Pembrolizumab (29) – Keytruda®

• Clinical trials
  • KEYNOTE 716 is a multicentre, double-blind, randomised controlled trial comparing pembrolizumab with placebo in the adjuvant treatment of melanoma.

a) Adults and children and adolescents aged 12 years and over with stage IIB or IIC melanoma following complete resection; adjuvant treatment

• The findings indicate an indication that pembrolizumab offers a non-quantifiable additional benefit compared with watchful waiting.
• Consequently, the certainty of the evidence for the observed additional benefit is classified as ‘indication’.
• mortality
  • Based on these analyses, no statistically significant difference was observed between the treatment arms.
  • Final analyses from the KEYNOTE 716 trial on the endpoint of overall survival are pending.
• Morbidity – Recurrences / Recurrence-free survival (RFS)
  • For the endpoint of recurrence, there is a statistically significant advantage for pembrolizumab compared with placebo.
  • Compared with placebo, pembrolizumab leads to a statistically significant prolongation of the time to recurrence or death.
  • Overall, therefore, with regard to the endpoints of recurrence and recurrence-free survival, there is a clear, clinically relevant advantage of pembrolizumab compared with watchful waiting.
  • However, as the observation period (median of approximately 27 months) as at the data cut-off date of 4 January 2022 is relatively short and not long enough to adequately reflect the high-risk period for recurrence, which spans 3 years following the primary diagnosis, the extent of this advantage cannot be reliably quantified based on the available data.
• Morbidity – Symptoms
  • For the endpoints of fatigue, pain, dyspnoea, loss of appetite and diarrhoea, a statistically significant disadvantage was observed in each case with pembrolizumab.
  • However, the respective 95% confidence interval for the standardised mean difference (SMD) did not lie entirely outside the irrelevance range of −0.2 to 0.2.
  • It cannot therefore be concluded in each case that the observed effect is clinically relevant.
  • For all other endpoints, no statistically significant difference was observed between the study arms.
  • With regard to symptoms, therefore, there are neither positive nor negative effects of pembrolizumab compared with a watch-and-wait approach.
• Health-related quality of life
  • For the endpoints of global health status, role functioning and social functioning, a statistically significant difference was observed in each case to the disadvantage of pembrolizumab.
  • However, the respective 95% confidence interval for the standardised mean difference (SMD) did not lie entirely outside the irrelevance range of −0.2 to 0.2.
  • It cannot therefore be concluded in each case that the observed effect is clinically relevant.
  • For all other endpoints, no statistically significant difference was observed between the study arms.
  • With regard to health-related quality of life, there are therefore neither positive nor negative effects of pembrolizumab compared with a watch-and-wait approach.
• Side effects
  • There was no statistically significant difference between the study arms in terms of serious adverse events.
  • For severe adverse events with a CTCAE grade of ≥ 3, a statistically significant disadvantage was observed compared to pembrolizumab.
  • An effect modification was observed for the characteristic ‘age’. For participants aged > 65 years, a statistically significant effect was observed to cause a disadvantage for pembrolizumab. For participants aged ≤ 65 years, no statistically significant difference was observed.
  • For the endpoint ‘discontinuation due to AEs’, a statistically significant difference was observed to the disadvantage of pembrolizumab.
  • For the specific SAE – immune-mediated severe SAE, immune-mediated severe SAE, endocrine disorders (SOC, severe SAE), gastrointestinal disorders (SOC, severe SAE), liver and biliary disorders (SOC, severe AEs), and disorders of the skin and subcutaneous tissue (SOC, severe AEs), there was a statistically significant difference in favor of pembrolizumab in each case.
  • In summary, with regard to side effects, treatment with pembrolizumab has a disadvantage compared with a ‘wait-and-see’ approach due to the negative effects associated with severe AEs and therapy discontinuations caused by AEs.
• Overall assessment
  • Based on analyses of overall mortality, there is no statistically significant difference between the treatment arms.
  • With regard to the recurrence rate and recurrence-free survival, there are statistically significant, clear advantages of pembrolizumab over watchful waiting.
  • Preventing recurrence is an essential treatment objective in the current curative treatment setting.
  • However, as the observation period (median of approximately 27 months) as at the data cut-off date of 4 January 2022 is not long enough to adequately reflect the high-risk period for the occurrence of a recurrence—which is 3 years after the primary diagnosis— the extent of this advantage cannot be reliably quantified based on the available data.
  • With regard to symptoms (assessed using the EORTC QLQ-C30) and health status (assessed using the EQ-5D VAS), neither positive nor negative effects are evident.
  • Similarly, there are neither positive nor negative effects on health-related quality of life (assessed using the EORTC QLQ-C30).
  • In terms of side effects, pembrolizumab is associated with disadvantages in terms of severe AEs and therapy discontinuations due to AEs.
  • With regard to serious AEs, there are no statistically significant differences between the study arms.
  • In detail, pembrolizumab is associated with disadvantages in terms of specific AEs.
  • When the results are considered as a whole, in the present adjuvant therapy setting, clear positive effects—though not quantifiable with certainty in terms of extent—in relation to the prevention of recurrence are offset by relevant disadvantages regarding side effects.
  • There are no differences between the study arms in terms of overall mortality, symptoms, health status or quality of life.
  • The disadvantages relating to side effects are weighed against the aim of curative treatment in this context.
  • These do not call into question the advantage in terms of preventing recurrence.
  • Overall, pembrolizumab is found to offer a non-quantifiable additional benefit compared with a ‘watch-and-wait’ approach.

b) Children and adolescents aged 12 years and over with stage III melanoma following complete resection; adjuvant treatment

• No data were presented for the assessment of the additional benefit of pembrolizumab compared with the appropriate comparator therapy for children and adolescents aged 12 years and over with stage III melanoma following complete resection.
• The KEYNOTE 716 trial exclusively enrolled patients with tumour stage IIB or IIC.

Courtesy translation only, please refer to the German original.