Axitinib (1) – Inlyta®

• Clinical trials
  • The AXIS trial is an ongoing, comparative, two-arm, open-label Phase III trial.
  • Patients were randomised in a 1:1 ratio to receive axitinib or sorafenib.

a) Following prior treatment with sunitinib

• An additional benefit of axitinib following prior treatment with sunitinib is not proven compared with the appropriate comparator therapy, everolimus.
• Consequently, no evaluable data were available for a comparison with the appropriate comparator therapy in patients who had previously been treated with sunitinib.

b) Following prior treatment with a cytokine

• The certainty of the evidence (probability of additional benefit) is classified as ‘indication’.
• For adult patients with advanced clear-cell metastatic renal cell carcinoma who have previously received therapy with a cytokine, there is an indication of a minor additional benefit compared with the appropriate comparator therapy.
• The G-BA classifies the extent of the additional benefit of axitinib as minor, based on the criteria 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.
• On the basis of these considerations, the information in the dossier, the results of the benefit assessment and the expert opinions, the G-BA concludes that there is evidence of a minor additional benefit of axitinib compared with the appropriate comparator therapy.
• mortality
  • Overall survival did not differ statistically significantly between axitinib (25th quantile survival time: 15.9 months) and sorafenib (25th quantile survival time: 13.8 months; HR 0.813, p=0.288).
  • Additional benefit or less benefit of axitinib compared with the appropriate comparator therapy is not proven in terms of overall mortality.
• Morbidity – Symptoms (FKSI-DRS score)
  • As the FKSI-DRS consists exclusively of questions regarding symptoms, the FKSI-DRS is assigned to the endpoint category of morbidity and not to the dimension of ‘health-related quality of life’.
  • The responder analyses, in which the response criterion was the time to deterioration – defined as a decline of at least 3 points compared with the status at the start of the study — showed that, whilst deterioration in the FKSI-DRS occurred somewhat later with axitinib than with sorafenib (median 10.2 months for axitinib versus 7.6 for sorafenib; hazard ratio 0.933, p=0.357).
  • However, no statistically significant difference was observed between axitinib and sorafenib.
  • The proportions of patients experiencing a deterioration of at least 3 points on the FKSI-DRS also did not differ statistically significantly (56 patients (44.4%) for axitinib versus 57 patients (45.6%) for sorafenib).
  • Consequently, additional benefit or less benefit of axitinib for this endpoint is not proven.
• Health-related quality of life (FKSI-15)
  • For the ‘health-related quality of life’ dimension (FKSI-15), the data presented also do not indicate any additional benefit or less benefit of axitinib compared with the appropriate comparator therapy.
  • There was no significant difference between axitinib and sorafenib in terms of time to deterioration, defined as a decline of at least 5 points compared with baseline (responder analysis, data cut-off 31 August 2010), nor in the proportion of patients experiencing a deterioration of at least 5 points on the FKSI-15.
  • In the AXIS study, health-related quality of life was also measured using the EuroQol (EQ-)5D. However, no results were available for the population of patients who had received prior cytokine treatment.
• Side effects
  • There is no evidence that axitinib is more or minorly harmful than sorafenib with regard to the endpoints of time to first occurrence of severe adverse events (CTCAE grade ≥ 3), serious adverse events and therapy discontinuations due to adverse events.
  • The difference between the groups was not statistically significant.
  • The time to the first occurrence of an adverse event is longer with axitinib than with sorafenib. However, due to a lack of information on the nature of the events and the relevance of the delay, the difference cannot be interpreted.
  • An AE was documented in almost all patients during the course of the study; it is not possible to draw any conclusions regarding a greater or minor impact on the overall rate of adverse events.
  • With regard to the analyses of the most common adverse events, ‘hand-foot syndrome’ (29.4% vs. 57.7%; HR=0.350, p<0.001), ‘rash’ (13.5% vs. 29.3%; HR=0.396, p=0.002) and “alopecia” (4.8% vs. 35.8%; HR=0.102, p<0.001), which were statistically significant in favour of axitinib.
  • Hand-foot syndrome, in particular, is a distressing event for patients. In the study, there were few overall events of hand-foot syndrome of CTCAE grade 3 (4.8% vs. 18.7%). For alopecia, only events with a CTCAE grade of 1 were observed, and for the rash dimension, events were predominantly of CTCAE grade 1 or 2.
  • For ‘fatigue’ (36.5% versus 24.4%; HR=1.624, p=0.039), ‘dysphonia’ (30.2% versus 12.2%; HR=2.643, p=0.001) and “nausea” (21.4% versus 11.4%; HR=1.963, p=0.041), there are indications of greater adverse effects with axitinib.
  • Statistically significant differences between the groups, to the detriment of axitinib, were observed for all three endpoints. Fatigue, in particular, represents a distressing event for patients. In the study, there were few overall cases of fatigue of CTCAE grade 3 (11.9% vs. 3.3%).
  • Following a comprehensive, balanced assessment of the results regarding adverse events, and taking into account the severity grades of the most common adverse events presented here, the G-BA concludes that the additional benefit in terms of side effects should be assessed as ‘minor’.
  • A classification as ‘considerable’ is not justified. The most common adverse events did not lead to statistically significant differences in therapy discontinuation rates. Similarly, no difference was observed in the overall rate of serious and severe adverse events. Furthermore, no improvement in health-related quality of life – which would reflect a relevant reduction in serious side effects or a significant reduction in other side effects – could be established (see section ‘Health-related quality of life’).
  • Compared with the appropriate comparator therapy, sorafenib, this therefore constitutes, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, this constitutes a moderate—and not merely minor—improvement in treatment-related benefit that has not previously been achieved, as a significant reduction in side effects is achieved.

Courtesy translation only, please refer to the German original.