Lenvatinib (Kisplyx, 1) – Kisplyx®

• Clinical trials
  • The Phase 2 part of Study 205 was used for the benefit assessment; in this part, 153 patients were randomised in a 1:1:1 ratio to receive treatment with the lenvatinib-everolimus combination (51 patients), lenvatinib monotherapy (52 patients) and everolimus monotherapy (50 patients).
  • Study 205 is a randomised, open-label, actively controlled Phase 1b/2 study.

a) adult patients with advanced renal cell carcinoma (RCC) following prior treatment targeting vascular endothelial growth factor (VEGF)

• For adult patients with advanced renal cell carcinoma (RCC) following prior treatment targeting vascular endothelial growth factor (VEGF), there is a hint of a minor additional benefit compared with the appropriate comparator therapy, everolimus.
• The G-BA classifies the extent of the additional benefit of lenvatinib as minor, 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, everolimus, there is, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, there is a moderate – and not merely minor – improvement in the therapy-relevant benefit, as a relevant prolongation of survival is achieved whilst adverse effects are also present.
• For these reasons, the certainty of the finding (probability of additional benefit) for the overall conclusion on additional benefit is classified as a hint.
• mortality
  • For the present benefit assessment, the third data cut-off (31 July 2015) for overall survival is considered decisive and is used due to the highest level of data maturity: This shows a statistically significant advantage in overall survival with treatment using lenvatinib + everolimus compared with everolimus alone, with a median survival time of 25.5 months (lenvatinib + everolimus) compared with 15.4 months (everolimus), with an absolute difference of +10.1 months (hazard ratio (HR): 0.59, 95% confidence interval (CI) [0.36; 0.97]; p = 0.035).
  • However, due to the small number of patients – only 51 and 50 respectively (lenvatinib-everolimus arm and everolimus arm) – the analysis has minor statistical power and carries the risk that the advantage in terms of overall survival may be underestimated or overestimated.
• Morbidity – Progression-free survival
  • PFS was defined as the primary endpoint in Study 205 and was operationalised as the time from randomisation to radiologically confirmed disease progression or death from any cause.
  • The data cut-off for the primary analysis of PFS was 13 June 2014, at which point the median PFS differed statistically significantly between the treatment arms by an absolute difference of +7.2 months (12.8 versus 5.6 months for lenvatinib + everolimus versus everolimus alone; HR 0.45, 95% CI [0.26; 0.79], p = 0.0029).
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients.
• Morbidity – Symptoms
  • Symptoms were not recorded in study 205.
• quality of life
  • Health-related quality of life was not assessed in Study 205.
• Side effects
  • Three data cuts are available for the ‘side effects’ endpoint category (13 June 2014, 10 December 2014 and 31 July 2015), of which the third data cut-off (31 July 2015) is considered the most relevant due to the highest level of data maturity and is used for the present benefit assessment.
  • Adverse events occurred at least once in all patients (100%) in both study arms in Study 205; consequently, due to the very high proportion of adverse events in the overall rate, no conclusions regarding the assessment of additional benefit can be drawn from this comparison.
  • Serious adverse events (SAEs) occurred in 58.5% of patients receiving the lenvatinib-everolimus combination and in 42.0% of patients receiving everolimus alone.
  • The vast majority of patients in both treatment arms were affected by severe adverse events (CTCAE grade ≥ 3), with more patients affected in the lenvatinib-everolimus combination arm (76.5 %) than in the everolimus monotherapy arm (54.0%).
  • Similarly, there were more therapy discontinuations due to adverse events with lenvatinib plus everolimus compared with everolimus monotherapy (25.5% versus 12.0%).
  • With regard to specific adverse events, diarrhoea and hypertension (both CTCAE grade 3 or 4) occurred in significantly more patients receiving the lenvatinib–everolimus combination than those receiving everolimus monotherapy (diarrhoea: 19.6% versus 2.0%; hypertension: 13.7% versus 2.0%).
  • In the case of diarrhoea – but not in the case of hypertension – this was also reflected in a statistically significant difference in the analysis of time to first event.
  • Consequently, with regard to severe diarrhoea (CTCAE grade 3 or 4), the lenvatinib–everolimus combination has a disadvantage compared with monotherapy.
• Overall assessment
  • With regard to mortality outcomes, there is a statistically significant advantage for the overall survival endpoint, as the results demonstrate a relevant prolongation of survival.
  • In the side effects category, there is a statistically significant disadvantage with regard to diarrhoea (CTCAE grade 3 or 4), which occurred earlier with the lenvatinib-everolimus combination.
  • In the patient-relevant endpoint category of morbidity, no data were collected on symptoms, and no data were collected for the patient-relevant endpoint of health-related quality of life.
  • However, findings on morbidity and quality of life are of particular importance at this advanced stage of the disease.
  • In the overall assessment, a moderate – rather than merely minor – improvement in treatment-related benefit is identified, and thus a minor additional benefit of the lenvatinib-everolimus combination compared with everolimus monotherapy is identified.

Courtesy translation only, please refer to the German original.