Ipilimumab (6) – Yervoy®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer draws on the results of the open-label, randomised, controlled, multicentre study CA209-9LA, which has been ongoing since August 2017, in which ipilimumab in combination with nivolumab and platinum-based chemotherapy is compared with platinum-based chemotherapy alone.

a) Adult patients with metastatic non-small cell lung cancer (NSCLC) with a Tumour Proportion Score [TPS] of ≥ 50% (PD-L1 expression) and without EGFR mutations or ALK translocations; First-line treatment

• The pharmaceutical manufacturer has not submitted any data to demonstrate additional benefit.
• Consequently, additional benefit is not proven.

b) Adult patients with metastatic non-small cell lung cancer (NSCLC) with a Tumour Proportion Score [TPS] of < 50 % (PD-L1 expression) and without EGFR mutations or ALK translocations; First-line treatment

• Overall, in first-line treatment of patients with metastatic NSCLC without a sensitising EGFR mutation or ALK translocation and PD-L1 expression < 50 %, there is an indication of a minor additional benefit for ipilimumab in combination with nivolumab and platinum-based chemotherapy compared with platinum-based chemotherapy alone.
• The certainty of evidence for the observed additional benefit is classified as ‘indication’.
• mortality
  • For the endpoint of overall survival, there is a statistically significant difference in favour of ipilimumab in combination with nivolumab and platinum-based chemotherapy.
  • The extent of the prolongation in overall survival achieved is assessed as a significant improvement in benefit compared with platinum-based chemotherapy.
  • There is an effect modification by the characteristic ‘adequately treated brain metastases at the start of the study (yes/no)’ for overall survival.
• morbidity
  • Progression-free survival
  • In the intervention arm, treatment with ipilimumab in combination with nivolumab and platinum-based chemotherapy resulted in a significantly longer progression-free survival than in the control arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • Symptoms (LCSS-ABSI) and health status (EQ-5D Visual Analogue Scale)
  • No statistically significant difference was observed between the treatment groups for the symptom-related endpoint. An additional benefit of ipilimumab in combination with nivolumab and platinum-based chemotherapy for the symptom-related endpoint is therefore not proven.
  • However, with regard to the response criteria of ≥ 7 points and ≥ 10 points, a statistically significant difference was observed in favour of ipilimumab in combination with nivolumab and platinum-based chemotherapy.
• quality of life
  • Health-related quality of life was not assessed in the CA209-9LA study.
• Side effects
  • Serious Adverse Events (SAEs)
  • For the SUE endpoint, there was a statistically significant difference in favor of nivolumab in combination with ipilimumab and platinum-based chemotherapy compared with platinum-based chemotherapy alone, which resulted in a disadvantage for ipilimumab.
  • Severe adverse events (CTCAE grade ≥ 3)
  • For the endpoint ‘severe adverse events’ (CTCAE grade ≥ 3), there is a statistically significant difference to the detriment of ipilimumab in combination with nivolumab and platinum-based chemotherapy.
  • Discontinuation due to AEs (discontinuation of at least one treatment component)
  • With regard to the endpoint of discontinuation due to AEs (discontinuation of at least one treatment component), ipilimumab in combination with nivolumab and platinum-based chemotherapy showed a negative effect compared with platinum-based chemotherapy alone.
  • Immune-mediated SUEs and severe AEs (CTCAE grade ≥ 3)
  • For the endpoints immune-mediated SUEs and immune-mediated severe AEs (CTCAE grade ≥ 3), there is a statistically significant difference to the detriment of ipilimumab in combination with nivolumab and platinum-based chemotherapy in each case.
  • Anaemia (PT, severe adverse events [CTCAE grade ≥ 3])
  • With regard to the endpoint of anaemia (severe AEs [CTCAE grade ≥ 3]), a detailed analysis reveals a statistically significant advantage in favour of ipilimumab in combination with nivolumab and platinum-based chemotherapy.
  • In detail, when considering the specific AEs for the endpoints ‘elevated lipase’ (PT, severe AEs [CTCAE grade ≥ 3]), ‘elevated amylase’ (PT, severe AEs [CTCAE grade ≥ 3]), liver and biliary disorders (SOC, severe AEs [CTCAE grade ≥ 3]), disorders of the skin and subcutaneous tissue (SOC, severe AEs [CTCAE grade ≥ 3]) and endocrine disorders (SOC, severe AEs [CTCAE grade ≥ 3]), in each case a statistically significant difference was observed to the detriment of ipilimumab in combination with nivolumab and platinum-based chemotherapy.
  • Based on the adverse effects relating to SAEs, severe SAEs (CTCAE grade ≥ 3) and therapy discontinuations due to SAEs, as well as, in detail, immune-mediated SAEs and severe SAEs (CTCAE grade ≥ 3) and other specific adverse events recorded, a relevant disadvantage of ipilimumab in combination with nivolumab and platinum-based chemotherapy can be identified compared with platinum-based chemotherapy alone, with significant and burdensome side effects for patients.
• Overall assessment
  • Results for the additional benefit of Ipilimumab in combination with Nivolumab and platin-based chemotherapy are available from the open-label, randomised, controlled CA2-9LA for the patient population with PD-L1 expression < 50 % are available for the endpoint categories of mortality, morbidity and side effects, compared with platinum-based chemotherapy.
  • In the endpoint category of mortality, there is a statistically significant difference in favour of ipilimumab in combination with nivolumab and platinum-based chemotherapy. The extent of the prolongation in overall survival achieved is assessed as a significant improvement in benefit compared with platinum-based chemotherapy.
  • In the morbidity endpoint category, no statistically significant difference was observed with regard to symptoms. For the health status endpoint, an advantage was observed for ipilimumab in combination with nivolumab and platinum-based chemotherapy.
  • Health-related quality of life was not assessed in the CA209-9LA study. Statements regarding quality of life are considered particularly important in cases of advanced cancer and in palliative care settings.
  • With regard to side effects, disadvantages of ipilimumab in combination with nivolumab and platinum-based chemotherapy compared with platinum-based chemotherapy alone were observed in the endpoints of SUEs, severe AEs (CTCAE grade ≥3), discontinuation due to adverse events, and, in detail, specific adverse events, relevant disadvantages of ipilimumab in combination with nivolumab and platinum-based chemotherapy compared with platinum-based chemotherapy alone were identified, with significant side effects that are burdensome for patients.
  • In a cost-benefit analysis, the negative effects associated with the side effects do not call into question the additional benefit derived from the improvement in overall survival; however, they do lead to a downgrading of the extent of the additional benefit.

Courtesy translation only, please refer to the German original.