Pembrolizumab (31) – Keytruda®

• Clinical trials
  • KEYNOTE 811 is a double-blind, randomised, multicentre trial comparing pembrolizumab in combination with trastuzumab and fluoropyrimidine- and platinum-based chemotherapy with placebo in combination with trastuzumab and fluoropyrimidine- and platinum-based chemotherapy.

Adults with locally advanced, unresectable or metastatic HER2-positive adenocarcinoma of the stomach or the gastro-oesophageal junction with PD-L1-expressing tumours (CPS ≥ 1); first-line treatment

• The additional benefit is not proven.
• Consequently, the G-BA concludes that for pembrolizumab in combination with trastuzumab, 5-fluorouracil and cisplatin for the first-line treatment of locally advanced, unresectable or metastatic HER2-positive adenocarcinoma of the stomach or the gastro-oesophageal junction in adults with PD-L1-expressing tumours (CPS ≥ 1) the additional benefit is not proven.
• mortality
  • Overall survival is defined in the KEYNOTE 811 trial as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, there is no statistically significant difference between pembrolizumab in combination with trastuzumab, 5-fluorouracil and cisplatin compared with trastuzumab in combination with 5-fluorouracil and cisplatin.
  • There is therefore no proof of additional benefit in terms of overall survival.
• Morbidity – Symptoms (EORTC QLQ-C30 and EORTC QLQ-STO22)
  • In the KEYNOTE 811 study, disease symptoms are assessed using the symptom scales of the cancer-specific questionnaire EORTC QLQ-C30 and the gastric cancer-specific supplementary module EORTC QLQ-STO22.
  • In the dossier, the pharmaceutical manufacturer provides event-time analyses for the time to first deterioration of at least 10 points, including questionnaire response rates, but only for the patient population under consideration with a CPS ≥ 1, irrespective of the chemotherapy regimen.
  • The patient population relevant for the benefit assessment corresponds to approximately 15% of this population; consequently, the available information on questionnaire response rates for the relevant patient population is not meaningful, and it is not possible to estimate the proportion of missing values.
  • The data are therefore considered unusable.
• Morbidity – Health status (EQ-5D VAS)
  • Health status is assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • In the dossier, the pharmaceutical manufacturer provides event time analyses for the first deterioration of at least 15 points, including questionnaire response rates, but only for the patient population under consideration with a CPS ≥ 1, irrespective of the chemotherapy regimen.
  • The patient population relevant for the benefit assessment corresponds to approximately 15% of this population; consequently, the available data on questionnaire response rates for the relevant patient population are not meaningful, and it is not possible to estimate the proportion of missing values.
  • The data are therefore considered unusable.
• quality of life
  • Health-related quality of life is assessed in the KEYNOTE 811 study using the functional scales of the cancer-specific EORTC QLQ-C30 questionnaire.
  • In the dossier, the pharmaceutical manufacturer provides event-time analyses for the time to first deterioration of at least 10 points, including questionnaire response rates, but only for the patient population under consideration (those with a CPS ≥ 1), regardless of the chemotherapy regimen.
  • The patient population relevant for the benefit assessment corresponds to approximately 15% of this population; consequently, the available information on questionnaire response rates for the relevant patient population is not meaningful, and it is not possible to estimate the proportion of missing values.
  • The data are therefore considered unusable.
• Side effects – Total adverse events (AEs)
  • Adverse events occurred in almost all study participants.
• Side effects – Serious adverse events (SAE), 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 discontinuation due to AEs
  • In the dossier, the pharmaceutical manufacturer presents analyses for the relevant patient population in the form of subgroup analyses for the endpoint ‘therapy discontinuation due to AEs’.
  • However, based on the information provided, it is unclear whether these analyses relate to the time to discontinuation of all active substance components or to the time to discontinuation of ≥ 1 active substance component.
  • The data are therefore considered unusable.
• Overall assessment
  • For the benefit assessment of pembrolizumab in combination with trastuzumab and fluoropyrimidine- and platinum-based chemotherapy for the first-line treatment of locally advanced unresectable or metastatic HER2-positive adenocarcinoma of the stomach or the gastro-oesophageal junction in adults with PD-L1-expressing tumours (CPS ≥ 1), results from the KEYNOTE 811 study are available for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • No statistically significant difference was observed in overall survival.
  • Symptoms of the disease were assessed in the study using the cancer-specific questionnaire EORTC QLQ-C30 and the gastric cancer-specific supplementary module EORTC QLQ-STO22. In addition, health status was assessed using the EQ-5D VAS. However, the respective analyses cannot be utilised due to unknown response rates for the relevant patient population.
  • Health-related quality of life was assessed in the study using the EORTC QLQ-C30 questionnaire. However, the relevant analyses are also not valid due to unknown response rates for the relevant patient population.
  • With regard to side effects, no advantage or disadvantage could be identified for pembrolizumab in combination with trastuzumab, 5-fluorouracil and cisplatin compared with trastuzumab, 5-fluorouracil and cisplatin. However, no usable results are available for the relevant patient population regarding therapy discontinuations due to AEs, cardiac disorders (severe AEs), immune-mediated AEs, severe immune-mediated AEs and other specific AEs.
  • In the overall assessment of the available results for patient-relevant endpoints, no statistically significant difference in overall survival was observed between the treatment groups. No evaluable data are available for assessing morbidity (symptoms of the disease, health status) and quality of life. With regard to side effects, no advantage or disadvantage can be inferred from the overall rates of SAE and severe AEs (CTCAE grade ≥ 3). No usable data are available for other endpoints in the side effects category.

Courtesy translation only, please refer to the German original.