Pembrolizumab (33) – Keytruda®

• Clinical trials
  • KEYNOTE-966 is an ongoing, multicentre, double-blind, randomised, controlled Phase III trial comparing pembrolizumab in combination with gemcitabine and cisplatin with cisplatin in combination with gemcitabine.

Adults with locally advanced, unresectable or metastatic biliary carcinoma; first-line treatment

• The conclusion is that pembrolizumab 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 pembrolizumab in combination with gemcitabine and cisplatin compared with cisplatin in combination with gemcitabine.
  • The extension in survival achieved is assessed as a relevant improvement, though one that does not go beyond a minor extent.
• Morbidity – Progression-free survival (PFS)
  • In the KEYNOTE-966 trial, PFS was defined as the time from randomisation to the first documented instance of disease progression or death from any cause, whichever occurred first.
  • There is a statistically significant advantage in favour of pembrolizumab 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. The ‘mortality’ component of the endpoint was assessed in this study 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 and EORTC QLQ-BIL21)
  • Patients’ symptoms are assessed in the study using the EORTC QLQ-C30 and the disease-specific supplementary module EORTC QLQ-BIL21.
  • The pharmaceutical manufacturer provided 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 EORTC QLQ-C30, a statistically significant difference in favor of pembrolizumab in combination with gemcitabine and cisplatin, compared with cisplatin in combination with gemcitabine, is observed for the endpoint of loss of appetite.
  • In the disease-specific supplementary module EORTC QLQ-BIL21, a statistically significant difference to the detriment of pembrolizumab in combination with gemcitabine and cisplatin was observed compared with cisplatin in combination with gemcitabine for the endpoints of fatigue, jaundice and side effects of treatment, a statistically significant disadvantage was observed for pembrolizumab in combination with gemcitabine and cisplatin compared with cisplatin in combination with gemcitabine. With regard to the assessment of the results for the endpoint ‘treatment-related side effects’, there are uncertainties due to the possible double-counting of these events, both as a morbidity endpoint and as safety endpoints.
  • Overall, within the morbidity endpoint category, pembrolizumab in combination with gemcitabine and cisplatin shows disadvantages in terms of symptoms for the endpoints of loss of appetite, fatigue, jaundice and side effects of treatment.
• 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 period up to the first deterioration of at least 15 points, which form the basis of this assessment.
  • No statistically significant difference was observed between the treatment groups for the health status endpoint.
• quality of life
  • In the KEYNOTE-966 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 for 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 was observed between the treatment groups for any of the health-related quality of life scales.
  • Overall, therefore, there is neither an advantage nor a disadvantage for pembrolizumab 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.
• Overall assessment
  • Results from the KEYNOTE-966 study are available for the assessment of the additional benefit of pembrolizumab 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.
  • For overall survival, there is a statistically significant advantage in favour of pembrolizumab in combination with gemcitabine and cisplatin compared with cisplatin in combination with gemcitabine. The prolongation in survival time achieved is assessed as a relevant improvement, albeit one that does not go beyond a minor extent.
  • In the morbidity endpoint category (assessed using the EORTC QLQ-C30, EORTC QLQ-BIL21 and EQ-5D-VAS), pembrolizumab in combination with gemcitabine and cisplatin was associated with disadvantages in terms of symptoms for the endpoints of loss of appetite, fatigue, jaundice and treatment-related side effects.
  • 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 pembrolizumab in combination with gemcitabine and cisplatin. In detail, with regard to side effects, there are both advantages and disadvantages associated with specific side effects.
  • In the overall assessment of the available results for patient-relevant endpoints, the advantage in overall survival is offset by disadvantages in terms of symptoms. However, these are not considered to be such as to justify a downgrading of the extent of the additional benefit.

Courtesy translation only, please refer to the German original.