Pembrolizumab (13) – Keytruda®

• Clinical trials
  • The pharmaceutical manufacturer has submitted data from the randomised, open-label, actively controlled and currently ongoing Phase III trial KEYNOTE 048 for the benefit assessment.
  • This three-arm trial compares treatment with pembrolizumab in combination with cisplatin or carboplatin and 5-FU against treatment with cetuximab in combination with cisplatin or carboplatin and 5-FU, as well as against pembrolizumab monotherapy.

Adult patients with metastatic or unresectable recurrent squamous cell carcinoma of the head and neck (HNSCC) with PD-L1-expressing tumours (Combined Positive Score [CPS] ≥ 1); first-line treatment

• In a cost-benefit analysis, the G-BA has approved pembrolizumab in combination with cisor carboplatin and 5-FU for the first-line treatment of metastatic or unresectable recurrent squamous cell carcinoma of the head and neck in adults with PD-L1-expressing tumours (CPS ≥ 1) compared with cetuximab in combination with cis- or carboplatin and 5-FU, a minor additional benefit was found.
• Based on the available evidence, the certainty of the evidence is therefore classified as ‘indication’.
• mortality
  • Overall survival is defined in the KEYNOTE 048 trial as the time from randomisation to death from any cause.
  • In the patient population relevant for the analysis, with PD-L1 expression CPS ≥ 1, 177 patients in the intervention arm (73.1%) and 213 in the control arm (90.6%). The median survival time was 13.6 months in the intervention arm and 10.4 months in the control arm, corresponding to a median prolongation of 3.2 months.
  • The time-to-event analysis revealed a statistically significant difference (hazard ratio (HR): 0.65; [95% confidence interval (CI): 0.53; 0.80]; p-value < 0.001).
  • This result demonstrates an extension in overall survival, which is regarded as a significant improvement.
• Morbidity – Progression-free survival (PFS)
  • PFS is a co-primary endpoint of the KEYNOTE 048 trial and is defined as the time from randomisation to the first occurrence of disease progression according to RECIST or death from any cause.
  • The event-time analysis shows no statistically significant difference between the treatment arms.
• Morbidity – Symptoms
  • In the KEYNOTE 048 study, patients’ symptoms are assessed using the symptom scales of the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires.
  • In the responder analysis for the time to the first confirmed clinically relevant deterioration of at least 10 points from baseline, a statistically significant difference was observed between the treatment arms on the ‘insomnia’ scale. This difference indicates a disadvantage for pembrolizumab in combination with cisplatin or carboplatin and 5-FU.
  • In summary, with regard to symptoms, a statistically significant disadvantage compared to pembrolizumab in combination with cisplatin or carboplatin and 5-FU was observed in only one of the 18 symptom scales considered, due to an increase in insomnia.
  • However, given the severity of the disease in question, this single disadvantage is not considered sufficient to infer an overall disadvantage in the morbidity endpoint category.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • To assess the health status of the study patients, the pharmaceutical manufacturer provides responder analyses for the time to the first confirmed clinically relevant deterioration of at least 7 or 10 points from baseline.
  • Instead of the responder analyses, the IQWIG’s dossier assessment draws on analyses of mean differences. The difference between the study arms is not statistically significant in terms of the mean difference.
  • No statistically significant differences are evident in the corresponding time-to-event analyses.
• quality of life
  • Health-related quality of life is reported by patients in the KEYNOTE 048 study and assessed using the functional scales of the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires.
  • In the responder analysis for the time to the first confirmed clinically relevant deterioration of at least 10 points from baseline, no statistically significant difference was observed between the treatment arms on any scale.
  • An additional benefit of pembrolizumab in combination with cisplatin or carboplatin and 5-FU is not proven in the quality of life category.
• Side effects – Total adverse events (AEs)
  • Almost all patients in the relevant treatment arms of the KEYNOTE 048 trial experienced an adverse event.
  • The results for the endpoint ‘Total adverse events’ are presented for supplementary information only.
• Overall assessment
  • For the benefit assessment of pembrolizumab in combination with cisplatin or carboplatin and 5-FU chemotherapy as first-line treatment for metastatic or unresectable recurrent squamous cell carcinoma of the head and neck (HNSCC) in adults with PD-L1-expressing tumours (Combined Positive Score [CPS] ≥ 1), results from the KEYNOTE 048 study on overall survival, morbidity, health-related quality of life and side effects are available.
  • In the mortality endpoint category, a statistically significant difference was observed between the treatment arms. Pembrolizumab in combination with cisplatin or carboplatin and 5-FU leads to a significant improvement in overall survival compared with cetuximab in combination with cisplatin or carboplatin and 5-FU.
  • With regard to morbidity, as assessed using the EORTC QLQ-C30, EORTC QLQ-H&N35 and EQ-5D VAS, a statistically significant difference is observed only on the ‘insomnia’ scale, to the detriment of pembrolizumab in combination with cisplatin or carboplatin and 5-FU. However, given the severity of the disease in question, this disadvantage is not considered sufficient to infer an overall disadvantage in the morbidity endpoint category.
  • With regard to health-related quality of life, treatment with pembrolizumab in combination with cisplatin or carboplatin and 5-FU shows neither positive nor negative effects.
  • In the ‘side effects’ endpoint category, there is a disadvantage for pembrolizumab in combination with cisplatin or carboplatin and 5-FU due to an increase in SAEs.
  • In the overall assessment of the results for all patient-relevant endpoints, the positive effect of a significant improvement in overall survival is offset by a relevant disadvantage in terms of serious side effects.
  • In its risk-benefit assessment, the G-BA recommends pembrolizumab in combination with cisor carboplatin and 5-FU for the first-line treatment of metastatic or unresectable recurrent squamous cell carcinoma of the head and neck in adults with PD-L1-expressing tumours (CPS ≥ 1) compared with cetuximab in combination with cis- or carboplatin and 5-FU, there was a minor additional benefit.

Courtesy translation only, please refer to the German original.