Nivolumab (13) – Opdivo®

• 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 nivolumab in combination with ipilimumab 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

• mortality
  • The endpoint of overall survival is defined in the CA209-9LA study as the period between the date of randomisation and the date of death from any cause.
  • For the overall survival endpoint, there is a statistically significant difference in favour of nivolumab in combination with ipilimumab 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.
• morbidity
  • Progression-free survival
  • Progression-free survival (PFS) was a secondary endpoint in the CA209-9LA study and was assessed by an independent review committee (BIRC) in accordance with the RECIST v1.1 criteria.
  • In the intervention arm, treatment with nivolumab in combination with ipilimumab 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.
  • The additional benefit of nivolumab in combination with ipilimumab and platinum-based chemotherapy for the endpoint ‘symptoms’ is not proven.
  • For the benefit assessment, the pharmaceutical manufacturer submitted responder analyses for the time to deterioration by ≥ 7, ≥ 10 and ≥ 15 points in the VAS score compared with baseline.
  • With regard to the response criteria of ≥ 7 points and ≥ 10 points, a statistically significant difference was observed in favour of nivolumab in combination with ipilimumab and platinum-based chemotherapy.
  • With regard to the response criterion of ≥ 15 points, no statistically significant difference was observed between the treatment groups.
• Health-related 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 had a disadvantage.
  • 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 nivolumab in combination with ipilimumab 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 active treatment component), there is a negative effect of nivolumab in combination with ipilimumab and platinum-based chemotherapy compared with platinum-based chemotherapy alone.
  • Specific adverse events
  • Immune-mediated SUEs and severe adverse events (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 nivolumab in combination with ipilimumab 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 statistically significant advantage in favour of nivolumab in combination with ipilimumab and platinum-based chemotherapy is evident when examined in detail.
  • 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]), skin and subcutaneous tissue disorders (SOC, severe AEs [CTCAE grade ≥ 3]), endocrine disorders (SOC, severe AEs [CTCAE grade ≥ 3])
  • A detailed analysis of the specific AEs for the endpoints reveals 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]) each showed a statistically significant difference to the detriment of nivolumab in combination with ipilimumab and platinum-based chemotherapy.
  • Based on the adverse effects relating to SAEs, severe SAEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs, as well as, in detail, immune-mediated SAEs and severe SAEs (CTCAE grade ≥ 3) and other specific adverse events recorded, a significant disadvantage of nivolumab in combination with ipilimumab and platinum-based chemotherapy compared with platinum-based chemotherapy alone can be identified, characterised by significant and burdensome side effects for patients.
• Overall assessment
  • Results for the additional benefit of Nivolumab in combination with Ipilimumab and platin-based chemotherapy are available from the open-label, randomised, controlled CA2-9LA are available for the patient population with PD-L1 expression < 50%, covering 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 nivolumab in combination with ipilimumab 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, there is no statistically significant difference with regard to symptoms.
  • For the health status endpoint, there is an advantage for nivolumab in combination with ipilimumab and platinum-based chemotherapy.
  • Health-related quality of life was not assessed in the CA209-9LA study.
  • With regard to side effects, no relevant disadvantages of nivolumab in combination with ipilimumab and platinum-based chemotherapy compared with platinum-based chemotherapy alone were observed in the endpoints of SUEs, severe side effects (CTCAE grade ≥3), discontinuation due to adverse events, and in the detailed analysis of specific adverse events, relevant disadvantages of nivolumab in combination with ipilimumab 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 of 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.