Lenvatinib (4) – Lenvima®

• Clinical trials
  • KEYNOTE 775/309 is a multicentre, open-label, randomised controlled trial comparing lenvatinib in combination with pembrolizumab with treatment at the clinician’s discretion, choosing between doxorubicin or paclitaxel.

Adult female patients with advanced or recurrent endometrial cancer who have experienced disease progression during or following prior platinum-based therapy, at any stage of the disease, for whom curative surgical treatment or radiotherapy is not an option

• Consequently, a considerable additional benefit is identified for lenvatinib in combination with pembrolizumab compared with the appropriate comparator therapy.
• Consequently, the certainty of the evidence for the identified additional benefit is classified as ‘indication’.
• mortality
  • In the KEYNOTE 775/309 study, overall survival is defined as the time from randomisation to death, regardless of the underlying cause of death.
  • For the endpoint of overall survival, a statistically significant difference was observed in favour of lenvatinib in combination with pembrolizumab.
  • This prolongation of survival time achieved by treatment with lenvatinib in combination with pembrolizumab, compared with treatment with the appropriate comparator therapy, is regarded as a significant improvement.
• Morbidity – Progression-free survival (PFS)
  • In the KEYNOTE 775/309 study, progression-free survival is defined as the time from randomisation to disease progression (assessed according to RECIST criteria version 1.1) or death, regardless of the underlying cause of death.
  • PFS was statistically significantly prolonged in the intervention arm compared with the control arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of this endpoint is already assessed as a standalone endpoint via the ‘overall survival’ endpoint. The morbidity component ‘disease progression’ is not assessed on the basis of symptoms, but exclusively by means of imaging procedures (radiologically determined disease progression according to the RECIST criteria). 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 assessment of the extent of the additional benefit.
• quality of life
  • Health-related quality of life is assessed in the KEYNOTE 775 / 309 using the symptom scales of the disease-specific questionnaire EORTC QLQ-C30 and the disease-specific supplementary module for endometrial cancer, EORTC QLQ-EN24.
  • The pharmaceutical manufacturer provided continuous analyses for this endpoint (differences in mean values compared with baseline), which have been used for the present benefit assessment.
  • For the endpoints of emotional functioning and social functioning, a statistically significant advantage was observed in favour of lenvatinib in combination with pembrolizumab in each case. The 95% confidence interval for the SMD did not lie entirely outside the irrelevance range of −0.2 to 0.2. It cannot therefore be concluded that the observed effect is clinically relevant.
  • For the endpoint ‘negative body image’, a statistically significant advantage was observed in favour of lenvatinib in combination with pembrolizumab. The 95% confidence interval for the SMD lay entirely outside the non-significant range of −0.2 to 0.2. This is interpreted as a significant effect.
  • No usable data were available for the endpoint of sexual enjoyment, as only 18.2% of patients were included in the analysis.
  • For all other endpoints, no statistically significant difference was observed between the study arms.
  • In the overall analysis, a significant difference between the treatments was observed for only a single endpoint: a positive effect on the ‘negative body image’ endpoint. Given the various aspects of health-related quality of life assessed in the study using the EORTC QLQ-C30 and EORTC QLQ-EN24 questionnaires, this single effect is not considered sufficient to conclude that there has been an overall improvement in health-related quality of life.
• Side effects – Adverse events (AEs)
  • In the KEYNOTE 775 / 309 study, AEs occurred in almost all patients in both study arms. The results are presented here for supplementary information only.
• Overall assessment
  • Data on mortality, morbidity, quality of life and side effects are available from the open-label, randomised, controlled KEYNOTE 775 / 309 trial for the benefit assessment of lenvatinib in combination with pembrolizumab.
  • For the endpoint of overall survival, there is a statistically significant difference in favour of lenvatinib in combination with pembrolizumab. The extent of the effect is assessed as a marked improvement.
  • With regard to symptoms (assessed using the EORTC QLQ-C30 and -EN24), the treatment with lenvatinib in combination with pembrolizumab showed positive effects on the endpoints of dyspnoea, lymphoedema, tingling/numbness, changes in taste and hair loss, whilst a negative effect was observed for the endpoint of diarrhoea. Overall, there is an advantage to lenvatinib in combination with pembrolizumab in terms of symptoms. With regard to health status (assessed using the EQ-5D VAS), neither positive nor negative effects were observed.
  • For health-related quality of life (assessed using the EORTC QLQ-C30 and -EN24), there is no improvement when all results are considered as a whole.
  • With regard to side effects, lenvatinib in combination with pembrolizumab is associated with disadvantages in terms of serious AEs and therapy discontinuations due to AEs. There are no statistically significant differences between the study arms with regard to serious AEs. In detail, the specific AEs predominantly show negative effects of lenvatinib in combination with pembrolizumab.
  • Overall, there is a clear improvement in overall survival. Furthermore, there are predominantly advantages in terms of symptom relief. However, these are offset by disadvantages in terms of serious AEs and therapy discontinuations due to AEs.

Courtesy translation only, please refer to the German original.