Nivolumab (4) – Opdivo®

• Clinical trials
  • In this randomised, open-label, controlled, multicentre Phase III trial, a total of 528 patients were randomised in a 1:1 ratio to receive treatment with nivolumab (292 patients) or docetaxel (290 patients).

1) Patients for whom treatment with docetaxel, pemetrexed, gefitinib, erlotinib or crizotinib is indicated

• mortality
  • Overall survival was assessed as the primary endpoint in the CA209-057 study and was defined as the time from randomisation to death, regardless of the cause of death.
  • For treatment with nivolumab compared with docetaxel, a statistically significant prolongation of overall survival was observed at the data cut-off date of 18 March 2015, which was relevant for the assessment (hazard ratio (HR) 0.73; 95% confidence interval (CI) [0.60; 0.89]; p = 0.002). The median survival time in the nivolumab arm (12.19 months) was 2.83 months longer than in the control arm (9.36 months).
  • For the endpoint of overall survival, as of the first data cut-off on 18 March 2015, there is proof of an effect modification by the characteristic ‘PD-L1 status’ with a cut-off value of ≥ 5% (interaction test p < 0.001). Patients with a PD-L1 status of ≥ 5% in the nivolumab arm showed a statistically significant median prolongation of survival of 18.2 months (HR 0.43; 95% CI [0.30; 0.63]; p < 0.001) of 10.1 months compared with the control group (8.1 months). Patients with a PD-L1 status < 5% did not show a statistically significant difference in median survival time in the nivolumab arm (9.7 months) compared with 10.1 months in the control arm.
  • With regard to overall survival, the ‘PD-L1 status’ variable also showed indications or evidence of an effect modification, even when using cut-off values of ≥ 1% (interaction test p < 0.065) and ≥ 10% (interaction test p < 0.001), there is an indication or proof of an effect modification.
  • When evaluating the data on overall survival, it should be noted that the Kaplan-Meier curves intersect after 7 months. The survival curve for the nivolumab arm lies slightly below that of the docetaxel arm for the first 6 months and then significantly above it thereafter.
• Morbidity – Progression-free survival (PFS)
  • PFS was assessed as a secondary endpoint in the CA209-057 trial and was defined as the time from randomisation to disease progression or death from any cause.
  • There was no statistically significant prolongation of median progression-free survival between the nivolumab arm (2.33 months) and the control arm (4.21 months) (HR 0.92; 95% CI [0.77; 1.11]; p = 0.3932).
  • When evaluating the PFS data, it should be noted that the Kaplan-Meier curves intersect after 7 months. The curve for the nivolumab arm lies below that of the docetaxel arm for the period up to 7 months and subsequently well above it. Furthermore, as the curves do not intersect until after the median progression-free survival, the data on progression-free survival are subject to uncertainty and do not allow for a plausible estimation of the effect for this endpoint.
• Health-related quality of life
  • However, the LCSS total score is not validated for determining health-related quality of life. The results on symptoms, collected using the ASBI section of the LCSS questionnaire, have already been assigned to the morbidity endpoint category, as have the VAS results from the EQ-5D.
  • Consequently, there are no relevant data available for assessing the effects of nivolumab on health-related quality of life.
• Side effects – Serious adverse events (SAE)
  • For the SAE endpoint, a statistically significant difference was observed between the treatment arms in favour of nivolumab (HR 0.78; 95% CI [0.61; 1.00]; p = 0.049). The median time to the first occurrence of a SAE was 5.91 months longer in the nivolumab arm (11.96 months) compared with the docetaxel arm (6.05 months). SAE occurred in 46.0% of patients in the nivolumab arm and in 50.7% of patients in the docetaxel arm.
  • There is also an indication of an effect modification by the ‘PD-L1 status’ variable with a cut-off value of ≥ 5% (interaction test p < 0.110). Patients with a PD-L1 status of ≥ 5% showed a statistically significant median prolongation of the time to first occurrence of a SAE in the nivolumab arm, at 13.20 months (HR 0.57; 95% CI [0.37; 0.88]; p = 0.011) of 13.20 months compared with the control group (5.00 months). Patients with a PD-L1 status < 5% did not show a statistically significant difference in the median time to the first occurrence of a SAE in the nivolumab arm (13.70 months) compared with the control arm (7.10 months) (HR 0.88; 95% CI [0.61; 1.27]; p = 0.499).
• Overall assessment
  • Results are available for the benefit assessment of nivolumab in the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with non-squamous histology following prior chemotherapy in adults, focusing on the endpoints of mortality, morbidity and side effects.
  • It is evident that treatment with nivolumab results in a moderate prolongation of median survival compared with docetaxel. At the same time, there is a significant reduction in serious and severe side effects with nivolumab compared with docetaxel. Hints of positive effects of nivolumab can also be observed in the endpoint categories of disease symptoms and health status. Furthermore, the risk of therapy discontinuation due to adverse events is significantly lower with nivolumab than with docetaxel.
  • For the endpoint category of mortality, proof or indications of an effect modification by the characteristic ‘PD-L1 status’ with cut-off values of ≥ 1%, ≥ 5% and ≥ 10% were demonstrated. For the endpoint categories ‘side effects’ and ‘morbidity’, there is also an indication of an effect modification by the characteristic ‘PD-L1 status’ with a cut-off value of ≥ 5%.
  • Taking these aspects into account and in view of remaining uncertainties, particularly regarding a possible cut-off value and the dynamics of PD-L1 expression, the additional benefit for the endpoints of overall survival, severe SAEs and health status were assessed on the basis of the overall population, despite the observed effect modification by the ‘PD-L1 status’ characteristic. The observed effect modification is nevertheless considered a relevant finding of the present benefit assessment.
  • Consequently, nivolumab is found to offer a considerable additional benefit compared with docetaxel for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in adults following prior chemotherapy.

2) Patients for whom treatment with docetaxel, pemetrexed, gefitinib, erlotinib and crizotinib is not indicated

• For patients for whom treatment with docetaxel, pemetrexed, gefitinib, erlotinib and crizotinib is not indicated, additional benefit is not proven.
• No relevant data were submitted that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.