Pembrolizumab (3) – Keytruda®

• Clinical trials
  • The KEYNOTE 024 trial is a randomised, open-label, active-controlled registration trial comparing pembrolizumab with platinum-based chemotherapy.

Patients with an ECOG performance status of 0, 1 or 2

• mortality
  • overall survival
  • For overall survival, there is a statistically significant difference in favour of pembrolizumab compared with cisplatin- or carboplatin-based chemotherapy (HR: 0.57 [0.36; 0.92], p = 0.020).
  • For the endpoint of overall survival, pembrolizumab demonstrates an additional benefit over the appropriate comparator therapy, the extent of which is considerable.
• Morbidity – Symptoms
  • The symptomatic endpoints were assessed using the symptom scales of the cancer-specific EORTC QLQ-C30 questionnaire and the lung cancer-specific EORTC QLQ-LC13 questionnaire.
  • For the endpoints of dyspnoea, loss of appetite, nausea and vomiting, constipation, alopecia, dysphagia, mouth pain and peripheral neuropathy, statistically significant differences were observed in each case in favour of pembrolizumab compared with cisplatin- or carboplatin-based chemotherapy.
  • Low response rates, a high proportion of informative censored data and the unblinded assessment of subjectively measured endpoints result in a high potential for bias regarding symptoms.
  • Accordingly, for each of these eight symptomatic endpoints, there is a hint of additional benefit from pembrolizumab compared with cisplatin- or carboplatin-based chemotherapy.
  • For the endpoints of fatigue, insomnia and haemoptysis, there is a statistically significant difference in favour of pembrolizumab compared with cisplatin- or carboplatin-based chemotherapy. However, the extent of the effect for these endpoints is no more than minimal.
  • health status
  • The health status endpoint was assessed using the visual analogue scale (VAS) of the EQ-5D. For the time to deterioration, there was no statistically significant difference for the 7-point response criterion, whilst for the 10-point response criterion, there was a statistically significant difference in favour of pembrolizumab compared with platinum-based chemotherapy.
  • However, the extent of the effect for this non-serious endpoint is no more than minor.
  • Overall, this provides no hint of additional benefit from pembrolizumab compared with platinum-based chemotherapy for the health status endpoint.
  • In the overall assessment of the results regarding patient-reported symptoms, the positive effects of pembrolizumab clearly predominate, demonstrating a significant improvement in symptoms overall for treatment with pembrolizumab compared with platinum-based chemotherapy.
  • There are hints of an improvement in treatment-related morbidity based on the endpoints of dyspnoea, loss of appetite, nausea and vomiting, constipation, alopecia, dysphagia, mouth pain and peripheral neuropathy.
• quality of life
  • Health-related quality of life was assessed using the functional scales and the scale for measuring overall health status from the disease-specific EORTC QLQ-C30 instrument.
  • The time-to-event analyses used for the evaluation showed a statistically significant positive effect for pembrolizumab on the following functional scales: physical functioning, role functioning and social functioning.
  • For the endpoints of overall health status, emotional functioning and cognitive functioning, no statistically significant difference was observed between the treatment arms.
  • In summary, the results for the endpoints of the questionnaire assessing health-related quality of life indicate advantages of treatment with pembrolizumab, which are overall assessed as a relevant improvement in health-related quality of life compared with platinum-based chemotherapy.
  • Overall, given the high potential for bias due to minor response rates, the high proportion of informative censorings and the unblinded collection of subjectively measured endpoints in the quality of life endpoint category, there is a hint of additional benefit from pembrolizumab compared with platinum-based chemotherapy.
• Side effects
  • SAE, severe AE (CTCAE ≥ 3), discontinuation due to AE
  • For the endpoints SAE and discontinuation due to AEs, there were no statistically significant differences between the treatment groups.
  • Consequently, for these endpoints, there is no hint that pembrolizumab causes greater or minor harm compared with cisplatin- or carboplatin-based chemotherapy.
  • An additional benefit of pembrolizumab is therefore not proven for these endpoints.
  • For the endpoint ‘severe AEs (CTCAE grade ≥ 3)’, a statistically significant difference was observed in favour of pembrolizumab compared with cisplatin- or carboplatin-based chemotherapy.
  • This provides a hint for minor harm associated with pembrolizumab compared with cisplatin- or carboplatin-based chemotherapy for these endpoints.
  • Immune-mediated AEs, SAE and severe AEs
  • For the endpoints immune-mediated AEs, SAE and severe AEs (CTCAE grade ≥ 3), statistically significant differences were observed in each case to the detriment of pembrolizumab compared with cisplatin- or carboplatin-based chemotherapy.
  • This provides a hint for greater harm associated with pembrolizumab compared with cisplatin- or carboplatin-based chemotherapy for all three endpoints.
  • The extent of this increased harm is assessed as considerable for the endpoint of immune-mediated AEs.
  • For the serious side effects – immune-mediated SAE and severe AEs (CTCAE grade ≥ 3) – a higher level of harm is observed.
  • The potential for bias in the analyses submitted subsequently by the marketing authorisation holder regarding immune-mediated AEs, SAE and severe AEs (CTCAE grade ≥ 3) is considered high due to the high proportion of observations with potentially informative censoring.
  • The pharmaceutical manufacturer has not provided any data on other specific AEs for the relevant patient population.
  • A high proportion of patients in the overall population discontinued treatment prematurely in both groups; AEs were subsequently monitored for only 30 days, and SAEs for only 90 days.
  • Overall, for the endpoint of severe AEs (CTCAE grade ≥ 3), an advantage of pembrolizumab over platinum-based chemotherapy can be observed.
  • Disadvantages are observed within the specific AEs for immune-mediated side effects.
  • In summary, with regard to side effects, treatment with pembrolizumab offers an advantage over platinum-based chemotherapy.

Courtesy translation only, please refer to the German original.