Lenvatinib (2) – Lenvima®

• Clinical trials
  • REFLECT is an open-label, randomised, controlled trial comparing lenvatinib with sorafenib.

a) Adult patients with advanced or inoperable HCC with Child-Pugh A or no liver cirrhosis who have not received prior systemic therapy

• An additional benefit of lenvatinib over the appropriate comparator therapy is not proven.
• When weighing up all the positive and negative effects of lenvatinib against the background of the significant uncertainties described, there is no additional benefit of lenvatinib over sorafenib for the treatment of adult patients with advanced or inoperable HCC with Child-Pugh A or no liver cirrhosis who have not received prior systemic therapy.
• The additional benefit is therefore not proven.
• mortality
  • Overall survival was assessed as the primary endpoint in the REFLECT trial and was defined as the time from randomisation to death, regardless of the cause of death.
  • Treatment with lenvatinib did not result in a statistically significant prolongation of overall survival compared with sorafenib.
  • No additional benefit of lenvatinib over sorafenib is therefore identified for the mortality endpoint category.
• Morbidity – Progression-free survival (PFS)
  • PFS was assessed as a secondary endpoint and was defined as the time from randomisation to the date of documented disease progression or to the date of death from any cause, whichever occurred first.
  • The median PFS was 7.3 months in the lenvatinib arm compared with 3.6 months in the sorafenib arm (absolute difference: 3.7 months), with the difference being statistically significant (hazard ratio (HR): 0.64; 95% CI [0.55; 0.75], p < 0.0001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The overall conclusion regarding the extent of the additional benefit remains unaffected, as even if the present PFS result were taken into account in the overall assessment, the overall conclusion regarding the extent of the additional benefit would remain unchanged.
• Morbidity – Symptoms – Diarrhoea
  • For the diarrhoea endpoint (EORTC-QLQ-C30), there is a statistically significant difference in favour of lenvatinib, with an absolute difference of +1.9 months (HR: 0.52; 95% CI [0.440–0.62]; p < 0.001).
• Morbidity – Symptoms – Pain
  • For the endpoint of pain (EORTC-QLQ-C30), there is a statistically significant difference in favour of lenvatinib compared with sorafenib (HR: 0.81; 95% CI [0.69; 0.95]; p < 0.009; absolute difference: +0.1 months). However, this effect is no more than marginal.
  • Furthermore, for the pain endpoint assessed using the disease-specific EORTC QLQ-HCC18, there is no statistically significant difference between the two study arms, and the direction of the effect is in fact the opposite (HR: 1.14; 95% CI [0.96; 1.35]; p < 0.132).
  • In summary, there is no additional benefit of lenvatinib over sorafenib for the endpoint of pain.
• Morbidity – Health Status (EQ-5D VAS)
  • In the REFLECT trial, health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • The responder analyses show no significant difference between the treatment arms, whether based on a MID of 7 or 10 points.
  • For the health status endpoint, the additional benefit of lenvatinib over sorafenib is not proven.
• Health-related quality of life – role functioning
  • For role functioning (EORTC-QLQ-C30), a statistically significant difference was observed in favour of lenvatinib, with an absolute difference of +0.1 months (HR: 0.82; 95% CI [0.70; 0.96]; p < 0.015).
• Side effects
  • Adverse events (AEs) occurred at least once in almost every patient in both study arms.
  • There were no statistically significant differences between the treatment arms for the endpoints ‘serious adverse events (SAEs)’, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
  • Overall, within the ‘side effects’ endpoint category, there were no statistically significant differences between the study arms regarding AEs, severe AEs (CTCAE grade ≥ 3) and SAEs.
  • With regard to specific AEs, lenvatinib showed both statistically significant advantages in terms of rash, alopecia and diarrhoea, and statistically significant disadvantages in terms of hypothyroidism, vomiting and dysphonia.
  • For specific serious AEs with a CTCAE grade of 3 or 4 and specific serious AEs, lenvatinib showed statistically significant advantages in terms of hand-foot syndrome, elevated aspartate aminotransferase and hypokalaemia, as well as statistically significant disadvantages with regard to hepatic encephalopathy, hypertension, proteinuria and reduced appetite.
• Overall assessment
  • An additional benefit of lenvatinib for overall survival is not proven, as no statistically significant difference was observed between the two treatment arms.
  • In the morbidity endpoint category, a minor but statistically significant advantage was observed for lenvatinib treatment with regard to the diarrhoea endpoint.
  • Similarly, in the health-related quality of life endpoint category, minor, statistically significant advantages were observed with lenvatinib for the endpoints of body image and nutrition, and only a minor advantage for the endpoint of role functioning.
  • The clinical relevance of the observed advantages remains unclear.
  • This is contrasted by statistically significant disadvantages with lenvatinib in the ‘cognitive functioning’ endpoint in the patient population from Western regions.
  • No statistically significant differences in side effects were observed between the two treatment arms.
  • The statistically significant advantages in the endpoint categories of morbidity and health-related quality of life are subject to considerable uncertainty, as a high proportion of the study population originated from Asia and the Pacific region.
  • Significant uncertainties arise from the open-label study design, the imbalances in patient characteristics between the two treatment arms, and the high proportion of the study population from Asia and the Pacific region, as there are particularly large differences in the indication for HCC, prognosis and disease progression.

b) Adult patients with advanced or inoperable HCC classified as Child-Pugh B who have not received prior systemic therapy

• An additional benefit is not proven.
• In its dossier, the pharmaceutical manufacturer does not provide any data for this patient group.
• Consequently, additional benefit is not proven for this patient group.

Courtesy translation only, please refer to the German original.