Nivolumab (7) – Opdivo®

• Clinical trials
  • For benefit assessment, the pharmaceutical manufacturer refers in the dossier to the results of the CA209-141 (CheckMate 141) trial, which is also the pivotal registration trial for this new indication for nivolumab.
  • This was a randomised, controlled, open-label trial comparing nivolumab with a treatment of the doctor’s choice (cetuximab, methotrexate or docetaxel).

a) Patients with early progression during or after platinum-based therapy

• There is a hint of considerable additional benefit for nivolumab as monotherapy for the treatment of squamous cell carcinoma of the head and neck in adults with early progression during or after platinum-based therapy.
• Consequently, the G-BA has determined that nivolumab as monotherapy for the treatment of squamous cell carcinoma of the head and neck in adults with early progression during or following platinum-based therapy offers considerable additional benefit compared with methotrexate.
• Taking all these uncertainties into account, the certainty of the evidence for the established additional benefit is classified overall as ‘hint’.
• Mortality – Overall survival
  • Treatment with nivolumab showed a statistically significant prolongation in overall survival compared with treatment with methotrexate (hazard ratio: 0.62 [0.44; 0.89], p = 0.008).
  • The median survival time in the nivolumab group was 7.5 months, compared with 4.4 months in the methotrexate group, meaning that a median survival benefit of 3.1 months was achieved with nivolumab.
• Morbidity – Progression-free survival
  • No statistically significant difference was observed for the endpoint of progression-free survival (PFS): in the nivolumab group, the median PFS was 2.00 months, compared with 2.20 months in the methotrexate group (hazard ratio: 0.88 [0.63; 1.24], p = 0.451).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. In this study, the ‘mortality’ component of the endpoint was assessed via the ‘overall survival’ endpoint as a separate endpoint. The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (radiologically determined disease progression according to the RECIST criteria). 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 the extent of the additional benefit.
• Morbidity – Symptoms
  • In the study, disease-related symptoms were documented by the patients and assessed using the cancer-specific EORTC QLQ-C30 questionnaire (symptom scales) and the EORTC QLQ-H&N35 questionnaire.
  • However, no meaningful data could be obtained from these questionnaires in the study, as the proportion of patients for whom no data are available was already very high at early stages of the analysis. It is therefore not possible to assess the extent to which nivolumab affects the symptoms of the disease compared with methotrexate.
• quality of life
  • Health-related quality of life was assessed in the study using the functional scales and the scale for measuring overall health status from the cancer-specific EORTC QLQ-C30 questionnaire.
  • As with the assessment of symptoms using this questionnaire, no meaningful data on health-related quality of life could be obtained in the study, as the proportion of patients for whom no data are available is already very high at early analysis time points. It is therefore not possible to assess the extent to which nivolumab affects health-related quality of life compared with methotrexate.
• Side effects – Total adverse events (AEs)
  • Almost every patient in the study experienced at least one adverse event (AE) at least once, both during treatment with nivolumab and during treatment with methotrexate. Events that were not relevant to the patient were also recorded. The results for the endpoint ‘Total adverse events’ are therefore presented only as supplementary information.
• Overall assessment
  • The results for the additional benefit of Nivolumab as monotherapy for the treatment of head and neck squamous cell carcinoma in adults with early progression during or after platinum (CheckMate 141).
  • The study compared nivolumab with a treatment chosen by the investigator. The investigator could choose from three treatments: methotrexate, docetaxel or cetuximab, each as monotherapy.
  • For the present assessment, the methotrexate patient population of the study is used, which the G-BA considers to be an appropriate implementation of the appropriate comparator therapy. The methotrexate patient population comprises just under half of all patients in the study’s overall population.
  • With regard to overall survival, the study results show that treatment with nivolumab achieves a significant median survival benefit of 3.1 months compared with methotrexate (median 7.5 months versus 4.4 months).
  • With regard to the assessment of morbidity, in particular disease-specific symptoms and functional impairments caused by head and neck tumours, the study does not provide meaningful data, as the proportion of patients for whom no data are available is very high even at early analysis time points.
  • Furthermore, no meaningful data on health-related quality of life are available, as here too the proportion of patients for whom no data are available is very high even at early analysis time points. It is therefore not possible to assess the extent to which nivolumab, compared with methotrexate, affects patients’ health-related quality of life. Conclusions regarding quality of life and morbidity are considered particularly important in the context of palliative care, as is the case here.
  • With regard to side effects, neither a clear advantage nor a disadvantage can be identified. An additional benefit in terms of side effects is therefore not proven.
  • Overall, it is concluded that the extent to which overall survival is prolonged represents a significant improvement that has not previously been achieved in this indication, taking into account the severity of the disease. No additional benefit has been proven for other patient-relevant endpoints – morbidity, health-related quality of life and side effects.

b) Patients with late progression following platinum-based therapy, for whom repeat platinum-based therapy is also an option

• An additional benefit is not proven for nivolumab as monotherapy for the treatment of squamous cell carcinoma of the head and neck in adults with late progression following platinum-based therapy, for whom repeat platinum-based therapy is also an option.
• No data are available for this patient group to assess the additional benefit of nivolumab compared with the appropriate comparator therapy.
• The CA209-141 study, cited by the pharmaceutical manufacturer in the dossier for the benefit assessment, included patients who were resistant or refractory to platinum-based therapy (early progression during or shortly after platinum-based therapy), in accordance with the inclusion criterion that tumour progression or recurrence must have been detected during or within 6 months of the last dose of platinum-based chemotherapy.
• Consequently, patients who experienced progression at a later stage or who had a correspondingly long period of remission following initial platinum-based therapy were not included in this study. For these patients, provided the necessary conditions are met – for example, with regard to the associated toxicities – a repeat course of platinum-based therapy may also be considered as part of an individualised treatment plan, particularly where there has been a sufficiently long period of remission following initial platinum-based therapy.

Courtesy translation only, please refer to the German original.