Pembrolizumab (17) – Keytruda®

• Clinical trials
  • KEYNOTE 590 is an ongoing, double-blind, randomised, multicentre trial comparing pembrolizumab in combination with cisplatin and 5-fluorouracil with placebo in combination with cisplatin and 5-fluorouracil.
  • KEYNOTE 062 is a three-arm, partially blinded, randomised, multicentre trial which is double-blinded in the arms used for the benefit assessment. In the intervention arm, patients were treated with pembrolizumab in combination with cisplatin and 5-fluorouracil or capecitabine, whilst in the comparison arm they were treated with placebo in combination with cisplatin and 5-fluorouracil or capecitabine.

a) Adults with locally advanced or metastatic, non-curable squamous cell carcinoma of the oesophagus with PD-L1-expressing tumours (Combined Positive Score (CPS) ≥ 10); first-line treatment

• Consequently, the G-BA has approved pembrolizumab in combination with platinum- and fluoropyrimidine--based chemotherapy for the first-line treatment of adults with locally advanced, unresectable or metastatic squamous cell carcinoma of the oesophagus with PD-L1-expressing tumours (CPS ≥ 10).
• Consequently, the certainty of evidence for the established additional benefit is classified as ‘indication’.
• mortality
  • Overall survival is defined in the KEYNOTE 590 trial as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant difference was observed between the treatment groups in favour of pembrolizumab in combination with cisplatin and 5-fluorouracil compared with cisplatin in combination with 5-fluorouracil.
  • The extent of the prolongation in overall survival achieved is assessed as a significant improvement.
• Morbidity – Progression-free survival (PFS)
  • In the KEYNOTE 590 trial, PFS is defined as the period from randomisation to the first documented instance of disease progression or death from any cause, whichever occurs first.
  • A statistically significant difference in PFS was observed between the treatment groups, in favour of pembrolizumab in combination with cisplatin and 5-fluorouracil.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding additional benefit remains unaffected.
• Morbidity – Symptoms (EORTC QLQ-C30 and EORTC QLQ-OES18)
  • In the KEYNOTE 590 study, disease symptoms are assessed using the symptom scales of the cancer-specific questionnaire EORTC QLQ-C30 and the oesophageal cancer-specific supplementary module EORTC QLQ-OESI18.
  • For the endpoints assessed using the EORTC QLQ-C30 – fatigue, nausea and vomiting, insomnia, loss of appetite, constipation and diarrhoea – as well as for the endpoints assessed using the EORTC QLQ-OES18 – eating, reflux, pain, swallowing saliva, dry mouth, sense of taste, cough, speech and dysphagia, there were no statistically significant differences between the treatment arms.
  • By contrast, statistically significant differences in favour of pembrolizumab in combination with cisplatin and 5-fluorouracil were observed for the endpoints of pain and dyspnoea (EORTC QLQ-C30) and for the endpoint of swallowing (EORTC QLQ-OES18), there were statistically significant advantages in favour of pembrolizumab in combination with cisplatin and 5-fluorouracil.
  • For the endpoint of pain (EORTC QLQ-C30), an effect modification was observed for the characteristic of age. For patients aged ≥ 65 years, there was a statistically significant advantage in favour of pembrolizumab in combination with cisplatin and 5-fluorouracil compared with cisplatin in combination with 5-fluorouracil. For patients < 65 years of age, there is no statistically significant difference between the treatment arms.
• Morbidity – Health status (EQ-5D VAS)
  • Health status is assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • None of the analyses presented showed a statistically significant difference between the treatment arms.
• quality of life
  • Health-related quality of life is assessed in the KEYNOTE 590 trial using the functional scales of the cancer-specific EORTC QLQ-C30 questionnaire.
  • A statistically significant advantage in favour of pembrolizumab in combination with cisplatin and 5-fluorouracil was observed only for emotional functioning. Overall, therefore, no difference between the treatment arms relevant to the benefit assessment was observed for pembrolizumab in combination with cisplatin and 5-fluorouracil in the quality of life endpoint category.
• Side effects – Total adverse events (AEs)
  • Adverse events occurred in all study participants. The results are presented here for supplementary information only.
• Side effects – Serious adverse events (SAEs), severe adverse events (CTCAE grade ≥ 3)
  • No statistically significant difference was observed between the treatment arms for the endpoints SAE and severe AEs.
• Side effects – Therapy discontinuations due to AEs (≥ 1 active ingredient)
  • There is no statistically significant difference between the treatment arms.
• Overall assessment
  • Results from the KEYNOTE 590 trial are available for the benefit assessment of pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy as first-line treatment for adults with locally advanced, unresectable or metastatic squamous cell carcinoma of the oesophagus with PD-L1-expressing tumours (Combined Positive Score (CPS) ≥ 10), results from the KEYNOTE 590 trial are available for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • In this ongoing study, pembrolizumab in combination with cisplatin and 5-fluorouracil is being compared with the appropriate comparator therapy, cisplatin in combination with 5-fluorouracil.
  • A statistically significant advantage was observed for pembrolizumab in combination with cisplatin and 5-fluorouracil in terms of overall survival. The extent of the prolongation in survival is assessed as a significant improvement.
  • In the morbidity endpoint category, pembrolizumab in combination with cisplatin and 5-fluorouracil shows advantages in terms of the symptoms of pain, dyspnoea and difficulty swallowing.
  • With regard to health-related quality of life, there is no difference between the treatment arms that is relevant to the assessment.
  • With regard to side effects, neither an advantage nor a disadvantage can be identified for pembrolizumab in combination with cisplatin and 5-fluorouracil compared with cisplatin in combination with 5-fluorouracil. In detail, there is a disadvantage in terms of severe immune-mediated adverse events, whilst there are predominantly advantages in other specific adverse events.
  • When the available results on patient-relevant endpoints are considered as a whole, the clear advantage in overall survival and further advantages in terms of symptoms are not offset by any disadvantages.

b2) Adults with locally advanced or metastatic, non-curably treatable, HER2-positive adenocarcinoma of the oesophagus with PD-L1-expressing tumours (Combined Positive Score (CPS) ≥ 10); first-line treatment

• The additional benefit is not proven.
• The pharmaceutical manufacturer did not submit any data with the dossier to assess the additional benefit of pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.