Nivolumab (20) – Opdivo®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer has included in the dossier the results of the ongoing, open-label, randomised, controlled trial CheckMate 649, in which nivolumab in combination with FOLFOX (5-fluorouracil + folinic acid + oxaliplatin) or XELOX (capecitabine + oxaliplatin) is compared with FOLFOX or XELOX.

Adults with locally advanced or metastatic, non-curably treatable, HER2-negative adenocarcinoma of the stomach, the gastro-oesophageal junction or the oesophagus with PD-L1-expressing tumours (Combined Positive Score (CPS) ≥ 5); first-line treatment

• Consequently, the G-BA has determined that nivolumab provides a hint of considerable additional benefit compared with the appropriate comparator therapy.
• mortality
  • In the CheckMate 649 trial, overall survival is defined as the time from randomisation to death, regardless of the underlying cause of death.
  • For the overall survival endpoint, a statistically significant difference in favour of nivolumab in combination with FOLFOX or XELOX was observed in the relevant patient population (PD-L1-positive population), a statistically significant difference in favour of nivolumab in combination with FOLFOX or XELOX, the extent of which is assessed as a marked improvement in terms of prolonging survival.
• Morbidity – Progression-free survival (PFS)
  • In the CheckMate 649 trial, PFS is defined as the time from randomisation to disease progression according to RECIST criteria version 1.1 or death from any cause.
  • With nivolumab in combination with FOLFOX or XELOX, PFS was statistically significantly prolonged for the relevant patient population (PD-L1-positive population) compared with FOLFOX or XELOX alone.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories. The ‘mortality’ component of the endpoint is already assessed via the ‘overall survival’ endpoint as a standalone endpoint. The ‘disease progression’ component of the morbidity endpoint is assessed according to RECIST criteria and is therefore not symptom-based, but rather determined 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 additional benefit.
• Morbidity – Symptoms
  • Data on disease symptoms were not collected in the CheckMate 649 study.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • General health status is assessed in the CheckMate 649 study using the EQ-5D visual analogue scale (VAS). The assessment was intended to continue in the study until death.
  • However, as the data on response rates show that the corresponding proportions are minor in both arms after the end of treatment with the study medication, and as the response rate data are only available separately for the period during treatment and the period after treatment, it is not possible to conclusively assess the extent to which the presented responder analyses of ‘time to permanent deterioration’ are adequate. Against this background, the analyses of ‘time to permanent deterioration’ are not used for the present benefit assessment.
  • As the continuous analyses of change since the start of the study did not take into account assessments carried out after the end of treatment, these analyses are also not used for the present benefit assessment.
• quality of life
  • Health-related quality of life is assessed in the CheckMate 649 study using the FACT-Ga (Functional Assessment of Cancer Therapy-Gastric). This comprises the FACT-G (FACT-General) and the gastric cancer-specific subscale GaCS (FACT-Gastric Cancer Subscale).
  • With regard to the FACT-Ga endpoint (total score) for the relevant patient population (PD-L1-positive population), a statistically significant advantage was observed for nivolumab in combination with FOLFOX or XELOX. No statistically significant difference was observed between the treatment groups for the PWB, SWB, EWB and FWB subscales. No data were available for the GaCS subscale over the period used to calculate the total score.
• Side effects – Adverse events (AEs)
  • In the CheckMate 649 trial, AEs occurred in almost all patients in both treatment groups. The results are presented here for supplementary information only.
• Side effects – serious adverse events (SAEs) and severe adverse events (CTCAE grade ≥ 3)
  • For the endpoints SAEs and severe AEs, there was no statistically significant difference between the treatment groups for the relevant patient population.
• Side effects – Discontinuation due to AEs
  • For the endpoint ‘discontinuation due to AEs’, a statistically significant difference was observed for the relevant patient population, to the disadvantage of nivolumab in combination with FOLFOX or XELOX compared with FOLFOX or XELOX alone.
• Side effects – Specific adverse events
  • For the specific SAEs immune-mediated SAE, immune-mediated severe SAE, disorders of the skin and subcutaneous tissue (SOC, SAE), disorders of the immune system (SOC, SAE), elevated amylase (PT, severe AE) and peripheral neuropathy (PT, severe AE), there was a statistically significant difference in favor of nivolumab in combination with FOLFOX or XELOX for the relevant patient population in each case.
• Overall assessment
  • For the endpoint of overall survival, there was a statistically significant difference in favour of nivolumab in combination with FOLFOX or XELOX. The extent of the effect is assessed as a marked improvement.
  • Data on disease symptoms were not collected in the CheckMate 649 trial.
  • No usable data on health status are available from the CheckMate 649 trial.
  • With regard to health-related quality of life (assessed using the FACT-Ga), there is an advantage of nivolumab in combination with FOLFOX or XELOX.
  • With regard to side effects, there was no statistically significant difference between the treatment groups in terms of the endpoints ‘serious AEs’ and ‘severe adverse events’ (CTCAE grade ≥ 3). For the endpoint of treatment discontinuation due to AEs, there is a disadvantage associated with nivolumab in combination with FOLFOX or XELOX. In detail, nivolumab in combination with FOLFOX or XELOX shows negative effects compared with FOLFOX or XELOX alone in terms of specific AEs.
  • Overall, there is a marked improvement in overall survival. Furthermore, advantages are observed in health-related quality of life. This is offset by disadvantages regarding the endpoint of treatment discontinuation due to AEs, as well as, in more detail, with regard to specific AEs. Consequently, a considerable additional benefit is identified for nivolumab in combination with FOLFOX or XELOX compared with FOLFOX or XELOX alone.

Courtesy translation only, please refer to the German original.