Pembrolizumab (15) – Keytruda®

• Clinical trials
  • The benefit assessment is based on the results of the open-label, randomised, actively controlled, multicentre KEYNOTE 177 trial comparing pembrolizumab with a patient-specific treatment regimen selected from one of the following chemotherapies (folinic acid + 5-fluorouracil (5-FU) + oxaliplatin [FOLFOX], administered as the modified mFOLFOX6 regimen, or folinic acid + 5-FU + irinotecan [FOLFIRI]) ± bevacizumab or cetuximab.

a) Adult patients with metastatic colorectal cancer whose tumours exhibit high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) and who are suitable for intensive treatment; First-line treatment

• mortality
  • overall survival
  • In the KEYNOTE 177 trial, there was no statistically significant difference in overall survival between the treatment groups.
  • No additional benefit for pembrolizumab is therefore observed for the endpoint of overall survival.
• morbidity
  • Progression-free survival (PFS)
  • In the KEYNOTE 177 trial, PFS was defined as the time from randomisation to the date of disease progression or death from any cause, whichever occurred first.
  • Assessment of disease or tumour progression was carried out in accordance with the RECIST criteria, version 1.1.
  • The results show a statistically significant prolongation of PFS with pembrolizumab treatment compared with the control arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The morbidity component ‘disease progression’ was assessed solely by means of imaging procedures (radiologically determined disease progression according to the RECIST criteria).
  • Consequently, morbidity is not primarily assessed on the basis of disease symptoms, but solely on the basis of asymptomatic findings that are not directly relevant to the patient.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint.
  • This does not affect the overall conclusion regarding the extent of the additional benefit.
  • Symptoms (EORTC QLQ-C30 and EORTC QLQ-CR29)
  • The disease-related symptoms of the study participants were assessed using the symptom scales of the cancer-specific questionnaire EORTC QLQ-C30 and the colorectal cancer-specific questionnaire EORTC QLQ-CR29.
  • For both questionnaires, the timing of data collection within the treatment cycles differed between the study arms.
  • In the intervention arm, all assessments took place at the start of a new cycle, whilst in the control arm the assessments were carried out at weeks 9, 27 and 45, in the middle of the cycle.
  • Consequently, the burden of treatment over the course of the cycle is reflected differently across the study arms.
  • Despite the criticism set out in the IQWiG’s dossier assessment, the pharmaceutical manufacturer does not provide corresponding sensitivity analyses in its statement to assess the possible influence of the different assessment timepoints within the treatment cycle.
  • The analyses of symptoms provided therefore do not yield reliable results, which is why they are regarded as unusable.
• quality of life
  • Health status (EQ-5D VAS)
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • The uncertainties mentioned in relation to the assessment of disease symptoms, arising from differences in the timing of data collection between the study arms, also apply to the assessment of health-related quality of life using the EQ-5D VAS.
  • In line with the comments in the ‘Symptoms’ section, the presented analyses of health-related quality of life are therefore also considered unusable.
  • Health-related quality of life was assessed using the functional scales of the cancer-specific EORTC QLQ-C30 questionnaire and the colorectal cancer-specific EORTC QLQ-CR29 questionnaire.
  • The uncertainties mentioned in relation to the assessment of disease symptoms, arising from differences in the timing of data collection between the study arms, also apply to the assessment of health-related quality of life.
  • In line with the comments in the ‘Symptoms’ section, the presented analyses of health-related quality of life are therefore also considered unusable.
• Side effects
  • Adverse events (total AEs)
  • In the KEYNOTE 177 study, 97.4% of patients in the intervention arm and approximately 99.3% of patients in the control arm experienced an adverse event.
  • The results for the endpoint ‘Total adverse events’ are presented for supplementary information only.
  • Serious adverse events
  • For the endpoint ‘serious adverse events’ (SAEs), there was a statistically significant advantage in favour of pembrolizumab compared with FOLOFX/FOLFIRI ± bevacizumab or cetuximab.
  • Severe adverse events (CTCAE grade ≥ 3)
  • For the endpoint ‘severe AEs’ (CTCAE grade ≥ 3), there is a statistically significant advantage in favour of pembrolizumab compared with FOLOFX/FOLFIRI ± bevacizumab or cetuximab.
  • Discontinuation due to AEs
  • For the endpoint of discontinuation due to AEs (CTCAE grade ≥ 3), there was no statistically significant difference between the treatment groups.
  • Severe immune-mediated adverse events (CTCAE grade ≥ 3)
  • For the endpoint of severe immune-mediated adverse events (CTCAE grade ≥ 3), there was no statistically significant difference between the treatment groups.
  • Immune-mediated SUEs
  • For the endpoint ‘immune-mediated SUEs’, there was a statistically significant difference in favour of pembrolizumab compared with FOLOFX/FOLFIRI ± bevacizumab or cetuximab, representing a disadvantage.
  • Specific AE
  • For the specific adverse events mucositis (adverse events), decreased appetite (adverse events), peripheral neuropathy (adverse events), peripheral sensory neuropathy (adverse events), epistaxis (adverse events), alopecia (AEs), palmar-plantar erythrodysesthesia syndrome (AEs), gastrointestinal disorders (severe AEs), fatigue (severe AEs), infections and parasitic diseases (severe AEs) and hypokalaemia (severe AEs), as well as for the endpoint ‘blood and lymphatic system disorders’ (SOC, severe AEs), a statistically significant advantage in favour of pembrolizumab was observed in each case compared with FOLOFX/FOLFIRI ± bevacizumab or cetuximab.
  • For the endpoint of arthralgia (adverse events), there is a statistically significant difference in favor of pembrolizumab compared with FOLOFX/FOLFIRI ± bevacizumab or cetuximab, with a disadvantage compared to these regimens.
  • Overall, the results regarding side effects show predominantly positive effects for pembrolizumab compared with patient-specific therapy with FOLOFX/FOLFIRI ± bevacizumab or cetuximab.
  • In particular, the advantages regarding serious adverse events and severe adverse events represent a significant improvement in therapeutic benefit.
  • In detail, there are disadvantages regarding immune-mediated SAEs, whilst there are predominantly advantages in specific SAEs.

b) Adult patients with metastatic colorectal cancer whose tumours exhibit high microsatellite instability (MSI-H) or a mismatch repair deficiency (dMMR) and who are not suitable for intensive therapy; First-line treatment

• For pembrolizumab as first-line treatment for adult patients with metastatic colorectal cancer whose tumours exhibit high microsatellite instability (MSI-H) or a mismatch repair deficiency (dMMR) and who are not suitable for intensive therapy, the additional benefit is not proven.
• The pharmaceutical manufacturer did not submit any data that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.