Ramucirumab (6) – Cyramza®

• Clinical trials
  • RELAY is a multicentre, double-blind, randomised controlled trial comparing ramucirumab in combination with erlotinib to erlotinib alone.

a) Adult patients with metastatic NSCLC harbouring the activating EGFR mutations L858R or del 19; first-line treatment

• Additional benefit is not proven for the treatment of adult patients receiving first-line treatment for metastatic NSCLC with the activating EGFR mutations L858R or del 19.
• mortality
  • In the RELAY study, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • No statistically significant difference was observed between ramucirumab in combination with erlotinib and erlotinib alone for the endpoint of overall survival (HR: 0.83 [95% CI: 0.53; 1.30]; p=0.421).
  • No additional benefit was observed for the endpoint of overall survival.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the RELAY trial and, according to the trial protocol/trial report, was defined as the time from randomisation to disease progression (assessed using RECIST criteria version 1.1) or death, regardless of the underlying cause of death.
  • PFS was statistically significantly prolonged by a median of 7.0 months in the intervention arm compared with the control arm (median 19.4 vs. 12.4 months; HR: 0.59 [95% CI: 0.46; 0.76]; p < 0.0001).
  • The results for the progression-free survival endpoint are not included in this review.
• Morbidity – time to diagnosis of CNS metastases
  • In the RELAY study, the time to diagnosis of CNS metastases was assessed as an exploratory endpoint. It was defined as the time from randomisation to the radiological detection of CNS metastases.
  • In the RELAY study, an analysis of event times revealed a statistically significant benefit in favour of ramucirumab in combination with erlotinib compared with erlotinib alone.
  • In light of the relevant uncertainties described regarding the interpretation and certainty of the available results, no additional benefit is inferred for the endpoint ‘time to diagnosis of CNS metastases’ based on the available data.
• Morbidity – Symptoms
  • Symptoms were assessed in the RELAY study using the LCSS ASBI (Lung Cancer Symptom Scale Average Symptom Burden Index) questionnaire.
  • In both analysis methods, no statistically significant difference was observed between the study arms.
• Morbidity – Health status (EQ-5D visual analogue scale)
  • General health status was assessed using the EQ-5D visual analogue scale.
  • In both analysis methods, no statistically significant difference was observed between the study arms.
• quality of life
  • Data on health-related quality of life were not collected in the RELAY study.
• Side effects – Adverse events (AE)
  • In RELAY, an adverse event occurred in 100% of patients in both the intervention and control arms.
• Side effects – Serious adverse events (SAEs)
  • No statistically significant difference was observed between the study arms with regard to serious adverse events.
• Side effects – Severe AEs (CTCAE grade ≥ 3)
  • With regard to severe adverse events with a CTCAE grade of ≥ 3, there was a statistically significant disadvantage of ramucirumab in combination with erlotinib compared with erlotinib alone.
• Side effects – Discontinuation due to AEs
  • No statistically significant difference was observed between the study arms for the endpoint of therapy discontinuation due to an AE.
• Side effects – Specific AEs
  • Ramucirumab in combination with erlotinib showed a statistically significant disadvantage compared with erlotinib in terms of the specific AEs ‘peripheral oedema’ (PT) and the specific severe AEs (CTCAE grade ≥ 3) ‘diarrhoea’ (PT), hypertension (PT) and infections and parasitic diseases (SOC).
• Overall assessment
  • In the mortality endpoint category, the available results for the overall survival endpoint show no statistically significant difference between the study arms.
  • In the morbidity category, there are no statistically significant differences between the study arms, neither in terms of symptoms (assessed using the LCSS ASBI) nor for the endpoint of general health status (assessed using the EQ-5D VAS).
  • For the endpoint ‘time to diagnosis of CNS metastases’, no additional benefit is identified on the basis of the available data, given the relevant uncertainties regarding the interpretation and reliability of the results, particularly in view of the very low number of events.
  • Data on health-related quality of life were not collected in the RELAY study.
  • With regard to side effects, no statistically significant difference was observed between the study arms for the endpoints of serious AEs and discontinuation due to AEs. With regard to severe adverse events (CTCAE grade ≥ 3), there is a moderate disadvantage associated with ramucirumab in combination with erlotinib compared with erlotinib alone.
  • Overall, the G-BA concludes that additional benefit is not proven with ramucirumab in combination with erlotinib compared with erlotinib alone in the first-line treatment of metastatic NSCLC with the activating EGFR mutations L858R or del 19.

b) Adult patients with metastatic NSCLC with activating EGFR mutations other than L858R or del 19; first-line treatment

• An additional benefit is not proven for the treatment of adult patients receiving first-line treatment for metastatic NSCLC with activating EGFR mutations other than L858R or del 19.
• No data were submitted for the assessment of the additional benefit of ramucirumab in combination with erlotinib compared with the appropriate comparator therapy for adult patients receiving first-line treatment for metastatic NSCLC with activating EGFR mutations other than L858R or del 19. The RELAY study submitted for assessment exclusively investigated patients with the activating EGFR mutations L858R or del 19.

Courtesy translation only, please refer to the German original.