Pembrolizumab (12) – Keytruda®

• Clinical trials
  • For the benefit assessment of pembrolizumab in combination with axitinib, the pharmaceutical manufacturer submitted the randomised, open-label Phase III trial KEYNOTE 426.

a) Adult patients with untreated, advanced renal cell carcinoma with a favourable or intermediate risk profile (IMDC score 0–2)

• Overall, there is a hint of considerable additional benefit from pembrolizumab in combination with axitinib compared with sunitinib.
• mortality
  • overall survival
  • For the endpoint of overall survival, a statistically significant difference was observed between the treatment arms in favour of pembrolizumab + axitinib (hazard ratio (HR): 0.57; 95% confidence interval (CI) [0.41; 0.80]; p-value: 0.001).
  • By the time of the underlying data cut-off, 58 patients (15.4%) in the pembrolizumab + axitinib arm and 90 patients (23.9%) had died; the median survival time had not yet been reached in either treatment arm.
  • The extent of the effect of the combination therapy of pembrolizumab + axitinib compared with sunitinib is assessed as a significant improvement in overall survival.
• Morbidity – Progression-free survival (PFS)
  • The PFS endpoint is defined as the period from randomisation to the first documented instance of disease progression or death from any cause, whichever occurs first. Evidence of disease progression is assessed according to the RECIST criteria (version 1.1).
  • There is a statistically significant advantage between the study arms in favour of pembrolizumab plus axitinib (HR: 0.70, 95% CI [0.57; 0.86]; p-value: < 0.001). Disease progression occurred in 169 patients (44.9%) in the pembrolizumab + axitinib arm and in 193 patients (51.2%) in the sunitinib arm. The median time to event was 18.0 months in the intervention arm and 12.5 months in the control arm, resulting in an absolute difference of 5.5 months.
  • 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 KEYNOTE 426 study as a standalone endpoint via the overall survival endpoint. The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (in accordance with RECIST version 1.1). 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.
• Health-related quality of life
  • Health-related quality of life was assessed using the functional scales and the global health status scale of the cancer-specific EORTC QLQ-C30 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 EORTC QLQ-C30 questionnaire.
  • 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 – Total adverse events (AEs)
  • Adverse events (AEs) occurred in almost all study participants. The results are presented here for supplementary information only.
• Overall assessment
  • Results from the KEYNOTE 426 study are available for the assessment of the additional benefit of pembrolizumab in combination with axitinib as first-line treatment for advanced renal cell carcinoma in adults with a favourable or intermediate risk profile (IMDC score 0–2), results from the KEYNOTE 426 trial are available for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • In the ongoing KEYNOTE 426 trial, pembrolizumab in combination with axitinib is being compared with the appropriate comparator therapy, sunitinib.
  • The combination therapy of pembrolizumab and axitinib results in a statistically significant, marked advantage in overall survival compared with sunitinib.
  • For the endpoint categories of morbidity and health-related quality of life, no usable data are available based on the analyses submitted by the pharmaceutical manufacturer for the EORTC QLQ-C30, FKSI-DRS and EQ-5D VAS assessment tools. This is due to differences in the timing of data collection across the study arms, which results in the treatment burden over the course of the cycle being represented unevenly across the study arms. The pharmaceutical manufacturer did not submit any further analyses in the present benefit assessment procedure to address the limitations of the data set and enable an assessment. It is therefore not possible, on the basis of the data submitted by the pharmaceutical manufacturer for the benefit assessment, to assess how the combination therapy affects patients’ disease-specific symptoms, health status and health-related quality of life.
  • In the endpoint category of side effects, the combination therapy shows disadvantages compared with sunitinib in terms of serious adverse events and therapy discontinuations due to adverse events. With regard to specific adverse events, both advantages and disadvantages can be identified in detail.
  • In its overall assessment of the available results on patient-relevant endpoints, the G-BA concludes that the significant advantage in overall survival outweighs the disadvantages in terms of serious side effects and therapy discontinuations. There is a significant improvement in treatment-related benefit that has not been achieved before.
  • Consequently, the G-BA identifies a considerable added benefit for pembrolizumab in combination with axitinib as first-line treatment for advanced renal cell carcinoma in adults with a favourable or intermediate risk profile (IMDC score 0–2) compared with the appropriate comparator therapy, sunitinib.

b) Adult patients with previously untreated, advanced renal cell carcinoma with an unfavourable risk profile (IMDC score ≥ 3)

• Overall, there is an indication of a considerable additional benefit from pembrolizumab in combination with axitinib compared with sunitinib.
• mortality
  • overall survival
  • There is a statistically significant difference between the treatment arms in favour of pembrolizumab + axitinib (HR: 0.50, 95% CI [0.29; 0.87]; p-value: 0.015). The median survival time is 21.8 months in the intervention arm and 10.1 months in the control arm, resulting in an absolute difference of 11.7 months.
  • The extent of the effect of the combination therapy of pembrolizumab + axitinib compared with sunitinib is assessed as a significant improvement in overall survival.
• Morbidity – Progression-free survival (PFS)
  • The PFS endpoint is defined as the time from randomisation to the first documented instance of disease progression or death from any cause, whichever occurs first. Disease progression is assessed according to the RECIST criteria (version 1.1).
  • There was a statistically significant advantage between the study arms in favour of pembrolizumab plus axitinib (HR: 0.57, 95% CI [0.35; 0.92]; p-value: 0.002). Disease progression occurred in 38 patients (67.9%) in the pembrolizumab + axitinib arm and in 39 patients (75.0%) in the sunitinib arm. The median time to event was 4.9 months in the intervention arm and 2.9 months in the control arm, resulting in an absolute difference of 3.0 months.
  • 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 KEYNOTE 426 study via the overall survival endpoint as a standalone endpoint. The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (in accordance with RECIST version 1.1). 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 using the functional scales and the global health status scale of the cancer-specific EORTC QLQ-C30 questionnaire.
  • The uncertainties mentioned in connection with 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 EORTC QLQ-C30 questionnaire.
  • 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 – Total adverse events (AEs)
  • Adverse events (AEs) occurred in almost all study participants. The results are presented here for supplementary information only.
• Overall assessment
  • Results from the KEYNOTE 426 study are available for the assessment of the additional benefit of pembrolizumab in combination with axitinib as first-line treatment for advanced renal cell carcinoma in adults with an unfavourable risk profile (IMDC score ≥ 3), results from the KEYNOTE 426 trial are available for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • In the ongoing KEYNOTE 426 trial, pembrolizumab in combination with axitinib is being compared with the appropriate comparator therapy, sunitinib.
  • The combination therapy of pembrolizumab and axitinib results in a statistically significant, marked advantage in overall survival compared with sunitinib.
  • For the endpoint categories of morbidity and health-related quality of life, no usable data are available based on the analyses submitted by the pharmaceutical manufacturer for the EORTC QLQ-C30, FKSI-DRS and EQ-5D VAS assessment tools. This is due to differences in the timing of data collection across the study arms, which results in the treatment burden over the course of the cycle being represented unevenly across the study arms. The pharmaceutical manufacturer did not submit any further analyses in the present benefit assessment procedure to address the limitations of the data set and enable an assessment.
  • It is therefore not possible, on the basis of the data submitted by the pharmaceutical manufacturer for the benefit assessment, to assess how the combination therapy affects patients’ disease-specific symptoms, health status and health-related quality of life.
  • In the endpoint category of side effects, the combination therapy shows an advantage over sunitinib in terms of severe adverse events (CTCAE grade ≥ 3). With regard to specific adverse events, a detailed analysis also reveals exclusively advantages for pembrolizumab in combination with axitinib compared with sunitinib.
  • In the overall assessment of the available results on patient-relevant endpoints, the advantages in terms of overall survival and the avoidance of severe side effects are assessed as a significant improvement in treatment-related benefit.
  • Consequently, the G-BA identifies a considerable added benefit for pembrolizumab in combination with axitinib as first-line treatment for advanced renal cell carcinoma in adults with an unfavourable risk profile (IMDC score ≥ 3) compared with the appropriate comparator therapy, sunitinib.

Courtesy translation only, please refer to the German original.