Durvalumab (1) – Imfinzi®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer has submitted the results of the pivotal PACIFIC trial. This was a double-blind, randomised, controlled trial designed to investigate the efficacy and safety of durvalumab compared with placebo, in each case in combination with best supportive care.

Adult patients with locally advanced, inoperable non-small cell lung cancer, whose tumours express PD-L1 in ≥ 1 % of tumour cells and whose disease has not progressed following platinum-based chemoradiotherapy

• For durvalumab for the treatment of locally advanced, inoperable non-non-small cell lung cancer in adults whose tumours express PD-L1 in ≥ 1% of tumour cells and whose disease has not progressed following platinum-based chemoradiotherapy, there is a hint of considerable additional benefit.
• Consequently, in terms of certainty of the findings, only a hint of additional benefit can be inferred.
• mortality
  • Overall survival was defined in the PACIFIC trial as the time from randomisation to death from any cause.
  • In the patient population relevant to the assessment, with PD-L1 expression of ≥ 1%, a total of 115 patients had died by the data cut-off date of 22 March 2018: 70 in the intervention arm and 45 in the control arm. Given the 2:1 randomisation ratio, this corresponds to a proportion of 33.0% and 49.5%, respectively. The median survival time in the control arm was 29.1 months; in the intervention arm, the median has not yet been reached. The difference is statistically significant (hazard ratio (HR): 0.54; [95% confidence interval (CI): 0.35; 0.81]; p-value 0.003).
  • In the endpoint category of mortality, the results of the PACIFIC trial show a marked improvement for durvalumab.
• Morbidity – Progression-free survival
  • In the PACIFIC study, the PFS endpoint is defined as the time from randomisation to the first objective disease progression according to RECIST 1.1 criteria or until death, regardless of the cause of death.
  • Progression-free survival differed statistically significantly between the two study arms, in favour of the intervention (HR: 0.44; [95% CI: 0.31–0.63]; p-value <0.0001). Treatment with durvalumab prolonged the median time to event by 18.3 months (23.9 months vs. 5.6 months). The proportion of patients experiencing an event was also higher in the control arm, at 72.5% compared with 46.7%.
  • 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 standalone endpoint. The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (in accordance with RECIST 1.1). Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding the extent of the additional benefit remains unaffected by this.
• Morbidity – EQ-5D Visual Analogue Scale
  • Results from the EQ-5D visual analogue scale at the 12-month assessment point are available for assessing the health status of the study patients. At later assessment points, the response rates are too minor.
  • Instead of the responder analyses, the IQWIG’s dossier assessment uses the analysis of the mean change at month 12 compared with baseline. The difference between the study arms is not statistically significant in terms of the mean difference.
  • The analyses submitted subsequently during the commenting procedure, with censoring for the event of death, are decisive for the benefit assessment. In each case, there are no statistically significant differences between the study arms.
• Health-related quality of life – Global health status & functional scales EORTC QLQ-C30
  • Neither the global health status nor the functional scales assessed show a statistically significant difference in the subsequently submitted responder analyses for the time to deterioration by ≥ 10 points.
  • For the quality of life endpoint category, there is no additional benefit of durvalumab based on the results of the EORTC QLQ-C30.
• Side effects
  • A large proportion of patients in both study arms experienced an adverse event during the course of their respective treatment. (96.2% vs. 92.2%). No statistically significant difference was observed in the overall rates of serious adverse events, nor in the rates of severe adverse events classified as Grade 3/4 according to the CTCAE.
  • In the intervention arm, 16.9% of patients discontinued treatment due to an adverse event, compared with 5.6% in the control arm. The difference is statistically significant, to the detriment of durvalumab (HR: 2.93 [95% CI: 1.26; 8.54]; p-value 0.010).
  • When specific adverse events were examined, disadvantages characteristic of this class of drug were observed with regard to severe immune-mediated adverse events of CTCAE grade 3/4 (HR: 4.86; [95% CI: 1.45; 30.21]; p-value 0.007).
  • Durvalumab also showed a disadvantage in the SOCs ‘skin and subcutaneous tissue disorders’ (all AEs: HR: 1.95; [95% CI: 1.26; 3.18]; p-value 0.002), cardiac disorders (SUEs: HR: 5.33; [95% CI: 1.07; 96.62]; p-value 0.039), as well as, at the level of the PTs, for dizziness (UEs: HR: 0.40; [95% CI: 0.18; 0.89]; p-value 0.026) and, within the PTs, for injury, poisoning and procedural complications (UEs: HR: 2.32; [95% CI: 1.35; 4.29]; p-value 0.002).
  • Overall, within the endpoint category of side effects, there are exclusively side effects unfavourable to durvalumab.
• Overall assessment
  • Compared with best supportive care, durvalumab leads to a significant prolongation of overall survival.
  • No relevant differences were observed for the endpoint categories of morbidity and health-related quality of life across any of the subscales of the measurement instruments used.
  • On the other hand, there are disadvantages in terms of treatment discontinuations due to adverse events (AEs) as well as certain specific adverse events (severe immune-mediated AEs, skin and subcutaneous tissue disorders, cardiac disorders, dizziness and injury, poisoning, and procedure-related complications).
  • In its cost-benefit assessment, the G-BA concludes that the advantage in terms of overall survival clearly outweighs the disadvantages. Consequently, taking into account the severity of the disease, a considerable additional benefit is identified for durvalumab. There is a significant improvement in treatment-related benefit that has not been achieved before.

Courtesy translation only, please refer to the German original.