 95% CI [0.68; 0.86], p < 0.001).
  • There is also proof of an effect modification by the characteristic ‘age’ for the PFS endpoint (interaction test: p = 0.004). In patients aged ≥ 65 years, ramucirumab had no significant effect on progression-free survival (HR 0.98; 95% CI [0.81; 1.19], p = 0.824); positive effects (HR 0.68; 95% CI [0.59; 0.79], p < 0.001) were observed only in younger patients (< 65 years).
  • 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 study via the ‘overall survival’ endpoint as a standalone endpoint. The ‘disease progression’ component of morbidity was not assessed on the basis of symptoms, but rather using 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.
• Health-related quality of life
  • In the ‘quality of life’ endpoint category, the pharmaceutical manufacturer has provided analyses of the total score of the LCSS questionnaire and the VAS of the EQ-5D.
  • However, the LCSS total score is not validated for determining health-related quality of life. The results on symptoms, collected using the ASBI section of the LCSS questionnaire, have already been assigned to the morbidity endpoint category, as have the results of the EQ-5D VAS.
  • Consequently, there are no relevant data available for assessing the effects of ramucirumab on health-related quality of life.
• Side effects – Serious adverse events (SAE)
  • No statistically significant difference was observed between the treatment groups for the SAE endpoint.
  • For the SAE endpoint, there is proof of an effect modification by the characteristic ‘age’ (interaction test: p < 0.001). In patients aged ≥ 65 years, ramucirumab had a negative impact on the time to the first occurrence of an SUE (HR 1.54; 95% CI [1.17; 2.03], p = 0.002). Younger patients (< 65 years) benefited from treatment with ramucirumab in terms of the time to first occurrence of an SUE (HR 0.70; 95% CI [0.56; 0.87], p = 0.001).
• Overall assessment
  • Results are available for the benefit assessment of ramucirumab across the endpoint categories of mortality, morbidity and side effects.
  • There is a slight prolongation of median survival, although this is offset by significant disadvantages in terms of side effects. No significant effects on disease symptoms could be detected, and no valid data on health-related quality of life were available.
  • The G-BA questions the generalisability of the results from the REVEL study to patients in the statutory health insurance system:
  • The advantages in overall survival were demonstrated in patients whose age differed from that of patients encountered in routine clinical practice: The median age of the study participants was 62 years; however, the mean age at diagnosis for non-small cell lung cancer in Germany is between 69 and 70 years. This is of particular relevance in light of the documented effect modification by the ‘age’ factor. In patients aged ≥ 65 years, ramucirumab had no significant effect on survival time; however, serious adverse events occurred more frequently and at an earlier stage than with docetaxel monotherapy in the comparator arm.
  • Furthermore, relevant patient populations within the therapeutic indication, such as patients at increased risk of bleeding or those with an ECOG performance status > 1, were not investigated in the REVEL trial due to the selected exclusion criteria. Consequently, the generalisability to the relevant real-world population is limited, and potential risks for these patients are severe to assess.
  • Taking into account the opinions of medical experts, the lack of robust data on health-related quality of life, and the existing uncertainty regarding the generalisability of the study results to clinical practice, the G-BA has reached the following conclusion in its balanced assessment: that the patient-relevant adverse effects of the new INN and the uncertainty of the data are of such significance that the potential advantage in terms of the minor extension of survival achieved in the REVEL registration trial does not outweigh these in the overall assessment of the new INN.

Courtesy translation only, please refer to the German original.