Ramucirumab (1) – Cyramza®

• Clinical trials
  • The RAINBOW trial is a multicentre, randomised, double-blind, placebo-controlled Phase IIIstudy investigating the efficacy and safety of ramucirumab in combination with paclitaxel in patients with metastatic or locally advanced, unresectable adenocarcinoma of the stomach or the gastro-oesophageal junction, whose disease progressed during or after first-line treatment with platinum and fluoropyrimidine.
  • The REGARD trial is a multicentre, randomised, double-blind, placebo-controlled Phase III trial to investigate the efficacy and safety of ramucirumabmonotherapy in patients with metastatic adenocarcinoma of the stomach or the gastro-oesophageal junction who experienced disease progression within four months of the last dose of first-line chemotherapy or within six months of the last dose of adjuvant treatment.

a) In combination with paclitaxel

• The G-BA classifies the extent of the additional benefit of ramucirumab in combination with paclitaxel as minor, based on the criteria set out 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.
• mortality
  • The primary endpoint, overall survival, was defined as the time (in months) between randomisation and death from any cause.
  • Overall survival in the intervention and control groups differed statistically significantly; the median survival time was 2.2 months longer with the combination of ramucirumab and paclitaxel than with paclitaxel alone (9.6 vs. 7.4 months; HR = 0.807; 95% CI [0.678; 0.962]; p = 0.0169).
  • The prolongation of survival is clinically relevant and is taken into account when assessing the extent of the additional benefit.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) was part of the study’s secondary endpoint on tumour assessment. The median PFS was 4.4 months in the combination arm receiving ramucirumab and paclitaxel versus 2.9 months in the control arm receiving placebo plus paclitaxel (HR = 0.635; 95% CI [0.536; 0.752]; p < 0.0001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of this endpoint is already assessed as a standalone endpoint via the primary endpoint ‘overall survival’. Furthermore, the ‘disease progression’ component of morbidity for PFS in the study was not assessed on a symptom-based basis, but rather using imaging procedures. For the benefit assessment, the pharmaceutical manufacturer carried out a post-hoc sensitivity analysis with regard to symptomatic progression (symptom-based assessment of progression + analysis of the time to deterioration and death). Due to methodological limitations (lack of validity of the surrogates for a patient-relevant endpoint), this post-hoc analysis cannot be taken into account. Taking the aforementioned aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint. The overall conclusion regarding the extent of the additional benefit remains unaffected.
• Health-related quality of life – quality of life (EORTC-QLQ-C30)
  • To assess health-related quality of life, the EORTC-QLQ-C30 questionnaire was used in the RAINBOW study.
  • As already explained under ‘morbidity’, only the results for cycle 2 are taken into account due to the minor response rates.
  • With regard to the time to deterioration in health-related quality of life, the combination of ramucirumab and paclitaxel demonstrated a statistically significant advantage on the emotional functioning scale compared with paclitaxel alone (p = 0.0012).
  • In the responder analyses for the second cycle, a statistically significant advantage of the combination of ramucirumab and paclitaxel over paclitaxel was observed for the scales measuring physical, emotional, cognitive and role functioning.
  • A change of at least 10 points was selected as the clinical relevance threshold (minimal important difference (MID)). However, the clear clinical relevance of this threshold in the indication of gastric cancer cannot be conclusively assessed. The results are therefore only used to a limited extent for the present assessment.
  • The improvement in quality of life is relevant to patients and, despite the uncertainty described, is taken into account in assessing the extent of the additional benefit, given the severity of the disease.
• Side effects
  • To address the imbalance regarding the differing treatment durations in the two treatment groups (median treatment duration of 18.9 weeks with ramucirumab in combination with paclitaxel versus approximately 12.1 weeks with placebo in combination with paclitaxel), the dossier presented both non-time-adjusted (absolute frequencies) and time-adjusted (time-to-event) analyses.
  • Overall, a comparable proportion of patients in the groups reported at least one AE (99.1% vs. 97.9%). There were more serious AEs (SAE) (47 vs. 42 %), CTCAE grade ≥ 3 AEs (82 vs. 63 %) and therapy discontinuations due to an AE (31 vs. 24 %) were observed with the combination of ramucirumab and paclitaxel.
  • In the analyses of time to first occurrence of an adverse event, conducted using survival analyses to account for the differing treatment durations across the study arms, no statistically significant differences were observed in the time to first occurrence of AEs, SAE or therapy discontinuations due to an AE. Adverse events (AEs) of CTCAE grade ≥ 3 occurred statistically significantly earlier with the combination of ramucirumab and paclitaxel (1.4 vs. 2.8 months, HR: 0.461; 95% CI [1.218; 1.753]; p < 0.0001). In the supplementary time-weighted analysis of mean cumulative functions (MCF), which also captures recurrent events, a statistically significant disadvantage was observed for the combination of ramucirumab and paclitaxel compared with paclitaxel alone for Grade ≥ 3 AEs (HR: 1.625; 95% CI [1.379; 1.916]). With regard to SAE, this analysis showed no difference.
  • The most common CTCAE grade ≥ 3 events occurring with the combination of ramucirumab and paclitaxel were neutropenia (40.7% vs. 18.8%), leucopenia (17.4 vs. 6.7 per cent), hypertension (14.1 vs. 2.4 per cent) and tumour progression (14.4 vs. 17.9 per cent).
  • In the RAINBOW trial, hypertension, bleeding/haemorrhage and proteinuria in particular occurred at a higher rate in the ramucirumab treatment group. These disadvantages are also confirmed by analyses of the time to the occurrence of an adverse event using survival analyses.
  • Based on the studies, differences of particular interest emerge between the study arms regarding CTCAE grade ≥ 3 events and the time to the occurrence of an adverse event, to the detriment of the combination of ramucirumab and paclitaxel, suggesting a disadvantage for the combination of ramucirumab and paclitaxel in this context.

b) In monotherapy, where patients are not suitable for combination therapy with paclitaxel

• The G-BA classifies the extent of the additional benefit of ramucirumab as monotherapy as minor, based on the criteria set out 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.
• mortality
  • The primary endpoint, overall survival, was defined as the time (in months) between randomisation and death from any cause.
  • Overall survival in the intervention and control groups differed statistically significantly; the median survival time was 1.4 months longer in the ramucirumab group than in the control group (5.2 vs. 3.8 months; HR = 0.776; 95% CI [0.603; 0.998]; p = 0.0473). When analysing the patient population comprising patients from Germany or Europe, the effect was not statistically significant (5.2 vs. 4.5 months, HR = 0.896; 95% CI [0.667; 1.205]; p = 0.4665).
  • As the data failed to show any statistically significant results regarding survival benefit, particularly for the group comprising study centres in North America, Europe, Australia and New Zealand, there is some uncertainty regarding the generalisability of the results to the German healthcare context. The differences across geographical regions may be due to random variations in distribution or differences in the rates of post-progression therapy (PDT).
  • The prolongation of survival in the overall population is relevant to patients and is taken into account when assessing the extent of the additional benefit.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) was part of the study’s secondary endpoint on tumour assessment. The median PFS was 2.1 months in the ramucirumab arm versus 1.3 months in the control arm (HR = 0.483; 95% CI [0.376; 0.620]; p < 0.0001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the mortality and morbidity categories. The ‘mortality’ component of the endpoint is already assessed as a standalone endpoint via the primary endpoint ‘overall survival’. Furthermore, the ‘disease progression’ component of morbidity for PFS in the study was not assessed on a symptom-based basis, but rather using imaging procedures. For the benefit assessment, the pharmaceutical manufacturer carried out a post-hoc sensitivity analysis with regard to symptomatic progression (symptom-based assessment of progression + analysis of the time to deterioration and death). Due to methodological limitations (lack of validity of the surrogates for a patient-relevant endpoint), this post-hoc analysis cannot be taken into account. Taking the aforementioned aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint. The overall conclusion regarding the extent of the additional benefit remains unaffected by this.
• Health-related quality of life – quality of life (EORTC-QLQ-C30)
  • Due to low response rates to the questionnaires, the data cannot be taken into account (see the comments above on symptoms (EORTC-QLQ-C30) under morbidity).
  • However, the clear clinical relevance of the selected cut-off value for the indication of gastric cancer (see discussion on morbidity) cannot be conclusively assessed. This can, however, be left open, as no conclusions regarding the extent of the additional benefit can be drawn from the data due to the minor response rates.
• Side effects
  • To address the imbalance regarding the differing treatment durations in the two treatment groups (median treatment duration of 8.0 weeks with ramucirumab plus BSC versus approximately 6.0 weeks with placebo plus BSC), the dossier presents not onlytime-adjusted (absolute frequencies), time-adjusted (time-to-event) analyses were also presented in the dossier.
  • Overall, 94.5% of patients on ramucirumab + BSC and 87.8% in the control arm reported at least one AE. The proportion of patients with at least one SAE was comparable between the groups (44.9% vs. 44.3%). AEs of CTCAE grade ≥ 3 occurred less frequently in the ramucirumab plus BSC arm (56.8% vs. 58.3%). A higher proportion of patients receiving ramucirumab plus BSC discontinued the study due to an AE (13.6% vs. 7.0%).
  • In the analyses of time to the occurrence of an adverse event, conducted using survival analyses to account for the differing treatment durations across the study arms, there were no statistically significant differences with regard to the time to the occurrence of an AE, SAE, CTCAE grade ≥ 3 AEs and therapy discontinuations due to an AE. The supplementary time-weighted analysis of mean cumulative functions (MCF), which also captures recurrent events, showed a statistically significant advantage for ramucirumab in terms of SAE (HR: 0.644; 95% CI [0.456; 0.910]). With regard to AEs of CTCAE grade ≥ 3, this analysis showed no difference.
  • The most common CTCAE grade ≥ 3 events occurring under ramucirumab were hypertension (7.2% vs. 2.6%), anaemia (6.4 vs. 7.8 per cent) and abdominal pain (5.1 vs. 2.6 per cent).
  • With regard to the pre-specified AEs of particular interest (of any grade) in the study report, hypertension (16.1% in the ramucirumab+BSC arm vs. 7.8% in the placebo+BSC arm) and haemorrhages / haemorrhages (12.7% vs. 11.3%). According to the analyses conducted on the time to onset of an AE, these did not occur statistically significantly earlier in the intervention group. With regard to side effects, there is a minor additional benefit for ramucirumab.

Courtesy translation only, please refer to the German original.