Pembrolizumab (35) – Keytruda®

a) Adults with resectable non-small cell lung cancer with tumour cell PD-L1 expression ≥ 1 % and a high risk of recurrence; neoadjuvant and adjuvant therapy

• For adults with PD-L1 expression ≥ 1 % for the neoadjuvant and subsequent adjuvant treatment of resectable non-small cell lung cancer with a high risk of recurrence, there are no suitable data available for assessing the additional benefit.
• The KEYNOTE 671 study is not suitable for assessing additional benefit, as the appropriate comparator therapy specified by the G-BA for the present resolution for patient population a) in the neoadjuvant treatment phase ‘nivolumab in combination with platinum-based therapy’ has not been implemented.
• Consequently, the additional benefit over the appropriate comparator therapy is not proven.

b) Adults with resectable non-small cell lung cancer with tumour cell PD-L1 expression < 1 % and a high risk of recurrence; neoadjuvant and adjuvant therapy

• In the KEYNOTE 671 trial, pembrolizumab in combination with platinum-based chemotherapy (neoadjuvant) followed by pembrolizumab (adjuvant) was compared with cisplatin and gemcitabine or cisplatin and pemetrexed (neoadjuvant) followed by placebo (adjuvant).
• Overall, pembrolizumab in combination with platinum-based chemotherapy (neoadjuvant) followed by pembrolizumab (adjuvant) shows no additional benefit compared with the appropriate comparator therapy.
• An additional benefit is not proven.
• mortality
  • In the KEYNOTE 671 trial, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • There was no statistically significant difference for pembrolizumab in combination with cisplatin and gemcitabine or cisplatin and pemetrexed (neoadjuvant treatment) followed by pembrolizumab (adjuvant treatment) showed no statistically significant difference compared with cisplatin and gemcitabine or cisplatin and pemetrexed (neoadjuvant treatment) followed by placebo (adjuvant treatment).
  • Uncertainties remain regarding the follow-up treatments administered after completion of the study medication.
• Morbidity – Failure of the curative approach (event-free survival, EFS)
  • The EFS endpoint was defined in the statistical analysis plan (SAP) of the KEYNOTE 671 trial as the time from randomisation to the occurrence of any of the following events:
  • Radiological disease progression according to RECIST 1.1 (for patients who have not undergone surgery, are not due to undergo surgery, or who have serious residual disease following an incomplete resection [R2 resection]),
  • local progression (primary tumour or regional lymph nodes) preventing the planned surgery,
  • inability to resect the tumour,
  • local or distant recurrence (for patients who are disease-free following surgery [R0 resection] or patients with microscopically positive margins [R1 resection]), or
  • death from any cause.
  • In addition, the pharmaceutical manufacturer presented a further operationalisation of the EFS endpoint as ‘post hoc adapted event-free survival’.
  • There are no statistically significant differences between the treatment arms in any of these cases.
• Morbidity – symptoms (assessed using the EORTC QLQ-C30 and EORTC QLQ-LC13) and health status (assessed using the EQ-5D VAS)
  • The data presented on patient-reported outcomes (PROs) are not used for evaluation, as the response rates decline sharply and vary over the course of the observation period.
  • Irrespective of this, the data presented cannot, in principle, be meaningfully interpreted due to the long and varying periods without data collection between the neoadjuvant and adjuvant therapy phases (at least 8 weeks, but up to 20 weeks depending on the individual patient).
  • Overall, the results are therefore not usable for the present benefit assessment.
• quality of life
  • Quality of life for patients is assessed in the KEYNOTE 671 study using the EORTC QLQ-C30.
  • The data presented on patient-reported outcomes (PROs) are not used for the assessment, as the response rates decline sharply and vary significantly over the course of the study.
  • Irrespective of this, the data provided cannot, in principle, be meaningfully interpreted due to the long and varying periods without data collection between the neoadjuvant and adjuvant treatment phases (at least 8 weeks, but up to 20 weeks depending on the individual patient).
  • Overall, the results are therefore not usable for the present benefit assessment.
• Side effects
  • Total adverse events
  • Adverse events occurred in almost all patients.
  • Serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3), therapy discontinuation due to AEs
  • No statistically significant differences were observed between the treatment arms for the endpoints SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuation due to AEs.
  • Specific AE
  • Immune-mediated SAEs, peripheral oedema (AE), general disorders and administration site conditions (SAE)
  • For the endpoints immune-mediated SAE, peripheral oedema (AE) and general disorders and administration site conditions (SAE), the intervention showed a disadvantage compared with the control arm in each case.
  • In the overall analysis of the results on side effects, there is neither an advantage nor a disadvantage for pembrolizumab in combination with cisplatin and gemcitabine or cisplatin and pemetrexed (neoadjuvant treatment), followed by pembrolizumab (adjuvant treatment).
  • In detail, there are disadvantages associated with specific AEs.
• Overall assessment
  • For the benefit assessment of pembrolizumab in combination with platinum-based chemotherapy (neoadjuvant treatment) followed by pembrolizumab (adjuvant treatment), data are available from the double-blind, randomised KEYNOTE 671 trial on mortality, morbidity, quality of life and side effects compared with cisplatin and gemcitabine or cisplatin and pemetrexed (neoadjuvant treatment) followed by placebo (adjuvant treatment).
  • For pembrolizumab in combination with platinum-based chemotherapy (neoadjuvant treatment) followed by pembrolizumab (adjuvant treatment) compared with cisplatin and gemcitabine or cisplatin and pemetrexed (neoadjuvant treatment) followed by placebo (adjuvant treatment), additional benefit is not proven.

Courtesy translation only, please refer to the German original.