Durvalumab (3) – Imfinzi®

• Clinical trials
  • TOPAZ-1 is an ongoing, multicentre, double-blind, randomised, controlled Phase III trial comparing durvalumab in combination with gemcitabine and cisplatin with cisplatin in combination with gemcitabine.

Adults with unresectable or metastatic biliary tumours (BTC); first-line treatment

• The findings indicate that durvalumab in combination with gemcitabine and cisplatin offers a minor additional benefit over cisplatin in combination with gemcitabine for the first-line treatment of adults with unresectable or metastatic biliary tumours (BTC).
• Overall, the certainty of evidence for the identified additional benefit is classified as an indication.
• mortality
  • For the endpoint of overall survival, a statistically significant advantage was observed in favour of durvalumab in combination with gemcitabine and cisplatin compared with cisplatin in combination with gemcitabine.
  • The extension in survival time achieved is assessed as a relevant improvement, though one that does not go beyond a minor extent.
• Morbidity – Progression-free survival (PFS)
  • In the TOPAZ-1 trial, PFS was defined as the time from randomisation to the first RECIST 1.1-defined radiological disease progression or to death from any cause without prior progression, regardless of whether the patient discontinued treatment or received another antineoplastic therapy prior to progression.
  • A statistically significant advantage was observed in favour of durvalumab in combination with gemcitabine and cisplatin compared with cisplatin in combination with gemcitabine.
  • 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 (radiologically determined disease progression according to the RECIST 1.1 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 (assessed using the EORTC QLQ-C30, EORTC QLQ-BIL21 and PGIS)
  • The pharmaceutical manufacturer submitted analyses for the period up to the first deterioration of at least 10 points for the benefit assessment. These form the basis of the present assessment.
  • In the disease-specific add-on module EORTC QLQ-BIL21, a statistically significant difference was observed for the endpoint ‘difficulties with drainage’, to the disadvantage of durvalumab in combination with gemcitabine and cisplatin compared with cisplatin in combination with gemcitabine.
  • The PGIS is a patient-reported single-item measurement tool for assessing the severity of symptoms or symptom complexes on a scale from 0 (no symptoms) to 6 (very severe symptoms). Higher scores are associated with more severe symptoms in patients.
  • The pharmaceutical manufacturer submitted data for the benefit assessment relating to the first occurrence of a deterioration to 5 points (severe symptoms) or 6 points (very severe symptoms). These form the basis of the present assessment.
  • No statistically significant difference was observed between the treatment groups for the PGIS.
• Morbidity – Health status (assessed using the EQ-5D VAS)
  • Health status is assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire. The pharmaceutical manufacturer provided analyses for the time to the first deterioration of at least 15 points, which form the basis of this assessment.
  • There is no statistically significant difference between the treatment groups for the health status endpoint.
• quality of life
  • In the TOPAZ-1 study, patients’ quality of life is assessed using the functional scales of the EORTC QLQ-C30 questionnaire and the disease-specific supplementary module EORTC QLQ-BIL21.
  • The pharmaceutical manufacturer provided analyses covering the period up to the first deterioration of at least 10 points for the benefit assessment, which form the basis of this assessment.
  • No statistically significant difference between the treatment groups was observed for any of the health-related quality of life scales.
  • An overall analysis of the results shows neither an advantage nor a disadvantage for durvalumab in combination with gemcitabine and cisplatin in terms of health-related quality of life.
• Side effects – Total adverse events
  • Adverse events occurred in almost all patients. The results for the endpoint ‘Total adverse events’ are presented here only as supplementary information.
• Side effects – Serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3), therapy discontinuation due to AEs
  • No statistically significant differences were observed between the treatment arms for the endpoints SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
• Overall assessment
  • Results from the TOPAZ-1 study are available for the assessment of the additional benefit of durvalumab in combination with gemcitabine and cisplatin, comparing it with cisplatin in combination with gemcitabine across the endpoint categories of mortality, morbidity, quality of life and side effects.
  • With regard to overall survival, there is a statistically significant advantage in favour of durvalumab in combination with gemcitabine and cisplatin compared with cisplatin in combination with gemcitabine. The extension in survival time achieved is assessed as a relevant improvement, albeit one that does not go beyond a minor extent.
  • With regard to symptoms (assessed using the EORTC QLQ-C30, EORTC QLQ-BIL21 and PGIS) and health status (assessed using the EQ5D-VAS), no difference relevant to the benefit assessment was found overall between the treatment groups.
  • With regard to the endpoint categories of health-related quality of life (assessed using the EORTC QLQ-C30 and EORTC QLQ-BIL21) and side effects, neither advantages nor disadvantages were observed for durvalumab in combination with gemcitabine and cisplatin. In detail, there are disadvantages in terms of specific AEs.
  • In the overall assessment of the available results for patient-relevant endpoints, the advantage in overall survival is not offset by any disadvantages in other endpoint categories that are relevant to the assessment.

Courtesy translation only, please refer to the German original.