Pembrolizumab (38) – Keytruda®

• Clinical trials
  • The KEYNOTE A18 trial is an ongoing, multicentre, double-blind, randomised, controlled (RCT) Phase III trial comparing pembrolizumab in combination with chemoradiotherapy against placebo in combination with chemoradiotherapy.

Adult female patients with locally advanced cervical cancer (stages III to IVA according to FIGO 2014) who have not received prior definitive treatment

• Consequently, the G-BA has determined that pembrolizumab in combination with chemoradiotherapy offers a non-quantifiable additional benefit over chemoradiotherapy alone for the treatment of locally advanced cervical cancer in adults who have not previously received definitive treatment.
• In summary, the G-BA derives an indication regarding the established additional benefit in terms of its significance.
• mortality
  • For the endpoint of overall survival, a statistically significant survival benefit in favour of pembrolizumab in combination with chemoradiotherapy is evident.
  • The data for the current data cut-off are based on a median follow-up period of just over 2 years (approximately 27 and 25 months in the two study arms, respectively). Given the curative nature of the current treatment approach and the typically prolonged course of the disease in cases of recurrent or progressive cervical cancer, the observation period of just over 2 years is to be regarded as short. Taking into account the event rates in both study arms, the data on overall survival are considered to be of limited informative value, although the statistically significant advantage in favour of pembrolizumab in combination with chemoradiotherapy is not in doubt.
  • Consequently, the extent of the additional benefit for the endpoint of overall survival cannot be reliably quantified.
• Morbidity – Progression-free survival (failure of the curative treatment approach)
  • Based on the analyses of PFS submitted by the pharmaceutical manufacturer, no conclusion can be drawn as to whether, and how many, of the patients achieved tumour-free status. These analyses, and the PFS endpoint as defined here, are therefore not suitable for reflecting the failure of the curative treatment approach. The PFS endpoint is not used for the present benefit assessment. The results are presented in the resolution only as supplementary information.
• Morbidity – Symptoms (EORTC QLQ-C30 and EORTC QLQ-CX24)
  • For the diarrhoea endpoint, there is a statistically significant difference in favour of pembrolizumab in combination with chemoradiotherapy that is associated with a disadvantage. However, based on the standardised mean difference, it cannot be concluded that the observed effect is clinically relevant.
  • For the other symptoms – fatigue, nausea and vomiting, pain, dyspnoea, insomnia, loss of appetite and constipation – assessed using the EORTC QLQ-C30 – as well as symptom experience, lymphoedema, peripheral neuropathy and menopausal symptoms – assessed using the EORTC QLQ-CX24 – no differences were observed. No suitable data are available for the symptom of sexual/vaginal function.
• Morbidity – Health status (EQ-5D, Visual Analogue Scale)
  • No statistically significant difference was observed between the treatment arms in terms of health status, as assessed using the EQ-5D VAS.
• quality of life
  • For the endpoint of emotional functioning, there is a statistically significant advantage in favour of pembrolizumab in combination with chemoradiotherapy. However, based on the standardised mean difference, it cannot be concluded that the observed effect is clinically relevant.
  • For the scales measuring global health status, physical functioning, role functioning, cognitive functioning and social functioning, assessed using the EORTC QLQ-C30, as well as the scales for sexual activity, concern about painful sexual intercourse, sexual enjoyment and body image, assessed using the EORTC QLQ-CX24, no statistically significant difference was observed in any case.
  • With regard to health-related quality of life, no overall advantage or disadvantage was observed for pembrolizumab in combination with chemoradiotherapy.
• Side effects – Total adverse events (AEs)
  • In the Keynote A18 trial, an AE occurred in almost all patients in both the control and intervention arms. The results are presented here for supplementary information only.
• Overall assessment
  • For the assessment of the additional benefit of pembrolizumab in combination with chemoradiotherapy in adult female patients with locally advanced cervical cancer (stages III to IVA according to FIGO 2014) who have not received prior definitive treatment, results are available on mortality, morbidity, health-related quality of life and side effects from the Keynote A18 trial. In this double-blind RCT, pembrolizumab in combination with chemoradiotherapy was compared with chemoradiotherapy alone.
  • The results for the overall survival endpoint show a statistically significant advantage for pembrolizumab in combination with chemoradiotherapy. Due to the short follow-up period at the time of data collection and taking into account the number of events in both study arms, the data on overall survival are considered to be of limited statistical significance. Consequently, the statistically significant advantage – which is not in doubt – cannot be reliably quantified in terms of the extent of the additional benefit. In the present therapeutic indication, chemoradiotherapy represents a curative treatment approach. There are no endpoints that can indicate failure of the curative treatment approach and which could therefore also be used for a more detailed interpretation of the overall survival data.
  • In the morbidity endpoint category, symptoms (EORTC QLQ-C30 and -CX24) and health status (EQ-5D VAS) were assessed. Overall, there is neither an advantage nor a disadvantage for pembrolizumab in combination with chemoradiotherapy.
  • With regard to health-related quality of life (EORTC QLQ-C30 and -CX24), no overall advantage or disadvantage was identified for pembrolizumab in combination with chemoradiotherapy.
  • With regard to side effects, no statistically significant differences were observed for the endpoints of SAE, severe AEs and discontinuation due to AEs. In detail, statistically significant disadvantages were observed for specific AEs. In the category of side effects, neither an advantage nor a disadvantage was identified.
  • Overall, there is a statistically significant advantage for the endpoint of overall survival, the extent of which cannot be quantified with certainty. With regard to morbidity, health-related quality of life and side effects, there are neither advantages nor disadvantages.

Courtesy translation only, please refer to the German original.