Pembrolizumab (34) – Keytruda®

• Clinical trials
  • KEYNOTE 091 is an ongoing, multicentre, triple-blind, randomised controlled Phase III trial comparing pembrolizumab with placebo.

Adults with non-small cell lung cancer at high risk of recurrence following complete resection and platinum-based chemotherapy; adjuvant treatment

• The conclusion is that pembrolizumab as monotherapy for the adjuvant treatment of NSCLC following complete resection and platinum-based chemotherapy in adult patients at high risk of recurrence offers no additional benefit compared with watchful waiting.
• mortality
  • In the KEYNOTE 091 trial, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • No statistically significant difference was observed between the treatment arms.
  • Uncertainties remain regarding the follow-up therapies administered after completion of the study medication.
• Morbidity – Recurrences (recurrence rate and disease-free survival)
  • Patients in this therapeutic indication are treated with a curative therapeutic approach. The failure of a curative therapeutic approach is, in principle, relevant to patients.
  • In this benefit assessment, relapses are considered using both the relapse rate and disease-free survival as endpoints.
  • There is a statistically significant difference in favour of pembrolizumab compared with watchful waiting, both for the event rate and for the time-dependent analysis.
  • With regard to the results for the recurrence endpoint, it should be noted that, as of the submitted 3rd data cut-off from January 2023 (final data cut-off for the recurrence endpoint) of the KEYNOTE 091 study, only a limited observation period with a median duration of approximately 35 months was available.
• Morbidity – Symptoms (assessed using the EORTC QLQ-C30 and EORTC QLQ-LC13)
  • Symptoms in patients are assessed in the KEYNOTE 091 study using the EORTC QLQ-C30 and the disease-specific supplementary module EORTC QLQ-LC13.
  • In the EORTC QLQ-C30, a statistically significant disadvantage was observed for the endpoint of loss of appetite, with pembrolizumab performing worse than a ‘watch-and-wait’ approach. However, based on the standardised mean difference, it cannot be concluded that the observed effect is clinically relevant.
  • For the endpoints of fatigue, nausea and vomiting, pain, dyspnoea, insomnia, constipation and diarrhoea, no statistically significant differences were observed between the treatment arms.
  • In the disease-specific supplementary module EORTC QLQ-LC13, there was also no statistically significant difference between the treatment arms for any of the endpoints assessed.
• Morbidity – Health status (assessed using the EQ-5D VAS)
  • Health status is assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • No statistically significant difference was observed between the treatment groups.
• quality of life
  • In the KEYNOTE 091 study, patients’ quality of life is assessed using the functional scales of the EORTC QLQ-C30 questionnaire.
  • For the social functioning endpoint, a statistically significant difference was observed in favour of pembrolizumab compared with watchful waiting, which represents a disadvantage. However, based on the standardised mean difference, it cannot be concluded that the observed effect is clinically relevant.
  • For the endpoints of global health status, physical functioning, role functioning, emotional functioning and cognitive functioning, no statistically significant difference was observed between the treatment arms in any case.
• Side effects – Total adverse events
  • Adverse events (AEs) occurred in almost all patients. The results for the endpoint ‘Total adverse events’ are presented for supplementary information only.
• Side effects – Serious SAEs (SAEs), severe AEs (CTCAE grade ≥ 3), therapy discontinuation due to AEs
  • For the endpoints SAEs, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs, a statistically significant disadvantage was observed in each case compared with watchful waiting for pembrolizumab.
• Side effects – Immune-mediated SAE, immune-mediated severe AEs (CTCAE ≥ 3)
  • For the endpoints immune-mediated SAE and immune-mediated severe AEs, a statistically significant difference was observed in each case, with a disadvantage for pembrolizumab compared with watchful waiting.
• Overall assessment
  • The benefit assessment of pembrolizumab as monotherapy for the adjuvant treatment of NSCLC following complete resection and platinum-based chemotherapy in adult patients at high risk of recurrence, is based on results from the KEYNOTE 091 trial regarding the endpoint categories of mortality, morbidity, quality of life and side effects, compared with watchful waiting.
  • No statistically significant difference in overall survival was observed between the treatment groups.
  • From the results on symptoms, health status and health-related quality of life (assessed using the EORTC QLQ-C30, EORTC QLQ-LC13 and EQ 5D-VAS), neither an advantage nor a disadvantage can be inferred for pembrolizumab compared with watchful waiting.
  • With regard to the results on recurrence, presented as recurrence rate and disease-free survival, an advantage of pembrolizumab compared with watchful waiting is observed. The prevention of recurrence represents an essential treatment goal in the present curative treatment setting.
  • The results on side effects indicate a significant disadvantage for pembrolizumab. This is based on statistically significant differences to the detriment of pembrolizumab in terms of serious adverse events (AEs), severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs. In detail, pembrolizumab has disadvantages compared with a ‘wait-and-see’ approach in terms of specific AEs.
  • Overall, the advantage in terms of the recurrence endpoint is offset by significant disadvantages regarding side effects.
  • Consequently, no additional benefit is identified for pembrolizumab as monotherapy for the adjuvant treatment of NSCLC following complete resection and platinum-based chemotherapy in adult patients at high risk of recurrence, compared with watchful waiting.

Courtesy translation only, please refer to the German original.