Pembrolizumab (2) – Keytruda®

• Clinical trials
  • The benefit assessment is based on the three-arm KEYNOTE-010 trial. In this open-label, randomised, controlled, multicentre Phase II/III trial, a total of 1,034 patients were randomised in a 1:1:1 ratio to receive treatment with pembrolizumab at a dose of 2 mg/kg body weight (345 patients), pembrolizumab at a dose of 10 mg/kg body weight (346 patients) or docetaxel (343 patients).

1) Patients for whom treatment with docetaxel, pemetrexed or nivolumab is indicated

• mortality
  • Overall survival was assessed as the primary endpoint in the KEYNOTE-010 trial. Treatment with pembrolizumab, compared with the control arm receiving docetaxel, demonstrated a statistically significant prolongation of overall survival (hazard ratio (HR) 0.71; 95% confidence interval (CI) [0.58; 0.88]; p = 0.002). The median survival time in the pembrolizumab arm (45.2 weeks) was 8.2 weeks longer than in the docetaxel arm (37.0 weeks).
  • For the endpoint of overall survival, there is an indication of an effect modification by the ‘PD-L1 status’ variable (interaction test p = 0.088). Patients treated with pembrolizumab who had a PD-L1 status of ≥ 50% showed a statistically significant median survival time of 64.8 weeks, representing an extension of 29.1 weeks compared with the docetaxel group (35.7 weeks) (HR 0.54; 95% CI [0.38; 0.77]; p < 0.001). In patients with a PD-L1 status of 1 to < 50%, there was no statistically significant difference in median survival between the pembrolizumab arm (40.9 weeks) and the docetaxel arm (37.4 weeks).
  • Despite the observed effect modification, the overall population is not stratified according to PD-L1 status.
  • For patients with a PD-L1 status of ≥ 50%, there is a significant advantage in terms of survival. For patients with a PD-L1 status of 1% to < 50%, although no statistically significant advantage was observed for the endpoint of overall survival, there was also no disadvantage compared with the appropriate comparator therapy, docetaxel.
  • Taking these aspects into account and in view of remaining uncertainties – particularly regarding a possible cut-off value and temporal dynamics, as well as the heterogeneous distribution of PD-L1 expression during the course of the disease – and due to a lack of consistency in the effect across other endpoints, the additional benefit for the endpoint of overall survival is assessed on the basis of the overall population, despite the observed effect modification by the ‘PD-L1 status’ characteristic.
• Morbidity – Progression-free survival (PFS)
  • PFS was assessed as the primary endpoint in the KEYNOTE-010 study. Imaging procedures (computed tomography, magnetic resonance imaging) were used to detect progression according to the RECIST criteria.
  • No statistically significant difference was observed between the treatment arms.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of the endpoint was assessed in the study via the ‘overall survival’ endpoint as a standalone endpoint. The ‘disease progression’ component of the morbidity endpoint was not assessed on the basis of symptoms, but rather using imaging procedures. Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Health-related quality of life
  • Health-related quality of life was assessed in the study using the functional scales of the cancer-specific EORTC QLQ-C30 questionnaire. The time to a deterioration of at least 10 points was considered.
  • No statistically significant difference was observed between the treatment groups for any of the endpoints (global health status, emotional functioning, cognitive functioning, physical functioning, role functioning, social functioning).
• Side effects – serious adverse events (SAEs), severe adverse events (CTCAE grade ≥ 3) and discontinuation due to adverse events
  • No statistically significant difference was observed between the treatment arms for the SAE endpoint.
  • For the endpoint of severe AEs (CTCAE grade ≥ 3), a statistically significant difference was observed between the treatment arms in favour of pembrolizumab (HR 0.54; 95% CI [0.43; 0.67]; p < 0.001). The median time to the first occurrence of a severe AE was prolonged by 20.8 weeks in the pembrolizumab arm (31.1 weeks) compared with the docetaxel arm (10.3 weeks). Severe AEs occurred in 46.6% of patients in the pembrolizumab arm and in 56.0% of patients in the docetaxel arm.
  • For the endpoint of therapy discontinuation due to AEs, there was a statistically significant advantage in the pembrolizumab arm compared with the docetaxel arm (HR 0.37; 95% CI [0.22; 0.62]; p < 0.001). Furthermore, more patients in the control group discontinued treatment due to adverse events (13.6% versus 8.3%).
• Overall assessment
  • For the benefit assessment of pembrolizumab in the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with PD-L1-expressing tumours following prior chemotherapy in adults, results are available for the endpoints of mortality, morbidity, health-related quality of life and side effects.
  • Compared with docetaxel, pembrolizumab results in a statistically significant prolongation of median overall survival by 8.2 weeks, which is assessed as a significant improvement not previously achieved.
  • Advantages of pembrolizumab over docetaxel can also be observed in terms of morbidity. Here, positive effects are evident in treatment-related morbidity due to the reduction in side effects of cytotoxic chemotherapy. No beneficial effects of pembrolizumab were observed with regard to disease-specific morbidity or health-related quality of life.
  • Compared with docetaxel, pembrolizumab leads to a significant reduction in severe AEs (CTCAE grade ≥ 3) as well as in the risk of therapy discontinuation due to AEs. Disadvantages of pembrolizumab compared with docetaxel are evident only in certain aspects of the side effects relating to specific immune-mediated AEs. For all other specific AEs, however, pembrolizumab showed advantages over docetaxel. Overall, a significant advantage of pembrolizumab over docetaxel can be observed with regard to side effects.

2) Patients for whom treatment with docetaxel, pemetrexed and nivolumab is not indicated

• For patients for whom treatment with docetaxel, pemetrexed and nivolumab is not indicated, additional benefit is not proven.
• No data were provided for the assessment of the additional benefit of pembrolizumab compared with the appropriate comparator therapy, best supportive care.

Courtesy translation only, please refer to the German original.