Axitinib (2) – Inlyta®

• Clinical trials
  • The AXIS and A4061051/L2 trials were open-label, randomised, controlled, multicentre Phase III trials.
  • In the AXIS trial, a total of 723 patients were randomised in a 1:1 ratio to receive either axitinib (N = 361) or sorafenib (N = 362 patients).
  • In the A4061051/L2 trial, 204 patients were randomised in a 2:1 ratio to receive treatment with axitinib (N = 135 patients) or sorafenib (N = 69 patients).

a) Following prior treatment with sunitinib

• An additional benefit is not proven for axitinib in the treatment of advanced renal cell carcinoma in adult patients following failure of prior therapy with sunitinib.
• The pharmaceutical manufacturer did not submit any data for the assessment of the additional benefit of axitinib for patients following prior treatment with sunitinib.

b) Following prior treatment with a cytokine

• There is a hint of a minor additional benefit for axitinib in the treatment of advanced renal cell carcinoma in adult patients following failure of prior therapy with a cytokine.
• In particular, the reduction in severe hand-foot syndrome, which is burdensome for the patient, results in a minor additional benefit of axitinib over sorafenib when side effects are considered as a whole.
• mortality
  • overall survival
  • Overall survival was assessed as a secondary endpoint in the AXIS and A4061051/L2 studies.
  • Neither study showed a statistically significant difference between the treatment arms.
  • An additional benefit of axitinib over the appropriate comparator therapy is not proven for overall survival.
• Morbidity – Progression-free survival (PFS)
  • PFS was assessed as the primary endpoint in the AXIS and A4061051/L2 studies and was defined as the time from randomisation to the first disease progression or death from any cause.
  • For the PFS endpoint, the AXIS trial showed a statistically significant difference in favour of axitinib compared with sorafenib. In the axitinib arm, the median PFS was 12.1 months, compared with 6.5 months in the control arm (hazard ratio (HR) 0.46; 95% confidence interval (CI) [0.32; 0.68]; p < 0.001). In the axitinib arm, 39.7% of patients experienced a progression event, compared with 55.2% in the sorafenib arm.
  • In the A4061051/L2 trial, no statistically significant difference was observed between the treatment arms (HR 0.86; 96% CI [0.50; 1.47]; p-value = 0.587). Here, 61.8% of patients in the axitinib arm experienced a progression event (sorafenib arm: 57.1%).
  • The meta-analysis reveals a statistically significant difference in favour of axitinib treatment compared with sorafenib treatment (HR 0.58; 95% CI [0.42; 0.78]; p-value < 0.001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The morbidity component ‘disease progression’ was not assessed on the basis of symptoms, but exclusively by means of imaging procedures.
• Morbidity – Symptoms (FKSI-DRS)
  • Disease-related symptoms were assessed in the AXIS and A4061051/L2 studies using the FKSI-DRS questionnaire.
  • In neither of the two studies was there a statistically significant difference between the treatment arms.
  • There is therefore no proof of an additional benefit of axitinib over sorafenib for this endpoint.
• Morbidity – Health status (VAS of the EQ-5D)
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • In neither of the two studies was there a statistically significant difference between the treatment arms, meaning that the additional benefit of axitinib over sorafenib for this endpoint is not proven.
• Health-related quality of life
  • In the AXIS and A4061051/L2 studies, no relevant data were collected for an assessment of health-related quality of life.
  • The pharmaceutical manufacturer used the FKSI-15 questionnaire to assess health-related quality of life. In addition to the 9 symptom questions in the FKSI-DRS, the FKSI-15 contains a further 6 questions. However, these are not suitable for assessing health-related quality of life, which is why the FKSI-15 is not used for this purpose.
• Side effects – Serious adverse events (SAE)
  • In the AXIS and A4061051/2L studies, progression of the underlying disease was documented as a SAE if the patient died as a result.
  • However, based on the data provided with the dossier submission, the AXIS study can be taken into account for the assessment of the SAE endpoint. No usable data are available for the A4061051/2L study.
  • In the AXIS study, there were no statistically significant differences between the axitinib and sorafenib arms for the SAE endpoint.
• Side effects – severe AEs (CTCAE grade 3 or 4)
  • In neither of the two studies was there a statistically significant difference between the treatment arms.
• Side effects – Discontinuation due to AEs
  • With regard to the endpoint ‘discontinuation due to AEs’, no usable data on the underlying individual events for the relevant patient population were available from the dossier.
  • Consequently, it cannot be ruled out that a significant proportion of discontinuations due to AEs may be attributable to progression of the underlying disease.
• Overall assessment
  • For the re-assessment of the benefits of axitinib for the treatment of advanced renal cell carcinoma in adult patients following failure of prior therapy with a cytokine, results are available for the endpoint categories of mortality, morbidity and side effects, based on the AXIS and A4061051/2L studies.
  • With regard to overall survival, disease-related symptoms and health status, no beneficial effects of axitinib over sorafenib were observed.
  • An assessment of health-related quality of life could not be carried out due to a lack of suitable data.
  • Differences between axitinib and sorafenib are evident only with regard to side effects, and even then exclusively for the specific adverse events considered. Here, axitinib shows advantages for the endpoints of alopecia, rash and hand-foot syndrome (CTCAE grade ≥ 3). Axitinib has disadvantages compared with sorafenib for the endpoints of dysphonia, fatigue (CTCAE grade ≥ 3), hypothyroidism and nausea.
  • Taking into account the available results for axitinib regarding side effects, the advantages of the active ingredient (INN) are not repealed by disadvantages in other relevant side effects.
  • Overall, the positive effects of axitinib compared with sorafenib are assessed as an unprecedented improvement in treatment-related benefit, as a significant reduction in side effects is achieved.
  • Axitinib is therefore found to offer a minor additional benefit for the treatment of advanced renal cell carcinoma in adult patients following failure of prior therapy with a cytokine.
• Overall assessment
  • On balance, the positive effects of axitinib compared with sorafenib are assessed as an improvement in treatment-related benefit not previously achieved, as a significant reduction in side effects is achieved.

Courtesy translation only, please refer to the German original.