Ponatinib (3) – Iclusig®

• Clinical trials
  • The PACE trial is a single-arm, multicentre, open-label Phase II trial designed to assess the efficacy and safety of ponatinib in patients with chronic phase (CP) CML, accelerated phase (AP) or blast crisis, or with Ph+ ALL, who were either resistant or intolerant (R/I) to prior treatment with dasatinib or nilotinib, or who had developed a T315L mutation following TKI therapy.

Adult patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib, who cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have a T315I mutation

• Overall, ponatinib is indicated for the treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib, who cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who harbour a T315I mutation, a hint of a non-quantifiable additional benefit has been identified, as the scientific evidence does not permit quantification.
• The certainty of the evidence is assessed as ‘a hint’ because only a single-arm, uncontrolled study is available and a comparative assessment is not possible.
• mortality
  • In the PACE trial, 78.1% of patients with Ph+ ALL died between the first dose of ponatinib and the end of the trial (R/I cohort: 80%; TKI cohort: 77.3%). At the time of analysis, the median overall survival (OS) was 33.1 weeks (R/I cohort: 56.5 weeks; T315I cohort: 28.4 weeks).
  • As no comparative data are available, no conclusion can be drawn from these results regarding the extent of the additional benefit.
• morbidity
  • No suitable data are available.
• quality of life
  • Quality of life was not assessed in the PACE study. Consequently, no data are available from the PACE study to evaluate the additional benefit of ponatinib in terms of quality of life.
• Side effects
  • In the Ph+ ALL population, all patients experienced at least one adverse event.
  • In 25 out of 32 patients with Ph+ ALL (78.1%), at least one serious adverse event (SAE) occurred (R/I cohort: 80.0%; T315I cohort: 77.3%). The most common SAEs (≥ 5%) according to PT were febrile neutropenia (21.9%), atrial fibrillation and tumour progression (12.5% each) and sepsis, septic shock and dehydration (6.3% each).
  • In 28 of 32 patients with Ph+ ALL (87.5%), at least one severe AE of CTCAE grade ≥ 3 occurred (R/I cohort: 90%; T315I cohort: 86.4%). The most common AEs of grade ≥ 3 were febrile neutropenia (25.0%), neutropenia (21.9%) and thrombocytopenia and anaemia (18.8% each).
  • An AEs led to permanent discontinuation of the study medication in 3 out of 32 patients with Ph+ ALL (9.4%) (R/I cohort: 10%; T315I cohort: 9.1%).
  • The most common AEs of particular interest were disorders of the skin and subcutaneous tissue (59.4%), infections and parasitic diseases (71.9%) and myelosuppression (59.4%).
  • No conclusions can be drawn regarding the extent of the additional benefit in terms of adverse events due to the lack of a control group.
• Overall assessment / Conclusion
  • For the benefit assessment of ponatinib for the treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib, who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who harbour a T315I mutation, results are available for the endpoint categories of mortality and side effects from the uncontrolled PACE trial.
  • Due to the single-arm study design, a comparative assessment of the study results as a whole is not possible.
  • Consequently, a quantitative assessment of the extent of the effect and a quantification of the additional benefit based on the data provided are not possible.
  • Consequently, the G-BA classifies the extent of the additional benefit of ponatinib in the present indication as unquantifiable, given the limited data available, on the basis of 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 treating the disease, as non-quantifiable. An additional benefit exists in accordance with Section 35a(1), sentence 11, first half-sentence, of SGB V, but is non-quantifiable because the scientific evidence does not permit this.

Courtesy translation only, please refer to the German original.