Pembrolizumab (1) – Keytruda®

• Clinical trials
  • The KEYNOTE 006 trial is a multicentre, randomised, actively controlled comparative trial in which patients with advanced melanoma – who had either previously received systemic therapy for advanced melanoma or were untreated – were treated with either pembrolizumab or ipilimumab.
  • To assess the additional benefit of pembrolizumab in previously treated patients, the pharmaceutical manufacturer presents, on the one hand, data from a randomised controlled trial, the KEYNOTE 002 trial, in which pembrolizumab was compared with patient-specific chemotherapy selected by the investigator in pre-treated patients.

a) Previously untreated patients with a BRAF V600-mutated tumour

• The additional benefit is not proven.
• For previously untreated patients with a BRAF V600-mutated tumour, the additional benefit compared with the appropriate comparator therapy, vemurafenib, is not proven, as the pharmaceutical manufacturer did not submit a study that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

b) Previously untreated patients with a BRAF V600 wild-type tumour

• For previously untreated patients with a BRAF V600 wild-type tumour, there is a hint of considerable additional benefit compared with the appropriate comparator therapy, ipilimumab.
• For this patient group, the G-BA classifies the extent of the additional benefit of pembrolizumab as considerable, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease.
• Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a significant improvement in treatment-related benefit that has not previously been achieved, particularly as it achieves a moderate prolongation of life expectancy and a significant reduction in serious/severe side effects.
• Consequently, the certainty of the evidence for the established additional benefit is classified in the ‘hint’ category.
• mortality
  • overall survival
  • The analyses of overall survival are based on the data cut-off from the second interim analysis following a minimum observation period of 12 months.
  • Treatment with pembrolizumab showed a statistically significant prolongation in overall survival compared with treatment with ipilimumab (HR: 0.65, 95% CI [0.44; 0.96]; p = 0.032).
  • The median survival time has not yet been reached in the pembrolizumab arm of the study, compared with a median survival time of 15.4 [9.8; n.a.] months in the ipilimumab arm of the study.
  • For the endpoint of overall survival, pembrolizumab demonstrates an additional benefit compared with the appropriate comparator therapy, ipilimumab, the extent of which is considerable.
• Morbidity – Symptoms
  • Symptoms were assessed in the study using the symptom scales of the cancer-specific EORTC QLQ-C30 questionnaire. The time to a deterioration of at least 10 points was analysed.
  • For the symptoms of fatigue (HR 0.66, 95% CI [0.49; 0.91]; p = 0.010) and nausea and vomiting (HR 0.67, 95% CI [0.46; 0.97]; p = 0.034), a statistically significant difference in favour of pembrolizumab was observed, although the extent of this difference was no more than marginal in each case.
  • For the remaining endpoints – dyspnoea, insomnia, pain, loss of appetite, diarrhoea and constipation – a numerical but not statistically significant difference was observed between pembrolizumab and the appropriate comparator therapy (ipilimumab), so that, whilst no additional benefit can be inferred from these symptoms alone, the results as a whole support the considerable additional benefit due to the same direction of effect.
• Morbidity – Health status
  • Health status was assessed in the study using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • No statistically significant difference in health status was observed between the treatment arms.
  • An additional benefit of pembrolizumab compared with the appropriate comparator therapy is therefore not proven for this endpoint.
• Health-related quality of life
  • Health-related quality of life was measured in the study using the functional scales of the disease-specific EORTC QLQ-C30 questionnaire. The time to a deterioration of at least 10 points was assessed.
  • For the social functioning endpoint, a statistically significant difference was observed in favour of pembrolizumab (HR 0.68, 95% CI [0.48; 0.95]; p = 0.023).
  • No statistically significant differences were observed for the other endpoints (global health status/quality of life, emotional functioning, cognitive functioning, physical functioning and role functioning).
  • Overall, pembrolizumab demonstrates additional benefit compared with the appropriate comparator therapy for one aspect of quality of life.
  • Against this background, the extent of the additional benefit is assessed as minor overall.
• Side effects – severe adverse events (SAE), severe adverse events (CTCAE ≥3), discontinuation due to adverse events (AE)
  • For the endpoints SAE, severe AEs (CTCAE ≥3) and discontinuation due to AEs, no statistically significant difference was observed between the treatment groups in any case.
  • Consequently, there are no hints for greater or minor harm from pembrolizumab compared with the appropriate comparator therapy for these endpoints; therefore, the additional benefit of pembrolizumab is not proven for these endpoints.
• Overall assessment
  • The G-BA classifies the extent of the additional benefit of pembrolizumab as considerable, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
  • Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, this represents a significant improvement in treatment-related benefit that has not previously been achieved, as a moderate prolongation of overall survival and a relevant reduction in serious/severe and non-serious side effects are achieved.
  • At the same time, a minor reduction in non-serious symptoms and a minor improvement in health-related quality of life (social functioning) have been observed, which, taken together, support a classification of the additional benefit of pembrolizumab in this patient population as ‘considerable’.
  • However, when the available findings on mortality, morbidity and quality of life, together with the findings on side effects, are considered as a whole, pembrolizumab does not demonstrate a sustained and, compared with the appropriate comparator therapy, previously unachieved major improvement in treatment-related benefit; in particular, it does not result in a cure of the disease, no major prolongation of life, no long-term freedom from severe symptoms and no substantial avoidance of serious side effects.
  • Therefore, classification as a major additional benefit is not justified.

c) Pre-treated patients

• For patients who have received prior treatment for advanced melanoma and for whom ipilimumab constitutes the appropriate comparator therapy in the sense of a patient-specific treatment, there is an indication of considerable additional benefit compared with the appropriate comparator therapy (ipilimumab).
• For this patient group, the G-BA classifies the extent of the additional benefit of pembrolizumab as considerable, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease.
• Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a significant improvement in treatment-related benefit that has not previously been achieved, particularly as it results in a relevant reduction in the incidence of serious / severe side effects is achieved.
• For patients who have previously received treatment for advanced melanoma and for whom ipilimumab does not constitute the appropriate comparator therapy, no studies relevant to the assessment of the additional benefit were submitted by the pharmaceutical manufacturer.
• Overall, the certainty of the evidence for the established additional benefit is therefore classified as an indication.
• mortality
  • overall survival
  • For treatment with pembrolizumab, there is no statistically significant difference in overall survival compared with patient-specific therapy (ipilimumab) (HR: 0.69, 95% CI [0.44; 1.09]; p = 0.112).
  • The median survival time has not yet been reached in the pembrolizumab arm of the study, compared with a median survival time of 14.0 [10.9; n.a.] months in the ipilimumab arm of the study.
  • For the endpoint of overall survival, there is therefore no additional benefit of pembrolizumab compared with the appropriate comparator therapy (patient-specific therapy (ipilimumab)) in pre-treated patients.
• Morbidity – Symptoms
  • Symptoms were assessed in the study using the symptom scales of the cancer-specific EORTC QLQ-C30 questionnaire. The time to a deterioration of at least 10 points was analysed.
  • For none of the symptoms considered (dyspnoea, fatigue, insomnia, pain, loss of appetite, diarrhoea, nausea and vomiting, and constipation) was there a statistically significant difference in favour of pembrolizumab.
  • An additional benefit of pembrolizumab over the appropriate comparator therapy is not proven with regard to symptoms.
• Morbidity – Health status
  • Health status was assessed in the study using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • No statistically significant difference in health status was observed between the treatment arms.
  • An additional benefit of pembrolizumab compared with the appropriate comparator therapy is therefore not proven for this endpoint.
• Health-related quality of life
  • Quality of life was measured in the study using the functional scales of the disease-specific EORTC QLQ-C30 questionnaire. The time to a deterioration of at least 10 points was assessed.
  • No statistically significant difference was observed in health-related quality of life for any of the domains assessed (global health status/quality of life, emotional functioning, cognitive functioning, physical functioning, role functioning, social functioning).
  • An additional benefit of pembrolizumab over the appropriate comparator therapy is therefore not proven with regard to quality of life.
• Side effects – severe adverse events (SAEs)
  • For the SAE endpoint, a statistically significant difference was observed in terms of time to onset in favour of pembrolizumab (HR: 0.54; 95% CI [0.54; 0.98]; p = 0.043).
  • No information is available on the incidence of SAE.
  • Due to the avoidance of serious/severe side effects, pembrolizumab offers an additional benefit over the appropriate comparator therapy for this endpoint, although the extent of this benefit is minor.
• Side effects – severe adverse events (CTCAE ≥3)
  • For this endpoint, a statistically significant difference was observed in the time to onset in favour of pembrolizumab (HR: 0.64; 95% CI [0.24; 0.78]; p = 0.017).
  • No information is available on the incidence of severe AEs.
  • Due to the avoidance of serious/severe side effects, pembrolizumab offers an additional benefit over the appropriate comparator therapy for this endpoint, the extent of which is considerable.
• Overall assessment
  • The G-BA classifies the extent of the additional benefit of pembrolizumab as considerable, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
  • Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a significant improvement in treatment-related benefit that has not previously been achieved, as a relevant reduction in serious/severe side effects (SAE, severe AEs (CTCAE ≥ 3) and discontinuation due to AEs; immune-mediated severe AEs (CTCAE ≥ 3)) is achieved.
  • However, when the available results on mortality, morbidity and quality of life, together with the results on side effects, are considered as a whole, pembrolizumab does not demonstrate a sustained and, compared with the appropriate comparator therapy, previously unachieved significant improvement in treatment-related benefit; in particular, it does not result in a cure of the disease, no major prolongation of survival, no long-term freedom from severe symptoms and no substantial avoidance of serious side effects.
  • Therefore, classification as ‘major additional benefit’ is not justified.

Courtesy translation only, please refer to the German original.