Ponatinib (2) – 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 Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL), who were either resistant or intolerant (R/I) to previous treatment with dasatinib or nilotinib, or who had developed a T315L mutation as a result of TKI therapy.
  • The OPTIC study is a multicentre, randomised Phase II trial designed to assess the safety and efficacy of ponatinib at three different starting doses (15 mg, 30 mg and 45 mg) in patients with CP-CML who had received at least two prior TKI therapies and were resistant to treatment or had a documented T315L mutation in their medical history, regardless of the type and number of prior TKI therapies.

Adult patients with chronic myeloid leukaemia (CML) in the chronic phase, accelerated phase or blast crisis who are resistant to treatment with dasatinib or nilotinib, who are unable to tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have a T315I mutation

• mortality
  • In the period between the first dose of ponatinib and the end of the PACE trial, the mortality rate in CP-CML was 22.1% (R/I cohort: 20.2%; T315I cohort: 28.1%), in AP-CML 47.0% (R/I cohort: 46.2%; T315I cohort: 50.0 per cent) and in the BK-CML group 87.1 per cent (R/I cohort: 84.2 per cent; T315I cohort: 91.7 per cent) of patients had died.
  • At the time of analysis, median survival had not yet been reached for either the CP-CML patients with R/I or those with the T315I mutation. Among AP-CML patients, the median OS was 241.3 weeks (R/I cohort: 241.3 weeks; T315I cohort: 263.9 weeks) and, for patients with BK-CML, at 29.9 weeks (R/I cohort: 26.6 weeks; T315I cohort: 29.9 weeks).
  • In the OPTIC study, between the first dose and the data cut-off for the interim analysis, 5 of the 94 patients with CP-CML (5.3%) in the 45 mg ponatinib per day dose cohort died.
  • The duration of follow-up for CP-CML patients at the data cut-off presented in the OPTIC study is significantly shorter than the duration of follow-up for CP-CML patients in the PACE study. Due to the minor follow-up period and the small study population, the data from the OPTIC study do not provide any information beyond that available from the PACE study.
  • As no comparative data are available, no conclusion can be drawn on the extent of the additional benefit based on these results.
• morbidity
  • The dossier reports a major molecular response (MMR).
  • In the PACE study, 108 out of 267 patients (40.4%) with CP-CML achieved an MMR over the entire study period. When the R/I and T315I cohorts with CP-CML were analysed separately, 71 out of 203 patients (35.0%) in the R/I cohort and 37 out of 64 patients (57.8%) in the T315I cohort achieved an MMR.
  • In AP-CML, 18 out of 83 patients (21.7%) achieved MMR, including 12 out of 65 patients with R/I (18.5%) and 6 out of 18 patients with the T315I mutation (33.3%). In BK-CML, 8 out of 62 patients (12.9%) achieved MMR, including 7 out of 38 patients with R/I (18.4%) and 1 out of 24 patients with the T315I mutation (4.2%).
  • Nevertheless, MMR is a laboratory parameter that does not reflect any immediately perceptible symptoms for patients. Furthermore, there is no validation of MMR as a surrogate parameter for a patient-relevant endpoint. The MMR endpoint is not considered to be either a directly patient-relevant endpoint or a validated surrogate endpoint and is therefore not taken into account in this assessment.
  • No usable data on MMR are available for the OPTIC study, as only the achievement of an MMR from month 3 onwards, and then every three months thereafter up to month 36, was documented.
• Health-related quality of life
  • Quality of life was not assessed in the PACE study. Consequently, no data are available from the PACE study to assess the additional benefit of ponatinib in terms of quality of life.
  • In the OPTIC study, quality of life was assessed using the FACT-Leu questionnaire for patients with CP-CML. Results were reported as part of the present interim analysis of the study during the commenting procedure. These are merely descriptive analyses. No statistical analyses suitable for benefit assessment are available. Furthermore, no MID was specified, meaning that no conclusions can be drawn regarding the clinical relevance of the change. The data are therefore classified as not assessable.
• Side effects
  • All patients with CML in the PACE study experienced at least one AE.
  • In 171 out of 270 patients (63.3%) with CP-CML, in 59 out of 85 patients (69.4%) with AP-CML, and in 53 out of 62 patients (85.5%) with BK-CML experienced at least one serious adverse event (SAE).
  • The most common events in CP-CML were pancreatitis (7.0%), atrial fibrillation (5.6%) and pneumonia (5.6%); in AP-CML, they were disease progression (12.9%), pneumonia (10.6 per cent) and pyrexia (9.4 per cent), and in BK-CML, progression (29.0 per cent), pneumonia (12.9 per cent) and anaemia (8.1 per cent).
  • In 239 out of 270 patients (88.5 %) with CP-CML, in 78 out of 85 patients (91.8%) with AP-CML, and 58 out of 62 patients (93.5%) with BK-CML experienced at least one severe AE with a CTCAE grade of ≥3.
  • The most common AEs of grade ≥ 3 in the CP-CML population were thrombocytopenia (35.2 %), neutropenia (16.7 per cent) and hypertension (13.7 per cent); in the AP-CML and BK-CML populations, thrombocytopenia (43.5% in the AP-CML population and 35.5% in the BK-CML population), neutropenia (36.5% in the AP-CML population and 29.0% in the BK-CML population) and anaemia (22.4% in the AP-CML population and 32.2% in the BK-CML population).
  • An AE led to discontinuation of the study medication in 21.1% of patients with CP-CML, 11.8% of patients with AP-CML and 14.5% of patients with BK-CML.
  • The most common AEs of particular interest in the CP, AP and BK-CML populations were disorders of the skin and subcutaneous tissue (82.6% in the CP-CML population; 80.0% in the AP-CML population; 69.4% in the BK-CML population), infections and parasitic diseases (63.3% in the CP-CML population; 76.5% in the AP-CML population; in the BK-CML population 56.5 per cent) and myelosuppression (54.8 per cent in the CP-CML population; 70.6 per cent in the AP-CML population; 67.7 per cent in the BK-CML population).
  • At the time of the interim analysis of the OPTIC study, at least one SAE had occurred in 30.9% of patients.
  • An AE led to discontinuation of the study medication in 13.8% of patients.
  • The duration of ponatinib exposure in CP-CML patients at the data cut-off point presented in the OPTIC study is significantly shorter than the duration of ponatinib exposure in CP-CML patients in the PACE study. Due to the minor duration of exposure and the small study population, the data from the OPTIC study do not provide any information beyond that provided by the PACE study.
  • No conclusions can be drawn regarding the extent of the additional benefit in terms of adverse events due to the absence of a control group.

Courtesy translation only, please refer to the German original.