Pembrolizumab (8) – Keytruda®

• Clinical trials
  • The benefit assessment is based on the results of the randomised, double-blind, placebo-controlled KEYNOTE-054 trial.

Adult patients with stage III melanoma with lymph node involvement following complete resection, for adjuvant treatment

• There is an indication for a non-quantifiable additional benefit for pembrolizumab as monotherapy for the adjuvant treatment of stage III melanoma with lymph node involvement following complete resection in adults.
• Overall, therefore, an indication is derived regarding the certainty of the established additional benefit.
• mortality
  • overall survival
  • According to the study protocol, no analysis of the overall survival endpoint was planned at the time of the first and second data cut-offs in the KEYNOTE-054 study.
  • At the time of the first data cut-off, 25 patients in the pembrolizumab arm and 35 patients in the placebo arm had died.
• Morbidity – Recurrences/Recurrence-free survival
  • Recurrences
  • For the recurrence endpoint, a statistically significant advantage of pembrolizumab compared with watchful waiting was observed at the time of the second data cut-off (relative risk (RR): 0.63; [95% confidence interval (CI): 0.54; 0.74]; p-value < 0.001). 30.7% of patients in the pembrolizumab arm and 48.7% in the placebo arm had experienced a recurrence by the time of the second data cut-off.
  • Recurrence-free survival
  • With regard to the endpoint of recurrence-free survival, a statistically significant advantage was observed with pembrolizumab treatment (hazard ratio (HR): 0.56; [95% CI: 0.44; 0.72]; p < 0.001). In the pembrolizumab arm, the median time to event had not yet been reached, whereas in the control arm it was 21.7 months.
  • Overall, therefore, with regard to the endpoints of recurrence and recurrence-free survival, there is a clear, clinically relevant advantage of pembrolizumab compared with watchful waiting.
  • However, as the follow-up period (median 21.6 months) at the 2nd data cut-off is relatively short and not long enough to adequately reflect the high-risk period for the occurrence of a recurrence—3 years after the primary diagnosis—the extent of this advantage cannot be clearly quantified based on the available data.
• Morbidity – Symptoms (EORTC QLQ-C30)
  • In the KEYNOTE-054 study, disease symptoms are assessed using the symptom scales of the cancer-specific questionnaire EORTC QLQ-C30.
  • In line with the comments on the assessment of symptoms using the EORTC QLQ-C30, the analyses presented are considered unusable.
• quality of life
  • Data on disease-related quality of life are collected using the EORTC QLQ-C30 functional scales (overall health status, physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning).
  • In line with the comments on the assessment of symptoms using the EORTC QLQ-C30, the analyses provided are considered unusable.
• Side effects – Total adverse events (AEs)
  • The results for the endpoint ‘Total Adverse Events’ are presented for supplementary purposes only.
  • In the pembrolizumab arm, 93.3% of patients experienced an adverse event, compared with 90.2% of patients in the placebo arm.
• Overall assessment / Conclusion
  • Data on morbidity, quality of life and side effects are available for the assessment of the additional benefit of pembrolizumab as monotherapy for the adjuvant treatment of stage III melanoma with lymph node involvement following complete resection in adults.
  • However, as the follow-up period (median 21.6 months) at the 2nd data cut-off is relatively short and not long enough to adequately reflect the high-risk period for recurrence, which is 3 years after the primary diagnosis, the extent of this advantage cannot be clearly quantified based on the available data.
  • The analyses presented by the pharmaceutical manufacturer regarding symptoms, as assessed using the EORTC QLQ-C30, and regarding health status, as measured using the EQ-5D VAS, are classified as unusable.
  • Accordingly, the analyses of the health-related quality of life endpoint, as assessed using the EORTC QLQ-C30, are also considered unusable.
  • In the category of side effects, there are significant disadvantages due to an increase in serious adverse events, severe adverse events and discontinuations due to adverse events.
  • In the overall assessment of the results for all available patient-relevant endpoints, the present adjuvant treatment scenario shows clear positive effects—albeit not clearly non-quantifiable in terms of extent—with regard to the prevention of recurrence, which are offset by relevant disadvantages relating to side effects.
  • Overall, pembrolizumab as monotherapy for the adjuvant treatment of stage III melanoma with lymph node involvement following complete resection is found to provide a non-quantifiable additional benefit.
• Overall assessment / Conclusion
  • Data on morbidity, quality of life and side effects are available for the assessment of the additional benefit of pembrolizumab as monotherapy for the adjuvant treatment of stage III melanoma with lymph node involvement following complete resection in adults.
  • However, as the follow-up period (median 21.6 months) at the 2nd data cut-off is relatively short and not sufficiently long to adequately reflect the high-risk period for recurrence, which is 3 years after the primary diagnosis, the extent of this advantage cannot be clearly quantified based on the available data.
  • The analyses presented by the pharmaceutical manufacturer regarding symptoms, as assessed using the EORTC QLQ-C30, and health status, as measured using the EQ-5D VAS, are classified as unusable.
  • Accordingly, the analyses of the health-related quality of life endpoint, as assessed using the EORTC QLQ-C30, are also considered unusable.
  • In the category of side effects, there are significant disadvantages due to an increase in serious adverse events, severe adverse events and discontinuations due to adverse events.
  • In the overall assessment of the results for all available patient-relevant endpoints, the present adjuvant treatment scenario shows clear positive effects – albeit not clearly non-quantifiable in terms of extent – with regard to the prevention of recurrence, which are offset by relevant disadvantages relating to side effects.
  • Overall, pembrolizumab as monotherapy for the adjuvant treatment of stage III melanoma with lymph node involvement following complete resection is found to provide a non-quantifiable additional benefit.

Courtesy translation only, please refer to the German original.