Pembrolizumab (11) – 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

• Consequently, the G-BA has determined that pembrolizumab monotherapy 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 cisplatin or carboplatin and 5-FU provides a considerable additional benefit.
• Based on the available evidence, the certainty of the finding is therefore classified as ‘hint’.
• 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 to the analysis with PD-L1 expression CPS ≥ 1, 197 patients in the intervention arm (76.7%) and 229 in the control arm (89.8%). The median survival time was 12.3 months in the intervention arm and 10.3 months in the control arm, corresponding to a median survival benefit of 2.0 months.
  • The time-to-event analysis reveals a statistically significant difference (hazard ratio (HR): 0.74; [95% confidence interval (CI): 0.61; 0.90]; p-value = 0.003).
  • In the endpoint category of mortality, the results of the KEYNOTE 048 study thus indicate an extension of overall survival, the extent of which is assessed as a minor improvement.
• morbidity
  • Progression-free survival (PFS)
  • PFS is a co-primary endpoint of the KEYNOTE 048 study 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.
  • Symptoms and health status (EQ-5D Visual Analogue Scale)
  • However, the analyses submitted by the pharmaceutical manufacturer regarding the time to the first confirmed clinically relevant deterioration of at least 10 points, or 7 and 10 points respectively, cannot be used in the present context.
  • In the morbidity endpoint category, therefore, the additional benefit of pembrolizumab as monotherapy is not proven.
• 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.
  • The same limitations described previously apply to the presented responder analyses, meaning that the results are also deemed to be non-interpretable.
  • Accordingly, additional benefit from pembrolizumab as monotherapy in the quality of life category is not proven.
• Side effects
  • Total adverse events (AEs)
  • Almost all patients in the relevant study arms of the KEYNOTE 048 trial experienced an adverse event.
  • Serious AEs
  • In the KEYNOTE 048 trial, approximately 41% of patients in the intervention arm and approximately 49% of patients in the control arm experienced a serious adverse event (SAE). The time-to-event analysis showed no statistically significant difference between the treatment arms.
  • Severe AEs (CTCAE grade ≥ 3)
  • Approximately 55% of patients in the intervention arm and approximately 83% of patients in the control arm experienced a severe adverse event (CTCAE grade ≥ 3). In the intervention arm, a severe AE (CTCAE grade ≥ 3) occurred at a median of 4.6 months later than in the control arm. The time-to-event analysis shows a statistically significant advantage for pembrolizumab as monotherapy.
  • Therapy discontinuation due to AEs
  • In the intervention arm, approximately 12% of patients, and in the control arm approximately 27%, discontinued treatment due to adverse events. The time-to-event analysis revealed a statistically significant advantage for pembrolizumab monotherapy.
  • Specific AE
  • Statistically significant advantages in favour of pembrolizumab monotherapy were observed in the following specific adverse events: paronychia (PT, AEs), disorders of the skin and subcutaneous tissue (SOC, AEs [CTCAE grade ≥ 3]), disorders of the ear and labyrinth (SOC, AEs), asthenia (PT, AEs), dizziness (PT, AEs), disorders of the blood and lymphatic system (SOC, AEs [CTCAE grade ≥ 3]), anaemia (PT, UEs [CTCAE grade ≥ 3]), disorders of the gastrointestinal tract (SOC, UEs [CTCAE grade ≥ 3]), Mucosal inflammation (PT, UEs [CTCAE grade ≥ 3]), Investigations (SOC, UEs [CTCAE grade ≥ 3]) and Hypomagnesaemia (PT, UEs [CTCAE grade ≥ 3]). By contrast, a disadvantage is observed in disorders of the respiratory tract, thoracic cavity and mediastinum (SOC, AEs [CTCAE grade ≥ 3]).
  • In the overall assessment of the ‘side effects’ endpoint category, there are clear advantages for pembrolizumab as monotherapy. In summary, there is a considerable additional benefit of pembrolizumab as monotherapy in the ‘side effects’ endpoint category.
• Overall assessment
  • For the benefit assessment of pembrolizumab as monotherapy for the first-line treatment of 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 are available regarding overall survival, morbidity, health-related quality of life and side effects.
  • In the mortality endpoint category, there is a statistically significant advantage in favour of pembrolizumab as monotherapy compared with treatment with cetuximab in combination with cisplatin or carboplatin and 5-FU.
  • Compared with cetuximab in combination with cisplatin or carboplatin and 5-FU, pembrolizumab monotherapy results in a prolongation of overall survival, the extent of which is assessed as a minor improvement.
  • With regard to morbidity and health-related quality of life, as assessed using the EORTC QLQ-C30, EORTC QLQ-H&N35 and EQ 5D-VAS instruments, no usable data are available overall.
  • In the endpoint category of side effects, there are clear advantages for pembrolizumab as monotherapy, as evidenced by a reduction in severe side effects (CTCAE grade ≥ 3) and therapy discontinuations due to side effects. In detail, advantages are also predominantly evident in the area of specific AEs. Pembrolizumab as monotherapy leads, overall, to a significant reduction in side effects.

Courtesy translation only, please refer to the German original.