Durvalumab (2) – Imfinzi®

• Clinical trials
  • The pharmaceutical manufacturer has submitted results from the randomised, open-label Phase III CASPIAN trial for the benefit assessment.
  • In addition to the global cohort, the pharmaceutical manufacturer submitted data from a Chinese cohort with an identical study protocol and statistical analysis plan to that of the global study population, but with a separate analysis.

Adult patients with advanced-stage small-cell lung cancer (ES-SCLC); for first-line treatment

• For adult patients with advanced-stage small cell lung cancer (ES-SCLC) receiving first-line treatment, there is a hint of a minor additional benefit.
• Overall, there is a hint of a minor additional benefit for durvalumab in combination with chemotherapy compared with chemotherapy alone.
• Mortality – overall survival
  • The meta-analysis of the two cohorts shows a statistically significant prolongation of overall survival with treatment using durvalumab in combination with chemotherapy compared with chemotherapy alone.
  • The extent of this effect is assessed as a minor improvement in overall survival.
• Morbidity – Progression-free survival (PFS)
  • The meta-analysis of the two cohorts shows a statistically significant difference in PFS between the treatment arms, giving an advantage to durvalumab in combination with chemotherapy compared with chemotherapy alone.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • 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
  • For the symptoms of nausea and vomiting, loss of appetite, diarrhoea and alopecia, there is a statistically significant advantage for durvalumab in combination with chemotherapy.
  • To assess the relevance of the result, the standardised mean difference in the form of Hedges’ g is used. In each case, the 95% confidence interval for the mean difference does not lie entirely outside the irrelevance range [−0.2; 0.2]. Consequently, it cannot be concluded that the effect is clinically relevant for any of the endpoints: nausea and vomiting, loss of appetite, diarrhoea and alopecia.
• Morbidity – Health status (EQ-5D, Visual Analogue Scale)
  • The MMRM analyses show no statistically significant difference between the treatment groups in terms of health status as measured by the EQ-5D.
• Morbidity – Health status (PGIC)
  • The data submitted subsequently by the pharmaceutical manufacturer regarding the time to deterioration in the PGIC, based on the meta-analysis, are not suitable for the benefit assessment, as it is unclear whether all available data were included in the time-to-event analysis or whether only data up to cycle 6 were taken into account. Furthermore, additional analyses, particularly for patient populations, are lacking. Consequently, the submitted PGIC analyses are not used for the benefit assessment.
• quality of life
  • Overall, there is no statistically significant difference in health-related quality of life between the treatment groups.
• Side effects – total adverse events (AEs)
  • In the CASPIAN study, AEs occurred in almost all participants in both cohorts.
• Side effects – serious AEs (SAEs)
  • With regard to SAEs, the meta-analysis of the two cohorts from the CASPIAN study revealed no statistically significant difference between the treatment arms.
  • However, an effect modification for this endpoint was observed based on the presence of brain metastases at the start of the study. For patients without brain metastases at the start of the study, there was no statistically significant difference between the treatment arms. In contrast, for patients with brain metastases at the start of the study, there was a statistically significant advantage in favour of durvalumab in combination with chemotherapy.
  • The corresponding subgroup results are presented; however, they do not lead to any specific conclusions in this regard in the overall assessment.
• Side effects – severe AEs (CTCAE grade ≥ 3), therapy discontinuations due to AEs
  • In the meta-analysis of the time-to-event analyses for both study cohorts, no statistically significant difference was observed between the treatment groups in either case.
• Side effects – immune-mediated SAEs
  • For the endpoint of immune-mediated SAEs, there is statistically significant heterogeneity between the cohorts. For the global cohort, there is no statistically significant difference between the treatment arms. No effect estimates are available for the cohort in China.
• Side effects – Immune-mediated severe AEs
  • For the endpoint of immune-mediated severe AEs (CTCAE grade ≥ 3), there is no statistically significant difference between the treatment arms. However, an effect modification by the characteristic of sex is observed.
  • Overall, there are uncertainties regarding the clinical relevance of this sex-specific effect modification; consequently, it is not taken into account further in this assessment.
• Side effects – PRO-CTCAE
  • No usable analyses are available for the PRO-CTCAE endpoint in the global cohort. This endpoint was not assessed in the Chinese cohort.
• Overall assessment
  • Durvalumab in combination with chemotherapy results in a statistically significant prolongation of overall survival compared with chemotherapy alone; the extent of this prolongation is assessed as a minor improvement.
  • No major differences were observed for the morbidity endpoints assessed using the EORTC-QLQ-LC13 and the EQ-5D visual analogue scale. In particular, no major differences were observed with regard to disease-specific symptoms.
  • With regard to the data on health-related quality of life, as reported by patients and collected using the EORTC-QLQ-C30 and EORTC-QLQ-LC13, there are no major differences overall between the treatment groups.
  • With regard to side effects, no overall advantage or disadvantage was observed for treatment with durvalumab in combination with chemotherapy.
  • In the overall assessment, durvalumab in combination with etoposide and either carboplatin or cisplatin as first-line treatment for adult patients with advanced-stage small-cell lung cancer was found to offer a minor additional benefit compared with cisplatin in combination with etoposide or carcarboplatin in combination with etoposide.

Courtesy translation only, please refer to the German original.