Nintedanib (1) – Vargatef®

• Clinical trials
  • The LUME-Lung 1 trial is a randomised, double-blind, phase IIIstudy which investigated the efficacy of nintedanib in combination with docetaxel in patients with locally advanced, metastatic or locally recurrent NSCLC following failure of first-line chemotherapy.

a) Adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) with adenocarcinoma histology following first-line chemotherapy

• There is an indication of a minor additional benefit for nintedanib in combination with docetaxel compared with the appropriate comparator therapy, docetaxel.
• The G-BA classifies the extent of the additional benefit of nintedanib in combination with docetaxel as ‘minor’ on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a moderate—and not merely minor—improvement in treatment-related benefit that has not previously been achieved, as a statistically significant, but minor prolongation of median survival has been observed.
• The probability of the additional benefit is classified as an ‘indication’ due to the availability of a study suitable for benefit assessment.
• Mortality – Overall survival
  • The median survival time with the combination of nintedanib and docetaxel was 12.6 months versus 10.3 months with placebo plus docetaxel (HR = 0.83; 95% CI [0.70; 0.99]; p = 0.036). Treatment with nintedanib thus resulted in a statistically significant prolongation of median overall survival by 2.3 months.
  • For the endpoint of overall survival, there was an indication of an effect modifier in the form of the presence of asymptomatic brain metastases at the start of treatment (interaction test p = 0.125).
  • Patients without brain metastases at the start of treatment: the median survival time with the combination of nintedanib and docetaxel was 13.5 months versus 10.3 months with placebo plus docetaxel (HR = 0.80; 95% CI [0.67; 0.96]; p = 0.015). Treatment with nintedanib thus resulted in a statistically significant prolongation of median overall survival by 3.2 months.
  • Patients with asymptomatic brain metastases at the start of treatment: No statistically significant difference was observed between the treatment groups in patients with brain metastases.
• Morbidity – Progression-free survival
  • The median PFS was 4.2 months with the combination of nintedanib and docetaxel versus 2.8 months in the control arm receiving placebo plus docetaxel (HR = 0.84; 95% CI [0.71; 1.00]; p = 0.049). This results in a difference of 1.4 months in favour of the treatment in the intervention arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component is already assessed as a standalone endpoint via the secondary endpoint ‘overall survival’. Furthermore, the ‘disease progression’ component of morbidity in the PFS analysis was not assessed on the basis of symptoms, but exclusively by means of imaging procedures.
• Morbidity – time to symptom worsening (EORTC QLQ-C30 symptom scales) – diarrhoea
  • For the endpoint ‘diarrhoea’, a statistically significant difference was observed in the time to symptom worsening, to the detriment of nintedanib [2.1 months in the intervention group versus 4.2 months in the control group (HR = 1.9; 95% CI [1.54; 2.34]; p < 0.001)].
• Morbidity – time to symptom worsening (EORTC QLQ-C30 symptom scales) – loss of appetite
  • No statistically significant differences were observed between the intervention and control groups for the endpoint of loss of appetite. However, there was proof of effect modification by the presence of asymptomatic brain metastases at the start of treatment (interaction test p = 0.043).
  • Patients without brain metastases at the start of treatment: In the group of patients without brain metastases, there was no statistically significant difference between the two treatment groups.
  • Patients with asymptomatic brain metastases at the start of treatment: For patients with brain metastases, a statistically significant difference was observed to the detriment of treatment with nintedanib. The median time to deterioration of the endpoint ‘loss of appetite’ was 1.6 months in the combination of nintedanib and docetaxel versus 2.8 months in the control arm receiving placebo plus docetaxel (HR = 2.35; 95% CI [1.12; 4.94]; p = 0.024).
• Health-related quality of life – time to deterioration in quality of life (EORTC QLQ-C30 functional scales)
  • No significant differences were observed between the intervention and control groups.
• Side effects
  • With regard to the endpoints of CTCAE grade ≥ 3 adverse events (AEs), total serious adverse events (SAEs) and therapy discontinuations due to AEs, no statistically significant differences were observed between the treatment groups.
• Conclusion
  • The G-BA classifies the extent of the additional benefit of nintedanib in combination with docetaxel as ‘minor’, based on an overall assessment of the effects on patient-relevant endpoints, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
  • Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a moderate—and not merely minor—improvement in treatment-related benefit that has not previously been achieved, as a statistically significant, but minor prolongation of median survival (overall survival) is evident from the data from the Phase III LUME-Lung 1 trial submitted by the pharmaceutical manufacturer for the benefit assessment.
  • The negative and positive effects of treatment with nintedanib – a shorter time to worsening of the symptoms of diarrhoea, nausea and vomiting, and a longer time to worsening of pain symptoms (arm/shoulder), are not pronounced to an extent that would call into question the assessment of the treatment-related benefit. With regard to endpoints in the categories of quality of life and side effects, there is no indication of a disadvantage associated with treatment with nintedanib.

Courtesy translation only, please refer to the German original.